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Yu X, Wu H, Wu Z, Lan Y, Chen W, Wu B, Deng Y, Liu J. Nuclear pore complex protein RANBP2 and related SUMOylation in solid malignancies. Genes Dis 2025; 12:101407. [PMID: 40271196 PMCID: PMC12017851 DOI: 10.1016/j.gendis.2024.101407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 04/28/2024] [Accepted: 06/21/2024] [Indexed: 04/25/2025] Open
Abstract
The growing interest in post-translational protein modification, particularly in SUMOylation, is driven by its crucial role in cell cycle regulation. SUMOylation affects various cell cycle regulators, including oncogenes, suggesting its relevance in cancer. SUMO E3 ligases are pivotal in this process, exhibiting diverse functionalities through structural domains and subcellular localizations. A less-explored SUMO E3 ligase, RANBP2, a component of the vertebrate nuclear pore complex, emerges as a central player in cellular cycle processes, as well as in tumorigenesis. The current studies illuminate the importance of RANBP2 and underscore the need for more extensive studies to validate its clinical applicability in neoplastic interventions. Our review elucidates the significance of RANBP2 across various types of malignancies. Additionally, it delves into exploring RANBP2 as a prospective therapeutic target for cancer treatment, offering insights into the avenues that scholars should pursue in their subsequent research endeavors. Thus, further investigation into RANBP2's role in solid tumorigenesis is eagerly awaited.
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Affiliation(s)
- Xinning Yu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Huatao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Zheng Wu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
- Department of Physiology, Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Yangzheng Lan
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
- Department of Physiology, Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Wenjia Chen
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
- Department of Physiology, Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Bingxuan Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Yu Deng
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
| | - Jing Liu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China
- Department of Physiology, Shantou University Medical College, Shantou, Guangdong 515041, China
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2
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Yin A, Gui Y, Wan L, Cai Q, Luo Y, Wang JZ, Liu R, Ying C, Wang X, Yang F. p53 SUMOylation promotes neurogenesis defects in APP/PS1 mice. J Alzheimers Dis 2025:13872877251340432. [PMID: 40336408 DOI: 10.1177/13872877251340432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Abstract
Backgroundp53 is a transcriptional factor that regulates numerous cellular processes, the stability and activity of p53 is essential to maintain its function. Post-translational modifications (PTMs), particularly SUMOylation, play a vital role in regulating p53 activity.ObjectiveTo investigate the neurogenesis related genes that downregulated by p53 SUMOylation in APP/PS1 mice, and the protected effect by overexpressing non-SUMOylated p53 (p53 K386R). Furthermore, to provide new clues for the mechanisms of Alzheimer's disease (AD).MethodsCo-immunoprecipitation was used to detect the p53 SUMOylation levels in neuro2a (N2a) cells and APP/PS1 mice overexpressing wild-type p53 (p53 WT) or p53 K386R. In addition, RNA sequencing (RNA-seq) was used to detect the p53 SUMOylation regulated genes. Then we used qPCR, western blot, and immunofluorescence to measure the expression of neuroglobin (ngb) and the effect of neurogenesis defects induced by p53 SUMOylation.ResultsWe verified that overexpression of p53 WT promoted p53 SUMOylation and p53 K386R decreased p53 SUMOylation in N2a cells and APP/PS1 mice. Ngb was related to neurogenesis which dramatically downregulated by p53 SUMOylation. In addition, we found p53 SUMOylation caused neuron reduction and impairment of neurogenesis.ConclusionsOur data support that p53 SUMOylation may lead to neurogenesis defects by downregulating ngb in AD, suggesting that inhibition of p53 SUMOylation may be served as a therapeutic strategy for preventing AD and provide a new target for future researches and interventions.
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Affiliation(s)
- Anqi Yin
- Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Nutrition & Food Hygiene and Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Yuran Gui
- Hubei Key Laboratory of Cognitive and Affective Disorders, School of Medicine, Jianghan University, Wuhan, China
| | - Lu Wan
- Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qinfeng Cai
- Department of Nutrition & Food Hygiene and Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Yong Luo
- Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian-Zhi Wang
- Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Cognitive and Affective Disorders, School of Medicine, Jianghan University, Wuhan, China
| | - Rong Liu
- Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chenjiang Ying
- Department of Nutrition & Food Hygiene and Ministry of Education Key Lab for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Xiaochuan Wang
- Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Cognitive and Affective Disorders, School of Medicine, Jianghan University, Wuhan, China
| | - Fumin Yang
- Department of Pathophysiology, Key Laboratory of Education Ministry of China for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Zhang Z, Wang X, Gao Y, Xian X, Zhang D, Zhao W, Wang X, Wang Y. Orchestrating anthocyanin biosynthesis in fruit of fruit trees: Transcriptional, post-transcriptional, and post-translational regulation. Int J Biol Macromol 2025; 307:141835. [PMID: 40064275 DOI: 10.1016/j.ijbiomac.2025.141835] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 02/17/2025] [Accepted: 03/05/2025] [Indexed: 03/15/2025]
Abstract
Coloration is an important appearance quality that contributes to product value. Anthocyanins, a type of flavonoid, not only impart rich plants color, but also contribute to human health because of their antioxidant properties, such as preventing cardiovascular disease and reducing obesity. This benefit mainly stems from various fruits. Accordingly, based on the consumption demand of beauty and nutrition, the creation of fruit tree products rich in anthocyanin is becoming an important breeding goal. The synthesis of anthocyanin has been investigated in various fruits, which is modulated by a variety of endogenous and exogenous factors, including transcription factors (TFs), plant hormones, and environmental factors (such as light, low temperature, drought). However, the detailed mechanisms in fruits of fruit trees have not been thoroughly elucidated. This review comprehensively examines the regulation of anthocyanin biosynthesis at the transcriptional, post-transcriptional, and post-translational levels, which is important for the application of molecular design strategies to cultivate high-quality fruits. At the transcriptional level, TFs were summarized to directly regulate anthocyanin biosynthesis genes, target non-anthocyanin biosynthesis pathway genes, interact with other proteins to mediate anthocyanin synthesis, and regulate anthocyanin synthesis by environmental factors and plant hormones. At the post-transcriptional level, non-coding RNAs (ncRNAs) were elucidated to mediate anthocyanin synthesis. At the post-translational level, a variety of post-translational modifications, including phosphorylation, ubiquitination, sumoylation, and persulfidation, have been elucidated to exhibit crucial functions in anthocyanin biosynthesis.
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Affiliation(s)
- Zhongxing Zhang
- College of Horticulture, Gansu Agricultural University, Lanzhou 730070, China
| | - Xiaoya Wang
- College of Horticulture, Gansu Agricultural University, Lanzhou 730070, China
| | - Yanlong Gao
- College of Horticulture, Gansu Agricultural University, Lanzhou 730070, China
| | - Xulin Xian
- College of Horticulture, Gansu Agricultural University, Lanzhou 730070, China
| | - Donghai Zhang
- College of Horticulture, Gansu Agricultural University, Lanzhou 730070, China
| | - Wenbing Zhao
- College of Horticulture, Gansu Agricultural University, Lanzhou 730070, China
| | - Xiaofei Wang
- College of Horticulture Science and Engineering, Shandong Agricultural University, Tai-An 271018, China.
| | - Yanxiu Wang
- College of Horticulture, Gansu Agricultural University, Lanzhou 730070, China.
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Zhang Z, Dong Y, Wang X, Gao Y, Xian X, Li J, Wang Y. Protein post-translational modifications (PTM S) unlocking resilience to abiotic stress in horticultural crops: A review. Int J Biol Macromol 2025; 306:141772. [PMID: 40049463 DOI: 10.1016/j.ijbiomac.2025.141772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 02/28/2025] [Accepted: 03/04/2025] [Indexed: 05/11/2025]
Abstract
Horticultural crops are extensively cultivated throughout the world as crucial economical crops, encompassing fruits, vegetables, ornamentals, medicinal and beverage plants, for purposes such as food supply, special nutrition provision, medical application or aesthetic enjoyment. However, abiotic stress triggered by extreme climate change, such as excessive salt and prolonged drought, directly leads to the decline of nutritional quality of horticultural crops, contributing to the shortage of high-quality fruits. Post-translational modifications of proteins, such as phosphorylation and ubiquitination, can alter protein characteristics by adding specific groups to amino acids, which in turn impacts protein stability to regulate plant growth and development as well as environmental stress. Consequently, the revelation of the molecular mechanism of horticultural crops response to abiotic stress at post-translational modification level (PTMs) has always attracted a lot of scholars, as it is crucial for the development and breeding of climate-resilient apple varieties. At PTMs level, this review focuses on summarizing research advancements in horticultural crops responses to environmental stress, including drought, salt, cold, high temperature and iron (Fe) deficiency, with emphasis on sucrose non-fermentative 1 (SNF1) associated protein kinases (SnRKs) and mitogen-activated protein kinase (MAPK) cascade mediated phosphorylation, E3 ubiquitin ligases and BTB/TAZ subfamily BT2 mediated ubiquitination, SIZ1 SUMO E3 ligase mediated sumoylation, Nitric oxide (NO) mediated S-nitrosylation, and other forms of PTMs including protein glycosylation and lysine acetylation. In conclusion, this review adopts protein modification as an entry point to illuminate the mechanism of key genes regulating abiotic stress at PTMs level, providing a foundation for the cultivation of horticultural crops with superior resistance.
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Affiliation(s)
- Zhongxing Zhang
- College of Horticulture Gansu Agricultural University, Lanzhou 730070, China
| | - Yongjuan Dong
- College of Horticulture Gansu Agricultural University, Lanzhou 730070, China
| | - Xiaoya Wang
- College of Horticulture Gansu Agricultural University, Lanzhou 730070, China
| | - Yanlong Gao
- College of Horticulture Gansu Agricultural University, Lanzhou 730070, China
| | - Xulin Xian
- College of Horticulture Gansu Agricultural University, Lanzhou 730070, China
| | - Juanli Li
- College of Horticulture Gansu Agricultural University, Lanzhou 730070, China
| | - Yanxiu Wang
- College of Horticulture Gansu Agricultural University, Lanzhou 730070, China.
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Xiao G, Jiang Z, Xing T, Chen Y, Zhang H, Qian J, Wang X, Wang Y, Xia G, Wang M. Small ubiquitin-like modifier protease gene TaDSU enhances salt tolerance of wheat. THE NEW PHYTOLOGIST 2025; 245:2540-2552. [PMID: 39367623 DOI: 10.1111/nph.20171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 09/09/2024] [Indexed: 10/06/2024]
Abstract
To identify efficient salt-tolerant genes is beneficial for coping with the penalty of salt stress on crop yield. Reversible conjugation (sumoylation and desumoylation) of Small Ubiquitin-Like Modifier (SUMO) is a crucial kind of protein modifications, but its roles in the response to salt and other abiotic stress are not well addressed. Here, we identify salt-tolerant SUMO protease gene TaDSU for desumoylation from wheat, and analyze its mechanism in salt tolerance and evaluate its role in yield in saline-alkaline fields. TaDSU overexpression enhances salt tolerance of wheat. TaDSU overexpressors have lower Na+ but higher K+ contents and consequently higher K+ : Na+ ratios than the wild-type under salt stress. TaDSU interacts with transcriptional factor MYC2, reduces the sumoylation level of SUMO1-conjugated MYC2, and promotes its transcription activity. MYC2 binds to the promoter of TaDSU and elevates its expression. TaDSU overexpression enhances grain yield of wheat in the saline soil without growth penalty in the normal field. Especially, TaDSU ectopic expression also enhances salt tolerance of Arabidopsis thaliana, showing this SUMO protease allele has the inter-species role in the adaptation to salt stress. Thus, TaDSU is an efficient candidate gene for molecular breeding of salt-tolerant crops.
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Affiliation(s)
- Guilian Xiao
- The Key Laboratory of Plant Development and Environmental Adaptation Biology, Ministry of Education, Shandong Key Laboratory of Precision Molecular Crop Design and Breeding, School of Life Sciences, Shandong University, Qingdao, 266237, China
| | - Zhengning Jiang
- Key Laboratory of Wheat Biology and Genetic Improvement for Low & Middle Yangtze Valley Ministry of Agriculture, Lixiahe Agricultural Institute of Jiangsu Province, Yangzhou, 225007, China
| | - Tian Xing
- The Key Laboratory of Plant Development and Environmental Adaptation Biology, Ministry of Education, Shandong Key Laboratory of Precision Molecular Crop Design and Breeding, School of Life Sciences, Shandong University, Qingdao, 266237, China
- College of Education Science, Nanjing Normal University, Nanjing, 210097, China
| | - Ye Chen
- The Key Laboratory of Plant Development and Environmental Adaptation Biology, Ministry of Education, Shandong Key Laboratory of Precision Molecular Crop Design and Breeding, School of Life Sciences, Shandong University, Qingdao, 266237, China
| | - Hongjian Zhang
- The Key Laboratory of Plant Development and Environmental Adaptation Biology, Ministry of Education, Shandong Key Laboratory of Precision Molecular Crop Design and Breeding, School of Life Sciences, Shandong University, Qingdao, 266237, China
| | - Jiajia Qian
- The Key Laboratory of Plant Development and Environmental Adaptation Biology, Ministry of Education, Shandong Key Laboratory of Precision Molecular Crop Design and Breeding, School of Life Sciences, Shandong University, Qingdao, 266237, China
| | - Xiutang Wang
- Shijiazhuang Academy of Agriculture and Forestry Sciences, Shijiazhuang, 050041, China
| | - Yanxia Wang
- Shijiazhuang Academy of Agriculture and Forestry Sciences, Shijiazhuang, 050041, China
| | - Guangmin Xia
- The Key Laboratory of Plant Development and Environmental Adaptation Biology, Ministry of Education, Shandong Key Laboratory of Precision Molecular Crop Design and Breeding, School of Life Sciences, Shandong University, Qingdao, 266237, China
| | - Mengcheng Wang
- The Key Laboratory of Plant Development and Environmental Adaptation Biology, Ministry of Education, Shandong Key Laboratory of Precision Molecular Crop Design and Breeding, School of Life Sciences, Shandong University, Qingdao, 266237, China
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Yang L, Wen Y, Yuan Z, Zhao D, Weng P, Li Y, Chen Q, Zhang W, Hu H, Yu C. Hypoxia-mediated SUMOylation of FADD exacerbates endothelial cell injury via the RIPK1-RIPK3-MLKL signaling axis. Cell Death Dis 2025; 16:121. [PMID: 39984463 PMCID: PMC11845712 DOI: 10.1038/s41419-025-07441-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 01/13/2025] [Accepted: 02/11/2025] [Indexed: 02/23/2025]
Abstract
Vascular endothelial cells are the predominant cell type in the cardiovascular system, and their dysfunction and death following hypoxic injury contribute to vascular lesions, playing an essential role in cardiovascular disease. Despite its importance, the mechanisms underlying vascular endothelial cell injury under hypoxia and potential therapeutic interventions remain poorly understood. Here, we constructed both an in vivo hypoxia model in C57BL/6 mice and an in vitro hypoxia model in HUVEC cells. Our findings demonstrated that hypoxia induces necroptosis in vascular endothelial cells and exacerbates inflammatory injury in vivo and in vitro, as evidenced by immunofluorescence and western blot. We identified FADD as a critical regulator of hypoxia-mediated necroptosis, with FADD knockdown significantly reversing hypoxia-induced necroptosis. Mechanistically, hypoxia affected protein conformation through SUMOylation of FADD and competitively inhibited its ubiquitination, leading to an increase in protein half-life and protein level of FADD. Furthermore, SUMOylation increased the interaction between FADD and RIPK1 and induced the formation of the FADD-RIPK1-RIPK3 complex, thereby promoting necroptosis in vascular endothelial cells. The SUMOylation inhibitor ginkgolic acid (GA) notably reduced hypoxia-induced vascular endothelial injury and inflammatory responses in male mice. Taken together, our research has uncovered a new process by which SUMOylation of FADD regulates hypoxia-induced necroptosis in endothelial cells, providing potential therapeutic targets for hypoxia-related cardiovascular diseases.
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Affiliation(s)
- Liming Yang
- College of Pharmacy, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing, China
| | - Yilin Wen
- College of Pharmacy, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing, China
| | - Zhiyi Yuan
- College of Pharmacy, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing, China
| | - Dezhang Zhao
- College of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Ping Weng
- College of Pharmacy, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing, China
| | - Yueyue Li
- College of Pharmacy, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing, China
| | - Qingyang Chen
- College of Pharmacy, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing, China
| | - Wanping Zhang
- College of Pharmacy, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing, China
| | - Hui Hu
- College of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Chao Yu
- College of Pharmacy, Chongqing Medical University, Chongqing, China.
- Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing, China.
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Imbert F, Langford D. Comprehensive SUMO Proteomic Analyses Identify HIV Latency-Associated Proteins in Microglia. Cells 2025; 14:235. [PMID: 39937027 PMCID: PMC11817477 DOI: 10.3390/cells14030235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 01/30/2025] [Accepted: 02/04/2025] [Indexed: 02/13/2025] Open
Abstract
SUMOylation, the post-translational modification of proteins by small ubiquitin-like modifiers, plays a critical role in regulating various cellular processes, including innate immunity. This modification is essential for modulating immune responses and influencing signaling pathways that govern the activation and function of immune cells. Recent studies suggest that SUMOylation also contributes to the pathophysiology of central nervous system (CNS) viral infections, where it contributes to the host response and viral replication dynamics. Here, we explore the multifaceted role of SUMOylation in innate immune signaling and its implications for viral infections within the CNS. Notably, we present novel proteomic analyses aimed at elucidating the role of the small ubiquitin-related modifier (SUMO) in human immunodeficiency virus (HIV) latency in microglial cells. Our findings indicate that SUMOylation may regulate key proteins involved in maintaining viral latency, suggesting a potential mechanism by which HIV evades immune detection in the CNS. By integrating insights from proteomics with functional studies, we anticipate these findings to be the groundwork for future studies on HIV-host interactions and the mechanisms that underlie SUMOylation during latent and productive infection.
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Affiliation(s)
- Fergan Imbert
- Department of Neuroscience, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA;
- Department of Cell Biology and Neuroscience, Rowan-Virtua School of Translational Biomedical Engineering and Sciences, Stratford, NJ 08084, USA
- Rowan-Virtua School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USA
| | - Dianne Langford
- Department of Cell Biology and Neuroscience, Rowan-Virtua School of Translational Biomedical Engineering and Sciences, Stratford, NJ 08084, USA
- Rowan-Virtua School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USA
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Shao Y, Chen Y, Zhu Q, Yi L, Ma Y, Zang X, Yao W. The Pharmacology and Toxicology of Ginkgolic Acids: Secondary Metabolites from Ginkgo biloba. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2025; 53:147-177. [PMID: 39880663 DOI: 10.1142/s0192415x25500077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2025]
Abstract
Ginkgolic acids (GAs) are distinctive secondary metabolites of Ginkgo biloba (G. biloba) primarily found in its leaves and seeds, with the highest concentration located in the exotesta. GAs are classified as long-chain phenolic compounds, and exhibit structural similarities to lignoceric acid. Their structural diversity arises from variations in the length of side chains and their number of double bonds, resulting in six distinct forms within G. biloba extracts (GBE). Of these, GA (C15:1) is the most prevalent. As inhibitors of SUMOylation, GAs demonstrate significant antitumor activity, and can exert antineoplastic effects through multiple pathways, which positions them as potentially promising therapeutic agents for cancer treatment. Additionally, GAs exhibit notable anti-inflammatory, antibacterial, and antiviral properties, highlighting their multifaceted medicinal potential. Although the pharmacological properties of GAs have been extensively investigated, the associated risks of liver and kidney damage must not be overlooked. GAs can induce significant hepatic damage by promoting cellular apoptosis, oxidative stress, and the disruption of various metabolic processes. Furthermore, a limited number of studies have indicated that GAs may exhibit nephrotoxicity, as well as adverse effects on the skin and nervous system. Due to their recognized toxicity, the concentration of GAs is typically regulated to within 5[Formula: see text]ppm in the standardized G. biloba leaf extract EGb 761. Currently, there is no definitive evidence supporting the mutagenic toxicity of GAs. This review primarily synthesizes recent advancements in understanding the pharmacological and toxicological effects of GAs, along with their underlying mechanisms. It is anticipated that this review will stimulate scholarly discourse and elicit valuable insights.
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Affiliation(s)
- Yuting Shao
- School of Pharmacy, Nantong University, 9 Seyuan Road, Nantong 226019, P. R. China
| | - Yun Chen
- School of Pharmacy, Nantong University, 9 Seyuan Road, Nantong 226019, P. R. China
| | - Qingyu Zhu
- School of Pharmacy, Nantong University, 9 Seyuan Road, Nantong 226019, P. R. China
| | - Lingyan Yi
- School of Pharmacy, Nantong University, 9 Seyuan Road, Nantong 226019, P. R. China
| | - Yifan Ma
- School of Pharmacy, Nantong University, 9 Seyuan Road, Nantong 226019, P. R. China
| | - Xiangxu Zang
- School of Pharmacy, Nantong University, 9 Seyuan Road, Nantong 226019, P. R. China
| | - Wenjuan Yao
- School of Pharmacy, Nantong University, 9 Seyuan Road, Nantong 226019, P. R. China
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Shkolnik D, Dey S, Hasan M, Matunis MJ, Brik A. Chemical protein synthesis combined with protein cell delivery reveals new insights on the maturation process of SUMO2. Chem Sci 2024; 16:191-198. [PMID: 39600502 PMCID: PMC11587528 DOI: 10.1039/d4sc06254j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Accepted: 11/07/2024] [Indexed: 11/29/2024] Open
Abstract
The Small Ubiquitin-like Modifier (SUMO) is a crucial post-translational modifier of proteins, playing a key role in various cellular functions. All SUMOs are synthesized as precursor proteins that must be proteolytically processed. However, the maturation process of cleaving the extending C-terminal tail, preceding SUMOylation of substrates, remains poorly understood, especially within cellular environments. Chemical protein synthesis coupled with cell delivery offers great opportunities to prepare SUMO analogues to investigate this process in vitro and in live cells. Applying this unique combination we show that SUMO2 analogues containing the native tail undergo rapid cleavage and nuclear localisation, while a Gly93Ala mutation impairs cleavage and alters localisation. Tail mutations (Val94Glu, Tyr95Ala) affected cleavage rates, highlighting roles in SUMO-SENP protease interactions. In cells, SUMO2 analogues containing tail mutations underwent cleavage and subsequently incorporated into promyelocytic leukemia nuclear bodies (PML-NBs). These findings advance our understanding of SUMO2 maturation and provide a foundation for future studies of this process for different SUMO paralogues in various cell lines and tissues.
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Affiliation(s)
- Dana Shkolnik
- Schulich Faculty of Chemistry, Technion Israel Institute of Technology Haifa 3200008 Israel
| | - Subhasis Dey
- Schulich Faculty of Chemistry, Technion Israel Institute of Technology Haifa 3200008 Israel
| | - Mahdi Hasan
- Schulich Faculty of Chemistry, Technion Israel Institute of Technology Haifa 3200008 Israel
| | - Michael J Matunis
- Department of Biochemistry and Molecular Biology, Johns Hopkins University, Bloomberg School of Public Health Baltimore Maryland USA
| | - Ashraf Brik
- Schulich Faculty of Chemistry, Technion Israel Institute of Technology Haifa 3200008 Israel
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Yu HX, Cao YJ, Yang YB, Shan JX, Ye WW, Dong NQ, Kan Y, Zhao HY, Lu ZQ, Guo SQ, Lei JJ, Liao B, Lin HX. A TT1-SCE1 module integrates ubiquitination and SUMOylation to regulate heat tolerance in rice. MOLECULAR PLANT 2024; 17:1899-1918. [PMID: 39552084 DOI: 10.1016/j.molp.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 09/29/2024] [Accepted: 11/14/2024] [Indexed: 11/19/2024]
Abstract
Heat stress poses a significant threat to grain yield. As an α2 subunit of the 26S proteasome, TT1 has been shown to act as a critical regulator of rice heat tolerance. However, the heat tolerance mechanisms mediated by TT1 remain elusive. In this study, we unveiled that small ubiquitin-like modifier (SUMO)-conjugating enzyme 1 (SCE1), which interacts with TT1 and acts as a downstream component of TT1, is engaged in TT1-mediated 26S proteasome degradation. We showed that SCE1 functions as a negative regulator of heat tolerance in rice, which is associated with its ubiquitination modification. Furthermore, we observed that small heat-shock proteins (sHSPs) such as Hsp24.1 and Hsp40 can undergo SUMOylation mediated by SCE1, leading to increased accumulation of sHSPs in the absence of SCE1. Reducing protein levels of SCE1 significantly enhanced grain yield under high-temperature stress by improving seed-setting rate and rice grain filling capacity. Taken together, these results uncover the critical role of SCE1 in the TT1-mediated heat tolerance pathway by regulating the abundance of sHSPs and SUMOylation, and ultimately modulating rice heat tolerance. These findings underscore the great potential of the TT1-SCE1 module in improving the heat tolerance of crops.
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Affiliation(s)
- Hong-Xiao Yu
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Ying-Jie Cao
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Yi-Bing Yang
- Joint Center for Single Cell Biology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Jun-Xiang Shan
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
| | - Wang-Wei Ye
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
| | - Nai-Qian Dong
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
| | - Yi Kan
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
| | - Huai-Yu Zhao
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Zi-Qi Lu
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Shuang-Qin Guo
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Jie-Jie Lei
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Ben Liao
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Hong-Xuan Lin
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China; University of the Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China.
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11
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Bergoug M, Mosrin C, Serrano A, Godin F, Doudeau M, Dundović I, Goffinont S, Normand T, Suskiewicz MJ, Vallée B, Bénédetti H. An Atypical Mechanism of SUMOylation of Neurofibromin SecPH Domain Provides New Insights into SUMOylation Site Selection. J Mol Biol 2024; 436:168768. [PMID: 39216515 DOI: 10.1016/j.jmb.2024.168768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 08/08/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Abstract
Neurofibromin (Nf1) is a giant multidomain protein encoded by the tumour-suppressor gene NF1. NF1 is mutated in a common genetic disease, neurofibromatosis type I (NF1), and in various cancers. The protein has a Ras-GAP (GTPase activating protein) activity but is also connected to diverse signalling pathways through its SecPH domain, which interacts with lipids and different protein partners. We previously showed that Nf1 partially colocalized with the ProMyelocytic Leukemia (PML) protein in PML nuclear bodies, hotspots of SUMOylation, thereby suggesting the potential SUMOylation of Nf1. Here, we demonstrate that the full-length isoform 2 and a SecPH fragment of Nf1 are substrates of the SUMO pathway and identify a well-defined SUMOylation profile of SecPH with two main modified lysines. One of these sites, K1731, is highly conserved and surface-exposed. Despite the presence of an inverted SUMO consensus motif surrounding K1731, and a potential SUMO-interacting motif (SIM) within SecPH, we show that neither of these elements is necessary for K1731 SUMOylation, which is also independent of Ubc9 SUMOylation on K14. A 3D model of an interaction between SecPH and Ubc9 centred on K1731, combined with site-directed mutagenesis, identifies specific structural elements of SecPH required for K1731 SUMOylation, some of which are affected in reported NF1 pathogenic variants. This work provides a new example of SUMOylation dependent on the tertiary rather than primary protein structure surrounding the modified site, expanding our knowledge of mechanisms governing SUMOylation site selection.
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Affiliation(s)
- Mohammed Bergoug
- Centre de Biophysique Moléculaire, CNRS, UPR 4301, Affiliated to University of Orléans, Rue Charles Sadron, 45071 Orléans Cedex 2, France
| | - Christine Mosrin
- Centre de Biophysique Moléculaire, CNRS, UPR 4301, Affiliated to University of Orléans, Rue Charles Sadron, 45071 Orléans Cedex 2, France
| | - Amandine Serrano
- Centre de Biophysique Moléculaire, CNRS, UPR 4301, Affiliated to University of Orléans, Rue Charles Sadron, 45071 Orléans Cedex 2, France
| | - Fabienne Godin
- Centre de Biophysique Moléculaire, CNRS, UPR 4301, Affiliated to University of Orléans, Rue Charles Sadron, 45071 Orléans Cedex 2, France
| | - Michel Doudeau
- Centre de Biophysique Moléculaire, CNRS, UPR 4301, Affiliated to University of Orléans, Rue Charles Sadron, 45071 Orléans Cedex 2, France
| | - Iva Dundović
- Centre de Biophysique Moléculaire, CNRS, UPR 4301, Affiliated to University of Orléans, Rue Charles Sadron, 45071 Orléans Cedex 2, France
| | - Stephane Goffinont
- Centre de Biophysique Moléculaire, CNRS, UPR 4301, Affiliated to University of Orléans, Rue Charles Sadron, 45071 Orléans Cedex 2, France
| | - Thierry Normand
- Centre de Biophysique Moléculaire, CNRS, UPR 4301, Affiliated to University of Orléans, Rue Charles Sadron, 45071 Orléans Cedex 2, France
| | - Marcin J Suskiewicz
- Centre de Biophysique Moléculaire, CNRS, UPR 4301, Affiliated to University of Orléans, Rue Charles Sadron, 45071 Orléans Cedex 2, France
| | - Béatrice Vallée
- Centre de Biophysique Moléculaire, CNRS, UPR 4301, Affiliated to University of Orléans, Rue Charles Sadron, 45071 Orléans Cedex 2, France
| | - Hélène Bénédetti
- Centre de Biophysique Moléculaire, CNRS, UPR 4301, Affiliated to University of Orléans, Rue Charles Sadron, 45071 Orléans Cedex 2, France.
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12
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Gao Y, Tan YS, Lin J, Chew LY, Aung HY, Palliyana B, Gujar MR, Lin KY, Kondo S, Wang H. SUMOylation of Warts kinase promotes neural stem cell reactivation. Nat Commun 2024; 15:8557. [PMID: 39419973 PMCID: PMC11487185 DOI: 10.1038/s41467-024-52569-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 09/12/2024] [Indexed: 10/19/2024] Open
Abstract
A delicate balance between neural stem cell (NSC) quiescence and proliferation is important for adult neurogenesis and homeostasis. Small ubiquitin-related modifier (SUMO)-dependent post-translational modifications cause rapid and reversible changes in protein functions. However, the role of the SUMO pathway during NSC reactivation and brain development is not established. Here, we show that the key components of the SUMO pathway play an important role in NSC reactivation and brain development in Drosophila. Depletion of SUMO/Smt3 or SUMO conjugating enzyme Ubc9 results in notable defects in NSC reactivation and brain development, while their overexpression leads to premature NSC reactivation. Smt3 protein levels increase with NSC reactivation, which is promoted by the Ser/Thr kinase Akt. Warts/Lats, the core protein kinase of the Hippo pathway, can undergo SUMO- and Ubc9-dependent SUMOylation at Lys766. This modification attenuates Wts phosphorylation by Hippo, leading to the inhibition of the Hippo pathway, and consequently, initiation of NSC reactivation. Moreover, inhibiting Hippo pathway effectively restores the NSC reactivation defects induced by SUMO pathway inhibition. Overall, our study uncovered an important role for the SUMO-Hippo pathway during Drosophila NSC reactivation and brain development.
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Affiliation(s)
- Yang Gao
- Neuroscience and Behavioral Disorders Programme, Duke-NUS Medical School, Singapore, Singapore
| | - Ye Sing Tan
- Neuroscience and Behavioral Disorders Programme, Duke-NUS Medical School, Singapore, Singapore
| | - Jiaen Lin
- Neuroscience and Behavioral Disorders Programme, Duke-NUS Medical School, Singapore, Singapore
| | - Liang Yuh Chew
- Neuroscience and Behavioral Disorders Programme, Duke-NUS Medical School, Singapore, Singapore
| | - Htet Yamin Aung
- Neuroscience and Behavioral Disorders Programme, Duke-NUS Medical School, Singapore, Singapore
| | - Brinda Palliyana
- Neuroscience and Behavioral Disorders Programme, Duke-NUS Medical School, Singapore, Singapore
| | - Mahekta R Gujar
- Neuroscience and Behavioral Disorders Programme, Duke-NUS Medical School, Singapore, Singapore
| | - Kun-Yang Lin
- Neuroscience and Behavioral Disorders Programme, Duke-NUS Medical School, Singapore, Singapore
| | - Shu Kondo
- Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Niijuku, Katsushika-ku, Tokyo, Japan
| | - Hongyan Wang
- Neuroscience and Behavioral Disorders Programme, Duke-NUS Medical School, Singapore, Singapore.
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- NUS Graduate School - Integrative Sciences and Engineering Programme (ISEP), National University of Singapore, Singapore, Singapore.
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13
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Kwak JS, Lee KH, Min WK, Lee SJ, Song JT, Seo HS. The transmembrane domain of the rice small protein OsS1Fa1 is responsible for subcellular localization and drought tolerance. PLANT BIOLOGY (STUTTGART, GERMANY) 2024; 26:1079-1087. [PMID: 39180227 DOI: 10.1111/plb.13711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 08/08/2024] [Indexed: 08/26/2024]
Abstract
OsS1Fa1, a homologue of spinach S1Fa, is a small protein in rice that contains four distinct conserved motifs and participates in drought tolerance. However, the biological functions of these conserved motifs have not been characterized to date. Therefore, we investigated the roles of these conserved domains in the localization and cellular function of OsS1Fa1. We analysed the subcellular localization of OsS1Fa1 using confocal laser scanning microscopy (CLSM), following particle bombardment and bacterial infiltration. An E. coli in vivo reconstituted sumoylation assay was conducted to investigate sumoylation of OsS1Fa1. We characterized the function of the transmembrane domain of OsS1Fa1 in drought tolerance using transgenic Arabidopsis plants. Fluorescence analysis showed that OsS1Fa1 localized to the nuclear and cytoplasmic membranes. Mutation and cell fractionation analyses revealed that the membrane localization domain determined the subcellular localization of OsS1Fa1. The rice homologue OsS1Fa2 and Arabidopsis orthologs AtS1Fa1, AtS1Fa2, and AtS1Fa3 also exhibited similar localization patterns as OsS1Fa1. Sumoylation analysis demonstrated that OsS1Fa1 was conjugated with the small ubiquitin-related modifier (SUMO). Transgenic analysis showed that overexpression of OsS1Fa1(TMm1), a mutant form of the transmembrane domain of OsS1Fa1, in Arabidopsis did not enhance drought stress tolerance, whereas OsS1Fa1 overexpression improved the drought tolerance of transgenic Arabidopsis. Our data indicate that rice and Arabidopsis S1Fa1 proteins localize in the nuclear and cytoplasmic membranes, and that transmembrane domain determines subcellular localization and plays an important role in drought stress tolerance.
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Affiliation(s)
- J S Kwak
- Department of Agriculture, Forestry and Bioresources, Seoul National University, Seoul, Korea
| | - K H Lee
- Department of Agriculture, Forestry and Bioresources, Seoul National University, Seoul, Korea
| | - W K Min
- Department of Agriculture, Forestry and Bioresources, Seoul National University, Seoul, Korea
| | - S J Lee
- Department of Agriculture, Forestry and Bioresources, Seoul National University, Seoul, Korea
| | - J T Song
- Department of Applied Biosciences, Kyungpook National University, Daegu, Korea
| | - H S Seo
- Department of Agriculture, Forestry and Bioresources, Seoul National University, Seoul, Korea
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14
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Duarte T, Omage FB, Rieder GS, Rocha JBT, Dalla Corte CL. Investigating SARS-CoV-2 virus-host interactions and mRNA expression: Insights using three models of D. melanogaster. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167324. [PMID: 38925484 DOI: 10.1016/j.bbadis.2024.167324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 04/22/2024] [Accepted: 06/19/2024] [Indexed: 06/28/2024]
Abstract
Responsible for COVID-19, SARS-CoV-2 is a coronavirus in which contagious variants continue to appear. Therefore, some population groups have demonstrated greater susceptibility to contagion and disease progression. For these reasons, several researchers have been studying the SARS-CoV-2/human interactome to understand the pathophysiology of COVID-19 and develop new pharmacological strategies. D. melanogaster is a versatile animal model with approximately 90 % human protein orthology related to SARS-CoV-2/human interactome and is widely used in metabolic studies. In this context, our work assessed the potential interaction between human proteins (ZNF10, NUP88, BCL2L1, UBC9, and RBX1) and their orthologous proteins in D. melanogaster (gl, Nup88, Buffy, ubc9, and Rbx1a) with proteins from SARS-CoV-2 (nsp3, nsp9, E, ORF7a, N, and ORF10) using computational approaches. Our results demonstrated that all the proteins have the potential to interact, and we compared the binding sites between humans and fruit flies. The stability and consistency in the structure of the gl_nsp3 complex, specifically, could be crucial for its specific biological functions. Lastly, to enhance the understanding of the influence of host factors on coronavirus infection, we also analyse the mRNA expression of the five genes (mbo, gl, lwr, Buffy, and Roc1a) responsible for encoding the fruit fly proteins. Briefly, we demonstrated that those genes were differentially regulated according to diets, sex, and age. Two groups showed higher positive gene regulation than others: females in the HSD group and males in the aging group, which could imply a higher virus-host susceptibility. Overall, while preliminary, our work contributes to the understanding of host defense mechanisms and potentially identifies candidate proteins and genes for in vivo viral studies against SARS-CoV-2.
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Affiliation(s)
- Tâmie Duarte
- Laboratory of Experimental Biochemistry and Toxicology, Department of Biochemistry and Molecular Biology, Center of Natural and Exact Sciences, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil; Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil
| | - Folorunsho Bright Omage
- Biological Chemistry Laboratory, Department of Organic Chemistry, Institute of Chemistry, University of Campinas (UNICAMP), Campinas, SP, Brazil; Computational Biology Research Group, Embrapa Agricultural Informatics, Campinas, SP, Brazil
| | - Guilherme Schmitt Rieder
- Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil
| | - João B T Rocha
- Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil
| | - Cristiane Lenz Dalla Corte
- Laboratory of Experimental Biochemistry and Toxicology, Department of Biochemistry and Molecular Biology, Center of Natural and Exact Sciences, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil; Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, 1000 Roraima Avenue, Santa Maria, RS 97105-900, Brazil.
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15
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Kaneoka H, Arakawa K, Masuda Y, Ogawa D, Sugimoto K, Fukata R, Tsuge-Shoji M, Nishijima KI, Iijima S. Sequential post-translational modifications regulate damaged DNA-binding protein DDB2 function. J Biochem 2024; 176:325-338. [PMID: 39077792 PMCID: PMC11444932 DOI: 10.1093/jb/mvae056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 07/04/2024] [Accepted: 07/12/2024] [Indexed: 07/31/2024] Open
Abstract
Nucleotide excision repair (NER) is a major DNA repair system and hereditary defects in this system cause critical genetic diseases (e.g. xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy). Various proteins are involved in the eukaryotic NER system and undergo several post-translational modifications. Damaged DNA-binding protein 2 (DDB2) is a DNA damage recognition factor in the NER pathway. We previously demonstrated that DDB2 was SUMOylated in response to UV irradiation; however, its physiological roles remain unclear. We herein analysed several mutants and showed that the N-terminal tail of DDB2 was the target for SUMOylation; however, this region did not contain a consensus SUMOylation sequence. We found a SUMO-interacting motif (SIM) in the N-terminal tail that facilitated SUMOylation. The ubiquitination of a SUMOylation-deficient DDB2 SIM mutant was decreased, and its retention of chromatin was prolonged. The SIM mutant showed impaired NER, possibly due to a decline in the timely handover of the lesion site to XP complementation group C. These results suggest that the SUMOylation of DDB2 facilitates NER through enhancements in ubiquitination.
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Affiliation(s)
- Hidenori Kaneoka
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan
| | - Kazuhiko Arakawa
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan
| | - Yusuke Masuda
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan
| | - Daiki Ogawa
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan
| | - Kota Sugimoto
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan
| | - Risako Fukata
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan
| | - Maasa Tsuge-Shoji
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan
| | - Ken-ichi Nishijima
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan
| | - Shinji Iijima
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan
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16
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de Roij M, Borst JW, Weijers D. Protein degradation in auxin response. THE PLANT CELL 2024; 36:3025-3035. [PMID: 38652687 PMCID: PMC11371164 DOI: 10.1093/plcell/koae125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 02/14/2024] [Accepted: 03/01/2024] [Indexed: 04/25/2024]
Abstract
The signaling molecule auxin sits at the nexus of plant biology where it coordinates essentially all growth and developmental processes. Auxin molecules are transported throughout plant tissues and are capable of evoking highly specific physiological responses by inducing various molecular pathways. In many of these pathways, proteolysis plays a crucial role for correct physiological responses. This review provides a chronology of the discovery and characterization of the auxin receptor, which is a fascinating example of separate research trajectories ultimately converging on the discovery of a core auxin signaling hub that relies on degradation of a family of transcriptional inhibitor proteins-the Aux/IAAs. Beyond describing the "classical" proteolysis-driven auxin response system, we explore more recent examples of the interconnection of proteolytic systems, which target a range of other auxin signaling proteins, and auxin response. By highlighting these emerging concepts, we provide potential future directions to further investigate the role of protein degradation within the framework of auxin response.
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Affiliation(s)
- Martijn de Roij
- Laboratory of Biochemistry, Wageningen University, Wageningen 6708WE, The Netherlands
| | - Jan Willem Borst
- Laboratory of Biochemistry, Wageningen University, Wageningen 6708WE, The Netherlands
| | - Dolf Weijers
- Laboratory of Biochemistry, Wageningen University, Wageningen 6708WE, The Netherlands
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17
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Kang K, Lin X, Chen P, Liu H, Liu F, Xiong W, Li G, Yi M, Li X, Wang H, Xiang B. T cell exhaustion in human cancers. Biochim Biophys Acta Rev Cancer 2024; 1879:189162. [PMID: 39089484 DOI: 10.1016/j.bbcan.2024.189162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 07/23/2024] [Accepted: 07/24/2024] [Indexed: 08/04/2024]
Abstract
T cell exhaustion refers to a progressive state in which T cells become functionally impaired due to sustained antigenic stimulation, which is characterized by increased expression of immune inhibitory receptors, but weakened effector functions, reduced self-renewal capacity, altered epigenetics, transcriptional programme and metabolism. T cell exhaustion is one of the major causes leading to immune escape of cancer, creating an environment that supports tumor development and metastatic spread. In addition, T cell exhaustion plays a pivotal role to the efficacy of current immunotherapies for cancer. This review aims to provide a comprehensive view of roles of T cell exhaustion in cancer development and progression. We summerized the regulatory mechanisms that involved in T cell exhaustion, including transcription factors, epigenetic and metabolic reprogramming events, and various microenvironmental factors such as cytokines, microorganisms, and tumor autocrine substances. The paper also discussed the challenges posed by T cell exhaustion to cancer immunotherapies, including immune checkpoint blockade (ICB) therapies and chimeric antigen receptor T cell (CAR-T) therapy, highlightsing the obstacles encountered in ICB therapies and CAR-T therapies due to T cell exhaustion. Finally, the article provides an overview of current therapeutic options aimed to reversing or alleviating T cell exhaustion in ICB and CAR-T therapies. These therapeutic approaches seek to overcome T cell exhaustion and enhance the effectiveness of immunotherapies in treating tumors.
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Affiliation(s)
- Kuan Kang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China
| | - Xin Lin
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China
| | - Pan Chen
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China
| | - Huai Liu
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Feng Liu
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
| | - Wei Xiong
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China
| | - Guiyuan Li
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China
| | - Mei Yi
- Department of Dermatology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Xiayu Li
- Hunan Key Laboratory of Nonresolving Infammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China.
| | - Hui Wang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China.
| | - Bo Xiang
- Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410008, Hunan, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha 410078, Hunan, China; FuRong Laboratory, Changsha 410078, Hunan, China.
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18
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Zhao H, Zhao P, Huang C. Targeted inhibition of SUMOylation: treatment of tumors. Hum Cell 2024; 37:1347-1354. [PMID: 38856883 DOI: 10.1007/s13577-024-01092-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Accepted: 06/05/2024] [Indexed: 06/11/2024]
Abstract
SUMOylation is a dynamic and reversible post-translational modification (PTM) of proteins involved in the regulation of biological processes such as protein homeostasis, DNA repair and cell cycle in normal and tumor cells. In particular, overexpression of SUMOylation components in tumor cells increases the activity of intracellular SUMOylation, protects target proteins against ubiquitination degradation and activation, promoting tumor cell proliferation and metastasis, providing immune evasion and increasing tolerance to chemotherapy and antitumor drugs. However, with the continuous research on SUMOylation and with the continued development of SUMOylation inhibitors, it has been found that tumor initiation and progression can be inhibited by blocking SUMOylation and/or in combination with drugs. SUMOylation is not a bad target when trying to treat tumor. This review introduces SUMOylation cycle pathway and summarizes the role of SUMOylation in tumor initiation and progression and SUMOylation inhibitors and their functions in tumors and provides a prospective view of SUMOylation as a new therapeutic target for tumors.
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Affiliation(s)
- Hongwei Zhao
- School of Basic Medical Sciences, Department of Medicine, Kunming University of Science and Technology, Kunming, China
| | - Panpan Zhao
- School of Basic Medical Sciences, Department of Medicine, Kunming University of Science and Technology, Kunming, China
| | - Chao Huang
- School of Basic Medical Sciences, Department of Medicine, Kunming University of Science and Technology, Kunming, China.
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19
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Ma XN, Li MY, Qi GQ, Wei LN, Zhang DK. SUMOylation at the crossroads of gut health: insights into physiology and pathology. Cell Commun Signal 2024; 22:404. [PMID: 39160548 PMCID: PMC11331756 DOI: 10.1186/s12964-024-01786-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 08/10/2024] [Indexed: 08/21/2024] Open
Abstract
SUMOylation, a post-translational modification involving the covalent attachment of small ubiquitin-like modifier (SUMO) proteins to target substrates, plays a pivotal role at the intersection of gut health and disease, influencing various aspects of intestinal physiology and pathology. This review provides a comprehensive examination of SUMOylation's diverse roles within the gut microenvironment. We examine its critical roles in maintaining epithelial barrier integrity, regulating immune responses, and mediating host-microbe interactions, thereby highlighting the complex molecular mechanisms that underpin gut homeostasis. Furthermore, we explore the impact of SUMOylation dysregulation in various intestinal disorders, including inflammatory bowel diseases and colorectal cancer, highlighting its implications as a potential diagnostic biomarker and therapeutic target. By integrating current research findings, this review offers valuable insights into the dynamic interplay between SUMOylation and gut health, paving the way for novel therapeutic strategies aimed at restoring intestinal equilibrium and combating associated pathologies.
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Affiliation(s)
- Xue-Ni Ma
- Key Laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, 730030, China
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730030, China
| | - Mu-Yang Li
- Key Laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, 730030, China
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730030, China
| | - Guo-Qing Qi
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Li-Na Wei
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - De-Kui Zhang
- Key Laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, 730030, China.
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, 730030, China.
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20
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Chowdhury MAR, Haq MM, Lee JH, Jeong S. Multi-faceted regulation of CREB family transcription factors. Front Mol Neurosci 2024; 17:1408949. [PMID: 39165717 PMCID: PMC11333461 DOI: 10.3389/fnmol.2024.1408949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 07/12/2024] [Indexed: 08/22/2024] Open
Abstract
cAMP response element-binding protein (CREB) is a ubiquitously expressed nuclear transcription factor, which can be constitutively activated regardless of external stimuli or be inducibly activated by external factors such as stressors, hormones, neurotransmitters, and growth factors. However, CREB controls diverse biological processes including cell growth, differentiation, proliferation, survival, apoptosis in a cell-type-specific manner. The diverse functions of CREB appear to be due to CREB-mediated differential gene expression that depends on cAMP response elements and multi-faceted regulation of CREB activity. Indeed, the transcriptional activity of CREB is controlled at several levels including alternative splicing, post-translational modification, dimerization, specific transcriptional co-activators, non-coding small RNAs, and epigenetic regulation. In this review, we present versatile regulatory modes of CREB family transcription factors and discuss their functional consequences.
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Affiliation(s)
- Md Arifur Rahman Chowdhury
- Department of Bioactive Material Sciences, Jeonbuk National University, Jeonju, Republic of Korea
- Department of Molecular Biology, and Research Center of Bioactive Materials, Jeonbuk National University, Jeonju, Republic of Korea
| | - Md Mazedul Haq
- Department of Bioactive Material Sciences, Jeonbuk National University, Jeonju, Republic of Korea
- Department of Molecular Biology, and Research Center of Bioactive Materials, Jeonbuk National University, Jeonju, Republic of Korea
| | - Jeong Hwan Lee
- Division of Life Sciences, Jeonbuk National University, Jeonju, Republic of Korea
| | - Sangyun Jeong
- Department of Bioactive Material Sciences, Jeonbuk National University, Jeonju, Republic of Korea
- Department of Molecular Biology, and Research Center of Bioactive Materials, Jeonbuk National University, Jeonju, Republic of Korea
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21
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Ramazi S, Dadzadi M, Darvazi M, Seddigh N, Allahverdi A. Protein modification in neurodegenerative diseases. MedComm (Beijing) 2024; 5:e674. [PMID: 39105197 PMCID: PMC11298556 DOI: 10.1002/mco2.674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 07/02/2024] [Accepted: 07/08/2024] [Indexed: 08/07/2024] Open
Abstract
Posttranslational modifications play a crucial role in governing cellular functions and protein behavior. Researchers have implicated dysregulated posttranslational modifications in protein misfolding, which results in cytotoxicity, particularly in neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and Huntington disease. These aberrant posttranslational modifications cause proteins to gather in certain parts of the brain that are linked to the development of the diseases. This leads to neuronal dysfunction and the start of neurodegenerative disease symptoms. Cognitive decline and neurological impairments commonly manifest in neurodegenerative disease patients, underscoring the urgency of comprehending the posttranslational modifications' impact on protein function for targeted therapeutic interventions. This review elucidates the critical link between neurodegenerative diseases and specific posttranslational modifications, focusing on Tau, APP, α-synuclein, Huntingtin protein, Parkin, DJ-1, and Drp1. By delineating the prominent aberrant posttranslational modifications within Alzheimer disease, Parkinson disease, and Huntington disease, the review underscores the significance of understanding the interplay among these modifications. Emphasizing 10 key abnormal posttranslational modifications, this study aims to provide a comprehensive framework for investigating neurodegenerative diseases holistically. The insights presented herein shed light on potential therapeutic avenues aimed at modulating posttranslational modifications to mitigate protein aggregation and retard neurodegenerative disease progression.
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Affiliation(s)
- Shahin Ramazi
- Department of BiophysicsFaculty of Biological SciencesTarbiat Modares UniversityTehranIran
| | - Maedeh Dadzadi
- Department of BiotechnologyFaculty of Advanced Science and TechnologyTehran Medical SciencesIslamic Azad UniversityTehranIran
| | - Mona Darvazi
- Department of BiophysicsFaculty of Biological SciencesTarbiat Modares UniversityTehranIran
| | - Nasrin Seddigh
- Department of BiochemistryFaculty of Advanced Science and TechnologyTehran Medical SciencesIslamic Azad UniversityTehranIran
| | - Abdollah Allahverdi
- Department of BiophysicsFaculty of Biological SciencesTarbiat Modares UniversityTehranIran
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22
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Sriram S, Kim KW, Ljunggren-Rose Å. Targeted DeSUMOylation as a therapeutic strategy for multiple sclerosis. J Neuroimmunol 2024; 392:578371. [PMID: 38788318 DOI: 10.1016/j.jneuroim.2024.578371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/07/2024] [Accepted: 05/14/2024] [Indexed: 05/26/2024]
Abstract
SUMO (small ubiquitin like modifier) conjugated proteins have emerged as an important post translational modifier of cellular function. SUMOylation modulates several cellular processes involved in transcriptional regulation of genes, protein-protein interactions and DNA damage and repair. Since abnormalities in SUMOylation has been observed in neoplastic and neurodegenerative disorders, the SUMO pathway has become an attractive site for targeting of new therapies to regulate SUMOylation and reduce disease burden. Conjugation of SUMO to their respective substrates is orchestrated by an enzymatic cascade involving three main enzymes, E1, activation enzyme, E2, conjugating enzyme and E3, a protein ligase. Each of these enzymes are therefore potential "druggable" sites for future therapeutics. SUMOylation is a well-known mechanism by which the innate immune response is regulated in response to viral infections and in the adaptive immune response to tumor immunity. We have shown that small molecules which inhibit the SUMO activation pathway are also capable of inhibiting autoimmune response. TAK981 which forms adducts with SUMO and anacardic acid which inhibits the E1 enzyme of the SUMO pathway were effective in preventing the development of experimental allergic encephalitis (EAE), a mouse model of multiple sclerosis. Anacardic acid and TAK981 inhibited activation of TH17 cells and reduced clinical and pathological injury in IL-17 mediated myelin oligodendrocyte glycoprotein (MOG) induced EAE. Ginkgolic acid, another known inhibitor of SUMO pathway, was also shown to be effective in reducing the severity of inflammatory arthropathies which is also IL-17 mediated. In addition, the increase in the transcription of myelin genes with TAK981 and anacardic acid improved remyelination in experimental models of demyelination. In the present review paper, we examine the mechanism of action of inhibitors of the SUMO pathway on regulating the immune response and the possibility of the use of these agents as therapeutics for MS.
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Affiliation(s)
- S Sriram
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
| | - Kwang Woon Kim
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
| | - Åsa Ljunggren-Rose
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
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23
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Thibault E, Brandizzi F. Post-translational modifications: emerging directors of cell-fate decisions during endoplasmic reticulum stress in Arabidopsis thaliana. Biochem Soc Trans 2024; 52:831-848. [PMID: 38600022 PMCID: PMC11088923 DOI: 10.1042/bst20231025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/23/2024] [Accepted: 04/02/2024] [Indexed: 04/12/2024]
Abstract
Homeostasis of the endoplasmic reticulum (ER) is critical for growth, development, and stress responses. Perturbations causing an imbalance in ER proteostasis lead to a potentially lethal condition known as ER stress. In ER stress situations, cell-fate decisions either activate pro-life pathways that reestablish homeostasis or initiate pro-death pathways to prevent further damage to the organism. Understanding the mechanisms underpinning cell-fate decisions in ER stress is critical for crop development and has the potential to enable translation of conserved components to ER stress-related diseases in metazoans. Post-translational modifications (PTMs) of proteins are emerging as key players in cell-fate decisions in situations of imbalanced ER proteostasis. In this review, we address PTMs orchestrating cell-fate decisions in ER stress in plants and provide evidence-based perspectives for where future studies may focus to identify additional PTMs involved in ER stress management.
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Affiliation(s)
- Ethan Thibault
- Department of Energy Plant Research Laboratory, Michigan State University, East Lansing, MI, U.S.A
- Department of Plant Biology, Michigan State University, East Lansing, MI, U.S.A
| | - Federica Brandizzi
- Department of Energy Plant Research Laboratory, Michigan State University, East Lansing, MI, U.S.A
- Department of Plant Biology, Michigan State University, East Lansing, MI, U.S.A
- Great Lakes Bioenergy Research Center, Michigan State University, East Lansing, MI, U.S.A
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24
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Abeywardana T, Wu X, Huang ST, Aldana Masangkay G, Rodin AS, Branciamore S, Gogoshin G, Li A, Du L, Tharuka N, Tomaino R, Chen Y. Regulation of Enhancers by SUMOylation Through TFAP2C Binding and Recruitment of HDAC Complex to the Chromatin. RESEARCH SQUARE 2024:rs.3.rs-4201913. [PMID: 38645262 PMCID: PMC11030540 DOI: 10.21203/rs.3.rs-4201913/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/23/2024]
Abstract
Enhancers are fundamental to gene regulation. Post-translational modifications by the small ubiquitin-like modifiers (SUMO) modify chromatin regulation enzymes, including histone acetylases and deacetylases. However, it remains unclear whether SUMOylation regulates enhancer marks, acetylation at the 27th lysine residue of the histone H3 protein (H3K27Ac). To investigate whether SUMOylation regulates H3K27Ac, we performed genome-wide ChIP-seq analyses and discovered that knockdown (KD) of the SUMO activating enzyme catalytic subunit UBA2 reduced H3K27Ac at most enhancers. Bioinformatic analysis revealed that TFAP2C-binding sites are enriched in enhancers whose H3K27Ac was reduced by UBA2 KD. ChIP-seq analysis in combination with molecular biological methods showed that TFAP2C binding to enhancers increased upon UBA2 KD or inhibition of SUMOylation by a small molecule SUMOylation inhibitor. However, this is not due to the SUMOylation of TFAP2C itself. Proteomics analysis of TFAP2C interactome on the chromatin identified histone deacetylation (HDAC) and RNA splicing machineries that contain many SUMOylation targets. TFAP2C KD reduced HDAC1 binding to chromatin and increased H3K27Ac marks at enhancer regions, suggesting that TFAP2C is important in recruiting HDAC machinery. Taken together, our findings provide insights into the regulation of enhancer marks by SUMOylation and TFAP2C and suggest that SUMOylation of proteins in the HDAC machinery regulates their recruitments to enhancers.
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Affiliation(s)
| | - Xiwei Wu
- Toni Stephenson Lymphoma Center Beckman Research Institute, City of Hope
| | | | | | - Andrei S Rodin
- Toni Stephenson Lymphoma Center Beckman Research Institute, City of Hope
| | - Sergio Branciamore
- Toni Stephenson Lymphoma Center Beckman Research Institute, City of Hope
| | - Grigoriy Gogoshin
- Toni Stephenson Lymphoma Center Beckman Research Institute, City of Hope
| | - Arthur Li
- Toni Stephenson Lymphoma Center Beckman Research Institute, City of Hope
| | - Li Du
- Toni Stephenson Lymphoma Center Beckman Research Institute, City of Hope
| | | | - Ross Tomaino
- Harvard Medical School Taplin Mass Spectrometry Facility
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25
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Zhu G, Zhang H, Xia M, Liu Y, Li M. EH domain-containing protein 2 (EHD2): Overview, biological function, and therapeutic potential. Cell Biochem Funct 2024; 42:e4016. [PMID: 38613224 DOI: 10.1002/cbf.4016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 04/02/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024]
Abstract
EH domain-containing protein 2 (EHD2) is a member of the EHD protein family and is mainly located in the plasma membrane, but can also be found in the cytoplasm and endosomes. EHD2 is also a nuclear-cytoplasmic shuttle protein. After entering the cell nuclear, EHD2 acts as a corepressor of transcription to inhibit gene transcription. EHD2 regulates a series of biological processes. As a key regulator of endocytic transport, EHD2 is involved in the formation and maintenance of endosomal tubules and vesicles, which are critical for the intracellular transport of proteins and other substances. The N-terminal of EHD2 is attached to the cell membrane, while its C-terminal binds to the actin-binding protein. After binding, EHD2 connects with the actin cytoskeleton, forming the curvature of the membrane and promoting cell endocytosis. EHD2 is also associated with membrane protein trafficking and receptor signaling, as well as in glucose metabolism and lipid metabolism. In this review, we highlight the recent advances in the function of EHD2 in various cellular processes and its potential implications in human diseases such as cancer and metabolic disease. We also discussed the prospects for the future of EHD2. EHD2 has a broad prospect as a therapeutic target for a variety of diseases. Further research is needed to explore its mechanism, which could pave the way for the development of targeted treatments.
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Affiliation(s)
- Guoqiang Zhu
- Department of Urology, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, Hunan, China
| | - Hu Zhang
- Department of Urology, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, Hunan, China
| | - Min Xia
- Hengyang Medical School, Institute of Clinical Medicine, The First Affiliated Hospital, University of South China, Hengyang, Hunan, China
- Hengyang Medical School, Cancer Research Institute, The First Affiliated Hospital, University of South China, Hengyang, Hunan, China
| | - Yiqi Liu
- Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Mingyong Li
- Department of Urology, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, Hunan, China
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26
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Ghimire S, Hasan MM, Fang XW. Small ubiquitin-like modifiers E3 ligases in plant stress. FUNCTIONAL PLANT BIOLOGY : FPB 2024; 51:FP24032. [PMID: 38669463 DOI: 10.1071/fp24032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 04/05/2024] [Indexed: 04/28/2024]
Abstract
Plants regularly encounter various environmental stresses such as salt, drought, cold, heat, heavy metals and pathogens, leading to changes in their proteome. Of these, a post-translational modification, SUMOylation is particularly significant for its extensive involvement in regulating various plant molecular processes to counteract these external stressors. Small ubiquitin-like modifiers (SUMO) protein modification significantly contributes to various plant functions, encompassing growth, development and response to environmental stresses. The SUMO system has a limited number of ligases even in fully sequenced plant genomes but SUMO E3 ligases are pivotal in recognising substrates during the process of SUMOylation. E3 ligases play pivotal roles in numerous biological and developmental processes in plants, including DNA repair, photomorphogenesis, phytohormone signalling and responses to abiotic and biotic stress. A considerable number of targets for E3 ligases are proteins implicated in reactions to abiotic and biotic stressors. This review sheds light on how plants respond to environmental stresses by focusing on recent findings on the role of SUMO E3 ligases, contributing to a better understanding of how plants react at a molecular level to such stressors.
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Affiliation(s)
- Shantwana Ghimire
- State Key Laboratory of Herbage Improvement and Grassland Agro-Ecosystems, College of Ecology, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Md Mahadi Hasan
- State Key Laboratory of Herbage Improvement and Grassland Agro-Ecosystems, College of Ecology, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Xiang-Wen Fang
- State Key Laboratory of Herbage Improvement and Grassland Agro-Ecosystems, College of Ecology, Lanzhou University, Lanzhou, Gansu 730000, China
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27
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Huang Z, Hua H, Du X, Zhen Z, Zhao W, Feng J, Li JA. A specific nanobody-based affinity chromatography resin as a platform for small ubiquitin-related modifier fusion protein purification. J Chromatogr A 2024; 1713:464508. [PMID: 38006661 DOI: 10.1016/j.chroma.2023.464508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 11/12/2023] [Accepted: 11/13/2023] [Indexed: 11/27/2023]
Abstract
As an excellent fusion tag for expressing heterologous proteins, yeast SUMO (small ubiquitin-related modifier) has unique advantages such as improving solubility, promoting stability, and reducing degradation, but it lacks a simple and rapid purification method. Camelid single-domain antibodies (VHHs or nanobodies) show great promise as an efficient tool in analytical application. In this study, VHHs against SUMO protein were isolated for the first time using biopanning of an immune camelid nanobody library. Among these nanobodies, VS2 demonstrated a high expression level (1.12 g L - 1), and a high affinity for SUMO (2.26 nM). Meanwhile, VHHs were coupled to agarose resins by cysteine at the C-terminal to form affinity chromatography resins. The VS2 resin showed excellent specificity and a dynamic binding capacity for SUMO, SUMO-DsbA (disulfide oxidoreductase) and SUMO-SAM (S-adenosylmethionine synthetase) were 2.41 mg/mL resin, 7.57 mg/mL resin and 16.23 mg/mL resin, respectively. Furthermore, the VS2 resin enabled one-step purification of SUMO-fusions [SUMO-Fc (human IgG1-Fc fragment), SUMO-IGF1 (human insulin-like growth factor 1), SUMO-FGF21 (human fibroblast growth factor 21), SUMO-G-CSF (human Granulocyte colony-stimulating factor), SUMO-PDGF (human platelet-derived growth factor) and SUMO-PAS200 (conformationally disordered polypeptide chains with expanded hydrodynamic volume comprising the small residues Pro, Ala-and Ser)], and maintained binding capacity and selectivity over 25 purification cycles, each including 15 min of cleaning-in-place with 0.1 M NaOH. This study demonstrated that the VS2 resin was a useful tool at the laboratory scale for one-step purification of various SUMO fusions from complex mixtures.
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Affiliation(s)
- Zongqing Huang
- Shanghai Duomirui Biotechnology Ltd, Shanghai 201203, China; China State Institute of Pharmaceutical Industry Ltd, Shanghai, 201203, China
| | - Haoju Hua
- Shanghai Duomirui Biotechnology Ltd, Shanghai 201203, China; China State Institute of Pharmaceutical Industry Ltd, Shanghai, 201203, China
| | - Xiuzhen Du
- Chia Tai Tianqing Pharma, Nanjing, 210000, China
| | - Zipeng Zhen
- Chia Tai Tianqing Pharma, Nanjing, 210000, China
| | - Wei Zhao
- Chia Tai Tianqing Pharma, Nanjing, 210000, China
| | - Jun Feng
- Shanghai Duomirui Biotechnology Ltd, Shanghai 201203, China; China State Institute of Pharmaceutical Industry Ltd, Shanghai, 201203, China.
| | - Ji-An Li
- China State Institute of Pharmaceutical Industry Ltd, Shanghai, 201203, China.
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28
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Chen Z, Luo J, Zhang Y, Zheng S, Zhang H, Huang Y, Wong J, Li J. SUMOylation is enriched in the nuclear matrix and required for chromosome segregation. J Biol Chem 2024; 300:105547. [PMID: 38072047 PMCID: PMC10794928 DOI: 10.1016/j.jbc.2023.105547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/19/2023] [Accepted: 12/01/2023] [Indexed: 01/04/2024] Open
Abstract
As an important posttranslational modification, SUMOylation plays critical roles in almost all biological processes. Although it has been well-documented that SUMOylated proteins are mainly localized in the nucleus and have roles in chromatin-related processes, we showed recently that the SUMOylation machinery is actually enriched in the nuclear matrix rather than chromatin. Here, we provide compelling biochemical, cellular imaging and proteomic evidence that SUMOylated proteins are highly enriched in the nuclear matrix. We demonstrated that inactivation of SUMOylation by inhibiting SUMO-activating E1 enzyme or KO of SUMO-conjugating E2 enzyme UBC9 have only mild effect on nuclear matrix composition, indicating that SUMOylation is neither required for nuclear matrix formation nor for targeting proteins to nuclear matrix. Further characterization of UBC9 KO cells revealed that loss of SUMOylation did not result in significant DNA damage, but led to mitotic arrest and chromosome missegregation. Altogether, our study demonstrates that SUMOylated proteins are selectively enriched in the nuclear matrix and suggests a role of nuclear matrix in mediating SUMOylation and its regulated biological processes.
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Affiliation(s)
- Zhaosu Chen
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Jing Luo
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Yunpeng Zhang
- Department of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Shaoqi Zheng
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Huifang Zhang
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Yuanyong Huang
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Jiemin Wong
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
| | - Jiwen Li
- Shanghai Key Laboratory of Regulatory Biology, Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
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29
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Ermisch AF, Wood JR. Regulation of Oocyte mRNA Metabolism: A Key Determinant of Oocyte Developmental Competence. ADVANCES IN ANATOMY, EMBRYOLOGY, AND CELL BIOLOGY 2024; 238:23-46. [PMID: 39030353 DOI: 10.1007/978-3-031-55163-5_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/21/2024]
Abstract
The regulation of mRNA transcription and translation is uncoupled during oogenesis. The reason for this uncoupling is two-fold. Chromatin is only accessible to the transcriptional machinery during the growth phase as it condenses prior to resumption of meiosis to ensure faithful segregation of chromosomes during meiotic maturation. Thus, transcription rates are high during this time period in order to produce all of the transcripts needed for meiosis, fertilization, and embryo cleavage until the newly formed embryonic genome becomes transcriptionally active. To ensure appropriate timing of key developmental milestones including chromatin condensation, resumption of meiosis, segregation of chromosomes, and polar body extrusion, the translation of protein from transcripts synthesized during oocyte growth must be temporally regulated. This is achieved by the regulation of mRNA interaction with RNA binding proteins and shortening and lengthening of the poly(A) tail. This chapter details the essential factors that regulate the dynamic changes in mRNA synthesis, storage, translation, and degradation during oocyte growth and maturation.
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Affiliation(s)
- Alison F Ermisch
- Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE, USA
| | - Jennifer R Wood
- Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE, USA.
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30
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Li J, Su L, Jiang J, Wang YE, Ling Y, Qiu Y, Yu H, Huang Y, Wu J, Jiang S, Zhang T, Palazzo AF, Shen Q. RanBP2/Nup358 Mediates Sumoylation of STAT1 and Antagonizes Interferon-α-Mediated Antiviral Innate Immunity. Int J Mol Sci 2023; 25:299. [PMID: 38203469 PMCID: PMC10778711 DOI: 10.3390/ijms25010299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/16/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Type I interferon (IFN-I)-induced signaling plays a critical role in host antiviral innate immune responses. Despite this, the mechanisms that regulate this signaling pathway have yet to be fully elucidated. The nucleoporin Ran Binding Protein 2 (RanBP2) (also known as Nucleoporin 358 KDa, Nup358) has been implicated in a number of cellular processes, including host innate immune signaling pathways, and is known to influence viral infection. In this study, we documented that RanBP2 mediates the sumoylation of signal transducers and activators of transcription 1 (STAT1) and inhibits IFN-α-induced signaling. Specifically, we found that RanBP2-mediated sumoylation inhibits the interaction of STAT1 and Janus kinase 1 (JAK1), as well as the phosphorylation and nuclear accumulation of STAT1 after IFN-α stimulation, thereby antagonizing the IFN-α-mediated antiviral innate immune signaling pathway and promoting viral infection. Our findings not only provide insights into a novel function of RanBP2 in antiviral innate immunity but may also contribute to the development of new antiviral therapeutic strategies.
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Affiliation(s)
- Jiawei Li
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350108, China; (J.L.); (L.S.); (J.J.); (Y.L.); (H.Y.); (Y.H.); (J.W.); (S.J.); (T.Z.)
| | - Lili Su
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350108, China; (J.L.); (L.S.); (J.J.); (Y.L.); (H.Y.); (Y.H.); (J.W.); (S.J.); (T.Z.)
| | - Jing Jiang
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350108, China; (J.L.); (L.S.); (J.J.); (Y.L.); (H.Y.); (Y.H.); (J.W.); (S.J.); (T.Z.)
| | - Yifan E. Wang
- Department of Biochemistry, University of Toronto, Toronto, ON M5G 1M1, Canada; (Y.E.W.); (Y.Q.)
| | - Yingying Ling
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350108, China; (J.L.); (L.S.); (J.J.); (Y.L.); (H.Y.); (Y.H.); (J.W.); (S.J.); (T.Z.)
| | - Yi Qiu
- Department of Biochemistry, University of Toronto, Toronto, ON M5G 1M1, Canada; (Y.E.W.); (Y.Q.)
| | - Huahui Yu
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350108, China; (J.L.); (L.S.); (J.J.); (Y.L.); (H.Y.); (Y.H.); (J.W.); (S.J.); (T.Z.)
| | - Yucong Huang
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350108, China; (J.L.); (L.S.); (J.J.); (Y.L.); (H.Y.); (Y.H.); (J.W.); (S.J.); (T.Z.)
| | - Jiangmin Wu
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350108, China; (J.L.); (L.S.); (J.J.); (Y.L.); (H.Y.); (Y.H.); (J.W.); (S.J.); (T.Z.)
| | - Shan Jiang
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350108, China; (J.L.); (L.S.); (J.J.); (Y.L.); (H.Y.); (Y.H.); (J.W.); (S.J.); (T.Z.)
| | - Tao Zhang
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350108, China; (J.L.); (L.S.); (J.J.); (Y.L.); (H.Y.); (Y.H.); (J.W.); (S.J.); (T.Z.)
| | - Alexander F. Palazzo
- Department of Biochemistry, University of Toronto, Toronto, ON M5G 1M1, Canada; (Y.E.W.); (Y.Q.)
| | - Qingtang Shen
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350108, China; (J.L.); (L.S.); (J.J.); (Y.L.); (H.Y.); (Y.H.); (J.W.); (S.J.); (T.Z.)
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Bao Y, Pan Q, Xu P, Liu Z, Zhang Z, Liu Y, Xu Y, Yu Y, Zhou Z, Wei W. Unbiased interrogation of functional lysine residues in human proteome. Mol Cell 2023; 83:4614-4632.e6. [PMID: 37995688 DOI: 10.1016/j.molcel.2023.10.033] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 09/06/2023] [Accepted: 10/23/2023] [Indexed: 11/25/2023]
Abstract
CRISPR screens have empowered the high-throughput dissection of gene functions; however, more explicit genetic elements, such as codons of amino acids, require thorough interrogation. Here, we establish a CRISPR strategy for unbiasedly probing functional amino acid residues at the genome scale. By coupling adenine base editors and barcoded sgRNAs, we target 215,689 out of 611,267 (35%) lysine codons, involving 85% of the total protein-coding genes. We identify 1,572 lysine codons whose mutations perturb human cell fitness, with many of them implicated in cancer. These codons are then mirrored to gene knockout screen data to provide functional insights into the role of lysine residues in cellular fitness. Mining these data, we uncover a CUL3-centric regulatory network in which lysine residues of CUL3 CRL complex proteins control cell fitness by specifying protein-protein interactions. Our study offers a general strategy for interrogating genetic elements and provides functional insights into the human proteome.
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Affiliation(s)
- Ying Bao
- Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; Changping Laboratory, Beijing 102206, China
| | - Qian Pan
- Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
| | - Ping Xu
- Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
| | - Zhiheng Liu
- Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
| | - Zhixuan Zhang
- Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
| | - Yongshuo Liu
- Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
| | - Yiyuan Xu
- Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
| | - Ying Yu
- Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
| | - Zhuo Zhou
- Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China.
| | - Wensheng Wei
- Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; Changping Laboratory, Beijing 102206, China.
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Ling T, Li S, Chen H, Wang Q, Shi J, Li Y, Bao W, Liang K, Piao HL. Lysine-372-dependent SUMOylation inhibits the enzymatic activity of glutamine synthases. FASEB J 2023; 37:e23319. [PMID: 38010918 DOI: 10.1096/fj.202301462rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 10/20/2023] [Accepted: 11/06/2023] [Indexed: 11/29/2023]
Abstract
Glutamine synthetase (GS) is a crucial enzyme involved in de novo synthesis of glutamine and participates in several biological processes, including nitrogen metabolism, nucleotide synthesis, and amino acid synthesis. Post-translational modification makes GS more adaptable to the needs of cells, and acetylation modification of GS at double sites has attracted considerable attention. Despite very intensive research, how SUMOylation affects GS activity at a molecular level remains unclear. Here, we report that previously undiscovered GS SUMOylation which is deficient mutant K372R of GS exhibits more bluntness under glutamine starvation. Mechanistically, glutamine deprivation triggers the GS SUMOylation, and this SUMOylation impaired the protein stability of GS, within a concomitant decrease in enzymatic activity. In addition, we identified SAE1, Ubc9, and PIAS1 as the assembly enzymes of GS SUMOylation respectively. Furthermore, Senp1/2 functions as a SUMO-specific protease to reverse the SUMOylation of GS. This study provides the first evidence that SUMOylation serves as a regulatory mechanism for determining the GS enzymatic activity, contributing to understanding the GS regulation roles in various cellular and pathophysiological processes.
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Affiliation(s)
- Ting Ling
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
- Department of analytical chemistry, University of Chinese Academy of Sciences, Beijing, China
| | - Siyi Li
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
- Cancer Research Institute, Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Huan Chen
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Qiuping Wang
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Jing Shi
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
- Department of Biochemistry & Molecular Biology, School of Life Sciences, China Medical University, Shenyang, China
| | - Yirong Li
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
- Department of analytical chemistry, University of Chinese Academy of Sciences, Beijing, China
| | - Wenjun Bao
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
- Department of analytical chemistry, University of Chinese Academy of Sciences, Beijing, China
| | - Kunming Liang
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
- Department of Biochemistry & Molecular Biology, School of Life Sciences, China Medical University, Shenyang, China
| | - Hai-Long Piao
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
- Department of analytical chemistry, University of Chinese Academy of Sciences, Beijing, China
- Cancer Research Institute, Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
- Department of Biochemistry & Molecular Biology, School of Life Sciences, China Medical University, Shenyang, China
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Han J, Mu Y, Huang J. Preserving genome integrity: The vital role of SUMO-targeted ubiquitin ligases. CELL INSIGHT 2023; 2:100128. [PMID: 38047137 PMCID: PMC10692494 DOI: 10.1016/j.cellin.2023.100128] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 10/09/2023] [Accepted: 10/09/2023] [Indexed: 12/05/2023]
Abstract
Various post-translational modifications (PTMs) collaboratively fine-tune protein activities. SUMO-targeted ubiquitin E3 ligases (STUbLs) emerge as specialized enzymes that recognize SUMO-modified substrates through SUMO-interaction motifs and subsequently ubiquitinate them via the RING domain, thereby bridging the SUMO and ubiquitin signaling pathways. STUbLs participate in a wide array of molecular processes, including cell cycle regulation, DNA repair, replication, and mitosis, operating under both normal conditions and in response to challenges such as genotoxic stress. Their ability to catalyze various types of ubiquitin chains results in diverse proteolytic and non-proteolytic outcomes for target substrates. Importantly, STUbLs are strategically positioned in close proximity to SUMO proteases and deubiquitinases (DUBs), ensuring precise and dynamic control over their target proteins. In this review, we provide insights into the unique properties and indispensable roles of STUbLs, with a particular emphasis on their significance in preserving genome integrity in humans.
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Affiliation(s)
- Jinhua Han
- Institute of Geriatrics, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, 310030, Zhejiang, China
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Yanhua Mu
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Jun Huang
- Institute of Geriatrics, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, 310030, Zhejiang, China
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, Zhejiang, China
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Esmaili F, Pourmirzaei M, Ramazi S, Shojaeilangari S, Yavari E. A Review of Machine Learning and Algorithmic Methods for Protein Phosphorylation Site Prediction. GENOMICS, PROTEOMICS & BIOINFORMATICS 2023; 21:1266-1285. [PMID: 37863385 PMCID: PMC11082408 DOI: 10.1016/j.gpb.2023.03.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 01/16/2023] [Accepted: 03/23/2023] [Indexed: 10/22/2023]
Abstract
Post-translational modifications (PTMs) have key roles in extending the functional diversity of proteins and, as a result, regulating diverse cellular processes in prokaryotic and eukaryotic organisms. Phosphorylation modification is a vital PTM that occurs in most proteins and plays a significant role in many biological processes. Disorders in the phosphorylation process lead to multiple diseases, including neurological disorders and cancers. The purpose of this review is to organize this body of knowledge associated with phosphorylation site (p-site) prediction to facilitate future research in this field. At first, we comprehensively review all related databases and introduce all steps regarding dataset creation, data preprocessing, and method evaluation in p-site prediction. Next, we investigate p-site prediction methods, which are divided into two computational groups: algorithmic and machine learning (ML). Additionally, it is shown that there are basically two main approaches for p-site prediction by ML: conventional and end-to-end deep learning methods, both of which are given an overview. Moreover, this review introduces the most important feature extraction techniques, which have mostly been used in p-site prediction. Finally, we create three test sets from new proteins related to the released version of the database of protein post-translational modifications (dbPTM) in 2022 based on general and human species. Evaluating online p-site prediction tools on newly added proteins introduced in the dbPTM 2022 release, distinct from those in the dbPTM 2019 release, reveals their limitations. In other words, the actual performance of these online p-site prediction tools on unseen proteins is notably lower than the results reported in their respective research papers.
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Affiliation(s)
- Farzaneh Esmaili
- Department of Information Technology, Tarbiat Modares University, Tehran 14115-111, Iran
| | - Mahdi Pourmirzaei
- Department of Information Technology, Tarbiat Modares University, Tehran 14115-111, Iran
| | - Shahin Ramazi
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 14115-111, Iran.
| | - Seyedehsamaneh Shojaeilangari
- Biomedical Engineering Group, Department of Electrical Engineering and Information Technology, Iranian Research Organization for Science and Technology (IROST), Tehran 33535-111, Iran
| | - Elham Yavari
- Department of Information Technology, Tarbiat Modares University, Tehran 14115-111, Iran
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Kim KW, Ljunggren-Rose Å, Matta P, Toki S, Sriram S. Inhibition of SUMOylation promotes remyelination and reduces IL-17 mediated autoimmune inflammation: Novel approach toward treatment of inflammatory CNS demyelinating disease. J Neuroimmunol 2023; 384:578219. [PMID: 37813042 DOI: 10.1016/j.jneuroim.2023.578219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/11/2023] [Accepted: 10/01/2023] [Indexed: 10/11/2023]
Abstract
Small ubiquitin like modifiers (SUMO) are reversible posttranslational modifiers of intracellular proteins. In the CNS, expression of myelin genes is regulated by state of SUMOylation of their respective transcription factors. In the immune system, deSUMOylation activates innate immune responses and promotes anti-viral immunity. However, the role played by SUMO in an adaptive immune response and in the development of T cell mediated autoimmune disease has not been previously described. TAK981 is a synthetic small molecule which by forming adducts with SUMO proteins prevents SUMOylation. We examined the expression of myelin genes and their transcription factors following culture with TAK981 in Oligodendrocyte Precursor Cells (OPC). We found that myelin basic protein (MBP), a key myelin protein, is upregulated in OPC in the presence of TAK981. We also found increased expression of transcription factors Sox10 and Myrf, which engage in the expression of MBP. In the Cuprizone model of demyelination/remyelination, animals which were treated with TAK981 showed increased remyelination in areas of demyelination and an increase in the number of maturing oligodendrocytes compared to vehicle treated controls. In in vitro cultures of lymphocytes, TAK981 reduced the expression of TH17 in T cells in mice immunized with MOGp35-55. Following in vivo treatment with TAK981, there was a significant reduction in the clinical and pathological severity in mice immunized to develop experimental allergic encephalitis (EAE). The dual effects of deSUMOylation on remyelination and in regulating an autoimmune adaptive response offers a novel approach to the management of human inflammatory demyelinating diseases such as multiple sclerosis.
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Affiliation(s)
- Kwang Woon Kim
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, United States of America
| | - Åsa Ljunggren-Rose
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, United States of America
| | - Pranathi Matta
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, United States of America
| | - Shinji Toki
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37212, United States of America
| | - Subramaniam Sriram
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, United States of America.
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Wu W, Huang C. SUMOylation and DeSUMOylation: Prospective therapeutic targets in cancer. Life Sci 2023; 332:122085. [PMID: 37722589 DOI: 10.1016/j.lfs.2023.122085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 09/05/2023] [Accepted: 09/12/2023] [Indexed: 09/20/2023]
Abstract
The SUMO family is a type of ubiquitin-like protein modification molecule. Its protein modification mechanism is similar to that of ubiquitination: both involve modifier-activating enzyme E1, conjugating enzyme E2 and substrate-specific ligase E3. However, polyubiquitination can lead to the degradation of substrate proteins, while poly-SUMOylation only leads to the degradation of substrate proteins through the proteasome pathway after being recognized by ubiquitin as a signal factor. There are currently five reported subtypes in the SUMO family, namely SUMO1-5. As a reversible dynamic modification, intracellular sentrin/SUMO-specific proteases (SENPs) mainly regulate the reverse reaction pathway of SUMOylation. The SUMOylation modification system affects the localization, activation and turnover of proteins in cells and participates in regulating most nuclear and extranuclear molecular reactions. Abnormal expression of proteins related to the SUMOylation pathway is commonly observed in tumors, indicating that this pathway is closely related to tumor occurrence, metastasis and invasion. This review mainly discusses the composition of members in the protein family related to SUMOylation pathways, mutual connections between SUMOylation and other post-translational modifications on proteins as well as therapeutic drugs developed based on these pathways.
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Affiliation(s)
- Wenyan Wu
- Kunming University of Science and Technology, Medical School, Kunming 650500, China
| | - Chao Huang
- Kunming University of Science and Technology, Medical School, Kunming 650500, China.
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Somashekara SC, Dhyani KM, Thakur M, Muniyappa K. SUMOylation of yeast Pso2 enhances its translocation and accumulation in the mitochondria and suppresses methyl methanesulfonate-induced mitochondrial DNA damage. Mol Microbiol 2023; 120:587-607. [PMID: 37649278 DOI: 10.1111/mmi.15145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 08/01/2023] [Accepted: 08/09/2023] [Indexed: 09/01/2023]
Abstract
Saccharomyces cerevisiae Pso2/SNM1 is essential for DNA interstrand crosslink (ICL) repair; however, its mechanism of action remains incompletely understood. While recent work has revealed that Pso2/Snm1 is dual-localized in the nucleus and mitochondria, it remains unclear whether cell-intrinsic and -extrinsic factors regulate its subcellular localization and function. Herein, we show that Pso2 undergoes ubiquitination and phosphorylation, but not SUMOylation, in unstressed cells. Unexpectedly, we found that methyl methanesulfonate (MMS), rather than ICL-forming agents, induced robust SUMOylation of Pso2 on two conserved residues, K97 and K575, and that SUMOylation markedly increased its abundance in the mitochondria. Reciprocally, SUMOylation had no discernible impact on Pso2 translocation to the nucleus, despite the presence of steady-state levels of SUMOylated Pso2 across the cell cycle. Furthermore, substitution of the invariant residues K97 and K575 by arginine in the Pso2 SUMO consensus motifs severely impaired SUMOylation and abolished its translocation to the mitochondria of MMS-treated wild type cells, but not in unstressed cells. We demonstrate that whilst Siz1 and Siz2 SUMO E3 ligases catalyze Pso2 SUMOylation, the former plays a dominant role. Notably, we found that the phenotypic characteristics of the SUMOylation-defective mutant Pso2K97R/K575R closely mirrored those observed in the Pso2Δ petite mutant. Additionally, leveraging next-generation sequencing analysis, we demonstrate that Pso2 mitigates MMS-induced damage to mitochondrial DNA (mtDNA). Viewed together, our work offers previously unknown insights into the link between genotoxic stress-induced SUMOylation of Pso2 and its preferential targeting to the mitochondria, as well as its role in attenuating MMS-induced mtDNA damage.
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Affiliation(s)
| | - Kshitiza M Dhyani
- Department of Biochemistry, Indian Institute of Science, Bangalore, India
| | - Manoj Thakur
- Sri Venkateswara College, University of Delhi, New Delhi, India
| | - Kalappa Muniyappa
- Department of Biochemistry, Indian Institute of Science, Bangalore, India
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Weng W, Gu X, Yang Y, Zhang Q, Deng Q, Zhou J, Cheng J, Zhu MX, Feng J, Huang O, Li Y. N-terminal α-amino SUMOylation of cofilin-1 is critical for its regulation of actin depolymerization. Nat Commun 2023; 14:5688. [PMID: 37709794 PMCID: PMC10502023 DOI: 10.1038/s41467-023-41520-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 09/01/2023] [Indexed: 09/16/2023] Open
Abstract
Small ubiquitin-like modifier (SUMO) typically conjugates to target proteins through isopeptide linkage to the ε-amino group of lysine residues. This posttranslational modification (PTM) plays pivotal roles in modulating protein function. Cofilins are key regulators of actin cytoskeleton dynamics and are well-known to undergo several different PTMs. Here, we show that cofilin-1 is conjugated by SUMO1 both in vitro and in vivo. Using mass spectrometry and biochemical and genetic approaches, we identify the N-terminal α-amino group as the SUMO-conjugation site of cofilin-1. Common to conventional SUMOylation is that the N-α-SUMOylation of cofilin-1 is also mediated by SUMO activating (E1), conjugating (E2), and ligating (E3) enzymes and reversed by the SUMO deconjugating enzyme, SENP1. Specific to the N-α-SUMOylation is the physical association of the E1 enzyme to the substrate, cofilin-1. Using F-actin co-sedimentation and actin depolymerization assays in vitro and fluorescence staining of actin filaments in cells, we show that the N-α-SUMOylation promotes cofilin-1 binding to F-actin and cofilin-induced actin depolymerization. This covalent conjugation by SUMO at the N-α amino group of cofilin-1, rather than at an internal lysine(s), serves as an essential PTM to tune cofilin-1 function during regulation of actin dynamics.
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Affiliation(s)
- Weiji Weng
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xiaokun Gu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yang Yang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Qiao Zhang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Qi Deng
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jie Zhou
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jinke Cheng
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Michael X Zhu
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Junfeng Feng
- Brain Injury Centre, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
- Shanghai Institute of Head Trauma, Shanghai, 200127, China.
| | - Ou Huang
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Yong Li
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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Camuel A, Teulet A, Carcagno M, Haq F, Pacquit V, Gully D, Pervent M, Chaintreuil C, Fardoux J, Horta-Araujo N, Okazaki S, Ratu STN, Gueye F, Zilli J, Nouwen N, Arrighi JF, Luo H, Mergaert P, Deslandes L, Giraud E. Widespread Bradyrhizobium distribution of diverse Type III effectors that trigger legume nodulation in the absence of Nod factor. THE ISME JOURNAL 2023; 17:1416-1429. [PMID: 37355742 PMCID: PMC10432411 DOI: 10.1038/s41396-023-01458-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 06/08/2023] [Accepted: 06/13/2023] [Indexed: 06/26/2023]
Abstract
The establishment of the rhizobium-legume symbiosis is generally based on plant perception of Nod factors (NFs) synthesized by the bacteria. However, some Bradyrhizobium strains can nodulate certain legume species, such as Aeschynomene spp. or Glycine max, independently of NFs, and via two different processes that are distinguished by the necessity or not of a type III secretion system (T3SS). ErnA is the first known type III effector (T3E) triggering nodulation in Aeschynomene indica. In this study, a collection of 196 sequenced Bradyrhizobium strains was tested on A. indica. Only strains belonging to the photosynthetic supergroup can develop a NF-T3SS-independent symbiosis, while the ability to use a T3SS-dependent process is found in multiple supergroups. Of these, 14 strains lacking ernA were tested by mutagenesis to identify new T3Es triggering nodulation. We discovered a novel T3E, Sup3, a putative SUMO-protease without similarity to ErnA. Its mutation in Bradyrhizobium strains NAS96.2 and WSM1744 abolishes nodulation and its introduction in an ernA mutant of strain ORS3257 restores nodulation. Moreover, ectopic expression of sup3 in A. indica roots led to the formation of spontaneous nodules. We also report three other new T3Es, Ubi1, Ubi2 and Ubi3, which each contribute to the nodulation capacity of strain LMTR13. These T3Es have no homology to known proteins but share with ErnA three motifs necessary for ErnA activity. Together, our results highlight an unsuspected distribution and diversity of T3Es within the Bradyrhizobium genus that may contribute to their symbiotic efficiency by participating in triggering legume nodulation.
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Affiliation(s)
- Alicia Camuel
- IRD, Laboratoire des Symbioses Tropicales et Méditerranéennes (LSTM), UMR IRD/Institut Agro/INRAE/Université de Montpellier/CIRAD, TA-A82/J- Campus de Baillarguet 34398, Montpellier cedex 5, France
- PHIM Plant Health Institute, Université de Montpellier, IRD, CIRAD, INRAE, Institut Agro, Montpellier, France
| | - Albin Teulet
- IRD, Laboratoire des Symbioses Tropicales et Méditerranéennes (LSTM), UMR IRD/Institut Agro/INRAE/Université de Montpellier/CIRAD, TA-A82/J- Campus de Baillarguet 34398, Montpellier cedex 5, France
- University of Cambridge, Sainsbury Laboratory (SLCU), Cambridge, CB2 1LR, UK
| | - Mélanie Carcagno
- LIPME, Université de Toulouse, INRAE, CNRS, Castanet-Tolosan, France
| | - Fazal Haq
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198, Gif-sur-Yvette, France
| | - Valérie Pacquit
- LIPME, Université de Toulouse, INRAE, CNRS, Castanet-Tolosan, France
| | - Djamel Gully
- IRD, Laboratoire des Symbioses Tropicales et Méditerranéennes (LSTM), UMR IRD/Institut Agro/INRAE/Université de Montpellier/CIRAD, TA-A82/J- Campus de Baillarguet 34398, Montpellier cedex 5, France
- PHIM Plant Health Institute, Université de Montpellier, IRD, CIRAD, INRAE, Institut Agro, Montpellier, France
| | - Marjorie Pervent
- IRD, Laboratoire des Symbioses Tropicales et Méditerranéennes (LSTM), UMR IRD/Institut Agro/INRAE/Université de Montpellier/CIRAD, TA-A82/J- Campus de Baillarguet 34398, Montpellier cedex 5, France
- PHIM Plant Health Institute, Université de Montpellier, IRD, CIRAD, INRAE, Institut Agro, Montpellier, France
| | - Clémence Chaintreuil
- IRD, Laboratoire des Symbioses Tropicales et Méditerranéennes (LSTM), UMR IRD/Institut Agro/INRAE/Université de Montpellier/CIRAD, TA-A82/J- Campus de Baillarguet 34398, Montpellier cedex 5, France
- PHIM Plant Health Institute, Université de Montpellier, IRD, CIRAD, INRAE, Institut Agro, Montpellier, France
| | - Joël Fardoux
- IRD, Laboratoire des Symbioses Tropicales et Méditerranéennes (LSTM), UMR IRD/Institut Agro/INRAE/Université de Montpellier/CIRAD, TA-A82/J- Campus de Baillarguet 34398, Montpellier cedex 5, France
| | - Natasha Horta-Araujo
- IRD, Laboratoire des Symbioses Tropicales et Méditerranéennes (LSTM), UMR IRD/Institut Agro/INRAE/Université de Montpellier/CIRAD, TA-A82/J- Campus de Baillarguet 34398, Montpellier cedex 5, France
- PHIM Plant Health Institute, Université de Montpellier, IRD, CIRAD, INRAE, Institut Agro, Montpellier, France
| | - Shin Okazaki
- Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, 183-8509, Japan
| | - Safirah Tasa Nerves Ratu
- Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, 183-8509, Japan
| | - Fatou Gueye
- Carrefour International, Bureau Régional Afrique de l'Ouest, Dakar, Sénégal
| | - Jerri Zilli
- Embrapa Agrobiologia, Bairro Ecologia, Seropedica, Rio de Janeiro, Brazil
| | - Nico Nouwen
- IRD, Laboratoire des Symbioses Tropicales et Méditerranéennes (LSTM), UMR IRD/Institut Agro/INRAE/Université de Montpellier/CIRAD, TA-A82/J- Campus de Baillarguet 34398, Montpellier cedex 5, France
- PHIM Plant Health Institute, Université de Montpellier, IRD, CIRAD, INRAE, Institut Agro, Montpellier, France
| | - Jean-François Arrighi
- IRD, Laboratoire des Symbioses Tropicales et Méditerranéennes (LSTM), UMR IRD/Institut Agro/INRAE/Université de Montpellier/CIRAD, TA-A82/J- Campus de Baillarguet 34398, Montpellier cedex 5, France
- PHIM Plant Health Institute, Université de Montpellier, IRD, CIRAD, INRAE, Institut Agro, Montpellier, France
| | - Haiwei Luo
- School of Life Sciences and State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Peter Mergaert
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198, Gif-sur-Yvette, France
| | - Laurent Deslandes
- LIPME, Université de Toulouse, INRAE, CNRS, Castanet-Tolosan, France
| | - Eric Giraud
- IRD, Laboratoire des Symbioses Tropicales et Méditerranéennes (LSTM), UMR IRD/Institut Agro/INRAE/Université de Montpellier/CIRAD, TA-A82/J- Campus de Baillarguet 34398, Montpellier cedex 5, France.
- PHIM Plant Health Institute, Université de Montpellier, IRD, CIRAD, INRAE, Institut Agro, Montpellier, France.
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Youssef A, Mohammed BK, Prasad A, del Aguila A, Bassi G, Yang W, Ulloa L. Splenic SUMO1 controls systemic inflammation in experimental sepsis. Front Immunol 2023; 14:1200939. [PMID: 37520526 PMCID: PMC10374847 DOI: 10.3389/fimmu.2023.1200939] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 06/22/2023] [Indexed: 08/01/2023] Open
Abstract
Introduction The recent discovery of TAK981(Subasumstat), the first-in-class selective inhibitor of SUMOylation, enables new immune treatments. TAK981 is already in clinical trials to potentiate immunotherapy in metastatic tumors and hematologic malignancies. Cancer patients have more than ten times higher risk of infections, but the effects of TAK981 in sepsis are unknown and previous studies on SUMO in infections are conflicting. Methods We used TAK981 in two sepsis models; polymicrobial peritonitis (CLP) and LPS endotoxemia. Splenectomy was done in both models to study the role of spleen. Western blotting of SUMO-conjugated proteins in spleen lysates was done. Global SUMO1 and SUMO3 knockout mice were used to study the specific SUMO regulation of inflammation in LPS endotoxemia. Splenocytes adoptive transfer was done from SUMO knockouts to wild type mice to study the role of spleen SUMOylation in experimental sepsis. Results and discussion Here, we report that inhibition of SUMOylation with TAK981 improved survival in mild polymicrobial peritonitis by enhancing innate immune responses and peritoneal bacterial clearance. Thus, we focused on the effects of TAK981 on the immune responses to bacterial endotoxin, showing that TAK981 enhanced early TNFα production but did not affect the resolution of inflammation. Splenectomy decreased serum TNFα levels by nearly 60% and TAK981-induced TNFα responses. In the spleen, endotoxemia induced a distinct temporal and substrate specificity for SUMO1 and SUMO2/3, and both were inhibited by TAK981. Global genetic depletion of SUMO1, but not SUMO3, enhanced TNFα production and metabolic acidosis. The transfer of SUMO1-null, but not wild-type, splenocytes into splenectomized wild-type mice exacerbated TNFα production and metabolic acidosis in endotoxemia. Conclusion These results suggest that specific regulation of splenic SUMO1 can modulate immune and metabolic responses to bacterial infection.
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Chanda A, Sarkar A, Deng L, Bonni A, Bonni S. Sumoylated SnoN interacts with HDAC1 and p300/CBP to regulate EMT-associated phenotypes in mammary organoids. Cell Death Dis 2023; 14:405. [PMID: 37414747 PMCID: PMC10326038 DOI: 10.1038/s41419-023-05921-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 06/14/2023] [Accepted: 06/22/2023] [Indexed: 07/08/2023]
Abstract
Protein post-translational modification by the small ubiquitin-like modifier (SUMO) regulates the stability, subcellular localization, and interactions of protein substrates with consequences on cellular responses including epithelial-mesenchymal transition (EMT). Transforming growth factor beta (TGFβ) is a potent inducer of EMT with implications for cancer invasion and metastasis. The transcriptional coregulator SnoN suppresses TGFβ-induced EMT-associated responses in a sumoylation-dependent manner, but the underlying mechanisms have remained largely unknown. Here, we find that sumoylation promotes the interaction of SnoN with the epigenetic regulators histone deacetylase 1 (HDAC1) and histone acetylase p300 in epithelial cells. In gain and loss of function studies, HDAC1 suppresses, whereas p300 promotes, TGFβ-induced morphogenetic changes associated with EMT-related events in three-dimensional multicellular organoids derived from mammary epithelial cells or carcinomas. These findings suggest that sumoylated SnoN acts via the regulation of histone acetylation to modulate EMT-related effects in breast cell organoids. Our study may facilitate the discovery of new biomarkers and therapeutics in breast cancer and other epithelial cell-derived cancers.
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Affiliation(s)
- Ayan Chanda
- Department of Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Anusi Sarkar
- Department of Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Lili Deng
- Department of Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Azad Bonni
- Neuroscience and Rare Diseases, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland
| | - Shirin Bonni
- Department of Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
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Elakhdar A, Slaski JJ, Kubo T, Hamwieh A, Hernandez Ramirez G, Beattie AD, Capo-chichi LJ. Genome-wide association analysis provides insights into the genetic basis of photosynthetic responses to low-temperature stress in spring barley. FRONTIERS IN PLANT SCIENCE 2023; 14:1159016. [PMID: 37346141 PMCID: PMC10279893 DOI: 10.3389/fpls.2023.1159016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 05/04/2023] [Indexed: 06/23/2023]
Abstract
Low-temperature stress (LTS) is among the major abiotic stresses affecting the geographical distribution and productivity of the most important crops. Understanding the genetic basis of photosynthetic variation under cold stress is necessary for developing more climate-resilient barley cultivars. To that end, we investigated the ability of chlorophyll fluorescence parameters (FVFM, and FVF0) to respond to changes in the maximum quantum yield of Photosystem II photochemistry as an indicator of photosynthetic energy. A panel of 96 barley spring cultivars from different breeding zones of Canada was evaluated for chlorophyll fluorescence-related traits under cold acclimation and freeze shock stresses at different times. Genome-wide association studies (GWAS) were performed using a mixed linear model (MLM). We identified three major and putative genomic regions harboring 52 significant quantitative trait nucleotides (QTNs) on chromosomes 1H, 3H, and 6H for low-temperature tolerance. Functional annotation indicated several QTNs were either within the known or close to genes that play important roles in the photosynthetic metabolites such as abscisic acid (ABA) signaling, hydrolase activity, protein kinase, and transduction of environmental signal transduction at the posttranslational modification levels. These outcomes revealed that barley plants modified their gene expression profile in response to decreasing temperatures resulting in physiological and biochemical modifications. Cold tolerance could influence a long-term adaption of barley in many parts of the world. Since the degree and frequency of LTS vary considerably among production sites. Hence, these results could shed light on potential approaches for improving barley productivity under low-temperature stress.
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Affiliation(s)
- Ammar Elakhdar
- Field Crops Research Institute, Agricultural Research Center, Giza, Egypt
- Institute of Genetic Resources, Faculty of Agriculture, Kyushu University, Fukuoka, Japan
| | - Jan J. Slaski
- Bio Industrial Services Division, InnoTech Alberta Inc., Vegreville, AB, Canada
| | - Takahiko Kubo
- Institute of Genetic Resources, Faculty of Agriculture, Kyushu University, Fukuoka, Japan
| | - Aladdin Hamwieh
- International Center for Agriculture Research in the Dry Areas (ICARDA), Giza, Egypt
| | - Guillermo Hernandez Ramirez
- Department of Renewable Resources, Faculty of Agriculture, Life and Environmental Sciences, University of Alberta, Edmonton, AB, Canada
| | - Aaron D. Beattie
- Department of Plant Sciences, College of Agriculture and Bioresources, University of Saskatchewan, Saskatoon, SK, Canada
| | - Ludovic J.A. Capo-chichi
- Department of Renewable Resources, Faculty of Agriculture, Life and Environmental Sciences, University of Alberta, Edmonton, AB, Canada
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Banerjee P, Rosales JE, Chau K, Nguyen MTH, Kotla S, Lin SH, Deswal A, Dantzer R, Olmsted-Davis EA, Nguyen H, Wang G, Cooke JP, Abe JI, Le NT. Possible molecular mechanisms underlying the development of atherosclerosis in cancer survivors. Front Cardiovasc Med 2023; 10:1186679. [PMID: 37332576 PMCID: PMC10272458 DOI: 10.3389/fcvm.2023.1186679] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/17/2023] [Indexed: 06/20/2023] Open
Abstract
Cancer survivors undergone treatment face an increased risk of developing atherosclerotic cardiovascular disease (CVD), yet the underlying mechanisms remain elusive. Recent studies have revealed that chemotherapy can drive senescent cancer cells to acquire a proliferative phenotype known as senescence-associated stemness (SAS). These SAS cells exhibit enhanced growth and resistance to cancer treatment, thereby contributing to disease progression. Endothelial cell (EC) senescence has been implicated in atherosclerosis and cancer, including among cancer survivors. Treatment modalities for cancer can induce EC senescence, leading to the development of SAS phenotype and subsequent atherosclerosis in cancer survivors. Consequently, targeting senescent ECs displaying the SAS phenotype hold promise as a therapeutic approach for managing atherosclerotic CVD in this population. This review aims to provide a mechanistic understanding of SAS induction in ECs and its contribution to atherosclerosis among cancer survivors. We delve into the mechanisms underlying EC senescence in response to disturbed flow and ionizing radiation, which play pivotal role in atherosclerosis and cancer. Key pathways, including p90RSK/TERF2IP, TGFβR1/SMAD, and BH4 signaling are explored as potential targets for cancer treatment. By comprehending the similarities and distinctions between different types of senescence and the associated pathways, we can pave the way for targeted interventions aim at enhancing the cardiovascular health of this vulnerable population. The insights gained from this review may facilitate the development of novel therapeutic strategies for managing atherosclerotic CVD in cancer survivors.
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Affiliation(s)
- Priyanka Banerjee
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Julia Enterría Rosales
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- School of Medicine, Instituto Tecnológico de Monterrey, Guadalajara, Mexico
| | - Khanh Chau
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Minh T. H. Nguyen
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
- Department of Life Science, University of Science and Technology of Hanoi, Vietnam Academy of Science and Technology, Hanoi, Vietnam
| | - Sivareddy Kotla
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Steven H. Lin
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Anita Deswal
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Robert Dantzer
- Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Elizabeth A. Olmsted-Davis
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Hung Nguyen
- Cancer Division, Burnett School of Biomedical Science, College of Medicine, University of Central Florida, Orlando, FL, United States
| | - Guangyu Wang
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - John P. Cooke
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
| | - Jun-ichi Abe
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Nhat-Tu Le
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, United States
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Shimada H, Tanaka K. Rice SUMOs and unification of their names. Genes Genet Syst 2023. [PMID: 37150617 DOI: 10.1266/ggs.22-00097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2023] Open
Abstract
Posttranslational modifications (PTMs) to proteins are regulatory mechanisms that play a critical role in regulating growth and development. The SUMO system is a rapid and dynamic PTM system employed by eukaryotic cells. Plant SUMOs are involved in many physiological processes, such as stress responses, regulation of flowering time and defense reactions to pathogen attack. In Arabidopsis thaliana and rice (Oryza sativa), eight and seven SUMO genes, respectively, were predicted by sequence analysis. Phylogenetic tree analysis of these SUMOs shows that they are divided into two groups. One consists of SUMOs that contain no SUMO acceptor site and are involved in monoSUMOylation of their target proteins. Rice OsSUMO1 and OsSUMO2 are in this group, and are structurally similar to each other and to Arabidopsis AtSUMO1. The other group is composed of SUMOs in which an acceptor site (ΨKXE/D) occurs inside the SUMO molecule, suggesting their involvement in polySUMOylation. Several studies on the rice SUMOs have been performed independently and reported. Individual names of rice SUMOs are confusing, because a unified nomenclature has not been proposed. This review clarifies the attribution of seven rice SUMOs and unifies the individual SUMO names.
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Affiliation(s)
- Hiroaki Shimada
- Department of Biological Science and Technology, Tokyo University of Science
| | - Katsunori Tanaka
- Department of Biosciences, School of Biological and Environmental Sciences, Kwansei Gakuin University
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Chen S, Fu X, Wang R, Li M, Yan X, Yue Z, Chen SW, Dong M, Xu A, Huang S. SUMO and PIAS repress NF-κB activation in a basal chordate. FISH & SHELLFISH IMMUNOLOGY 2023; 137:108754. [PMID: 37088348 DOI: 10.1016/j.fsi.2023.108754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 03/09/2023] [Accepted: 04/18/2023] [Indexed: 05/03/2023]
Abstract
Small ubiquitin-like modifier (SUMO) regulates various biological processes, including the MyD88/TICAMs-IRAKs-TRAF6-NF-κB pathway, one of the core immune pathways. However, its functions are inconsistent between invertebrates and vertebrates and have rarely been investigated in lower chordates, including amphioxus and fishes. Here, we investigated the SUMOylation gene system in the amphioxus, a living basal chordate. We found that amphioxus has a SUMOylation system that has a complete set of genes and preserves several ancestral traits. We proceeded to study their molecular functions using the mammal cell lines. Both amphioxus SUMO1 and SUMO2 were shown to be able to attach to NF-κB Rel and to inhibit NF-κB activation by 50-75% in a dose-dependent fashion. The inhibition by SUMO2 could be further enhanced by the addition of the SUMO E2 ligase UBC9. In comparison, while human SUMO2 inhibited RelA, human SUMO1 slightly activated RelA. We also showed that, similar to human PIAS1-4, amphioxus PIAS could serve as a SUMO E3 ligase and promote its self-SUMOylation. This suggests that amphioxus PIAS is functionally compatible in human cells. Moreover, we showed that amphioxus PIAS is not only able to inhibit NF-κB activation induced by MyD88, TICAM-like, TRAF6 and IRAK4 but also able to suppress NF-κB Rel completely in the presence of SUMO1/2 in a dose-insensitive manner. This suggests that PIAS could effectively block Rel by promoting Rel SUMOylation. In comparison, in humans, only PIAS3, but not PIAS1/2/4, has been reported to promote NF-κB SUMOylation. Taken together, the findings from amphioxus, together with those from mammals and other species, not only offer insights into the functional volatility of the animal SUMO system, but also shed light on its evolutionary transitions from amphioxus to fish, and ultimately to humans.
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Affiliation(s)
- Shenghui Chen
- Guangdong Key Laboratory of Pharmaceutical Functional Genes, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangdong, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Xianan Fu
- Guangdong Key Laboratory of Pharmaceutical Functional Genes, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangdong, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; Center for Evolution and Conservation Biology, Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China
| | - Ruihua Wang
- Guangdong Key Laboratory of Pharmaceutical Functional Genes, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangdong, China; Center for Regenerative and Translational Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510632, China
| | - Mingshi Li
- Guangdong Key Laboratory of Pharmaceutical Functional Genes, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangdong, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Xinyu Yan
- Guangdong Key Laboratory of Pharmaceutical Functional Genes, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangdong, China
| | - Zirui Yue
- Guangdong Key Laboratory of Pharmaceutical Functional Genes, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangdong, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Shang-Wu Chen
- Guangdong Key Laboratory of Pharmaceutical Functional Genes, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangdong, China
| | - Meiling Dong
- Guangdong Key Laboratory of Pharmaceutical Functional Genes, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangdong, China
| | - Anlong Xu
- Guangdong Key Laboratory of Pharmaceutical Functional Genes, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangdong, China; Beijing University of Chinese Medicine, Dong San Huang Road, Chao-yang District, Beijing, 100029, China
| | - Shengfeng Huang
- Guangdong Key Laboratory of Pharmaceutical Functional Genes, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangdong, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
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Morehouse BR. Phage defense origin of animal immunity. Curr Opin Microbiol 2023; 73:102295. [PMID: 37011504 DOI: 10.1016/j.mib.2023.102295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 02/17/2023] [Accepted: 02/22/2023] [Indexed: 04/05/2023]
Abstract
The innate immune system is the first line of defense against microbial pathogens. Many of the features of eukaryotic innate immunity have long been viewed as lineage-specific innovations, evolved to deal with the challenges and peculiarities of multicellular life. However, it has become increasingly apparent that in addition to evolving their own unique antiviral immune strategies, all lifeforms have some shared defense strategies in common. Indeed, critical fixtures of animal innate immunity bear striking resemblance in both structure and function to the multitude of diverse bacteriophage (phage) defense pathways discovered hidden in plain sight within the genomes of bacteria and archaea. This review will highlight many surprising examples of the recently revealed connections between prokaryotic and eukaryotic antiviral immune systems.
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Affiliation(s)
- Benjamin R Morehouse
- Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California Irvine, Irvine, CA 92697, USA.
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Du L, Liu W, Rosen ST, Chen Y. Mechanism of SUMOylation-Mediated Regulation of Type I IFN Expression. J Mol Biol 2023; 435:167968. [PMID: 36681180 DOI: 10.1016/j.jmb.2023.167968] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 01/07/2023] [Accepted: 01/11/2023] [Indexed: 01/20/2023]
Abstract
Type I interferons (IFN) are cytokines that bridge the innate and adaptive immune response, and thus play central roles in human health, including vaccine efficacy, immune response to cancer and pathogen infection, and autoimmune disorders. Post-translational protein modifications by the small ubiquitin-like modifiers (SUMO) have recently emerged as an important regulator of type I IFN expression as shown by studies using murine and cellular models and recent human clinical trials. However, the mechanism regarding how SUMOylation regulates type I IFN expression remains poorly understood. In this study, we show that SUMOylation inhibition does not activate IFNB1 gene promoter that is regulated by known canonical pathways including cytosolic DNA. Instead, we identified a binding site for the chromatin modification enzyme, the SET Domain Bifurcated Histone Lysine Methyltransferase 1 (SETDB1), located between the IFNB1 promoter and a previously identified enhancer. We found that SETDB1 regulates IFNB1 expression and SUMOylation of SETDB1 is required for its binding and enhancing the H3K9me3 heterochromatin signal in this region. Heterochromatin, a tightly packed form of DNA, has been documented to suppress gene expression through suppressing enhancer function. Taken together, our study identified a novel mechanism of regulation of type I IFN expression, at least in part, through SUMOylation of a chromatin modification enzyme.
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Affiliation(s)
- Li Du
- Toni Stephenson Lymphoma Center, Beckman Research Institute of City of Hope, Duarte, CA, USA; Judy and Bernard Briskin Center for Multiple Myeloma Research, Beckman Research Institute of City of Hope, Duarte, CA, USA; Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Wei Liu
- Toni Stephenson Lymphoma Center, Beckman Research Institute of City of Hope, Duarte, CA, USA; Department of Hematology, Xiangya Hospital, Central South University, Changsha, China
| | - Steven T Rosen
- Toni Stephenson Lymphoma Center, Beckman Research Institute of City of Hope, Duarte, CA, USA; Judy and Bernard Briskin Center for Multiple Myeloma Research, Beckman Research Institute of City of Hope, Duarte, CA, USA; Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA, USA; City of Hope Comprehensive Cancer Center, City of Hope National Medical Center, Duarte, CA, USA.
| | - Yuan Chen
- Division of Surgical Sciences, Department of Surgery and Moores Cancer Center, UC San Diego Health, San Diego, CA, USA.
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Sun W, Lei X, Lu Q, Wu Q, Ma Q, Huang D, Zhang Y. LncRNA FRMD6-AS1 promotes hepatocellular carcinoma cell migration and stemness by regulating SENP1/HIF-1α axis. Pathol Res Pract 2023; 243:154377. [PMID: 36827886 DOI: 10.1016/j.prp.2023.154377] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/07/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023]
Abstract
BACKGROUND Long non-cording RNAs (lncRNAs) drive the malignant progression of hepatocellular carcinoma (HCC), a cancer with high mortality rates but the function of FERM Domain Containing 6 antisense RNA 1 (FRMD6-AS1) in HCC has not been fully addressed. Hypoxia-inducible factors (HIFs) are transcription factors relevant to HCC under hypoxia and are regulated by SUMO-specific protease 1 (SENP1) through its deSUMOylation of HIF-1α. The current study investigated the role of FRMD6-AS1 in the regulation of SENP1-mediated deSUMOylation of HIF-1α. METHODS HUH7 and MHCC97H cells were treated with CoCl2 to mimic hypoxia in vitro and lentiviral vector-mediated FRMD6-AS1 overexpressing HCC cells were established. Wound-healing, Transwell, sphere formation assay, Western blotting analysis and animal experiments were performed. Expression of FRMD6-AS1, SENP1 mRNA and HIF-1α mRNA was assessed by RT-qPCR and of HIF-1α and SENP1 protein by Western blot. DeSUMOylation of HIF-1α was detected by immunoprecipitation. RNA immunoprecipitation with SENP1 antibody or IgG was performed to assess endogenous interactions between SENP1 and FRMD6-AS1. RESULTS FRMD6-AS1 was upregulated in HCC tissues and cells and its upregulation indicated poor prognosis for HCC patients. FRMD6-AS1 promoted HCC cells migration and stemness in vitro and also promoted tumor growth in an in vivo mouse xenograft model. Mechanistic studies showed that FRMD6-AS1 regulated the level of HIF-1α protein but not the mRNA and this effect was achieved by binding to SENP1 protein and enhancing its protease activity. Rescue experiments demonstrated the oncogenic role of the FRMD6-AS1/SENP1/ HIF-1α axis in HCC cells. CONCLUSIONS High FRMD6-AS1 expression was associated with poor prognosis of HCC patients. FRMD6-AS1 may have an oncogenic role in HCC via regulation of the SENP1/HIF-1α axis and may be a prognostic biomarker for HCC. Blockade of FRMD6-AS1 may offer a novel therapeutic approach to restrict HCC progression.
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Affiliation(s)
- Wen Sun
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310014, China
| | - Xiangxiang Lei
- School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou 310053, China
| | - Qiliang Lu
- Qingdao medical college, Qingdao university, Qingdao 266000, China
| | - Qingsong Wu
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310014, China
| | - Qiancheng Ma
- College of Bioscience Engineering, Zhejiang University of Technology, Hangzhou 310014, China
| | - Dongsheng Huang
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, No. 8, Yikang Street, Lin'an District, Hangzhou 310014, China.
| | - Yaping Zhang
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, No. 8, Yikang Street, Lin'an District, Hangzhou 310014, China.
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Zhu S, Hou J, Gao H, Hu Q, Kloeber JA, Huang J, Zhao F, Zhou Q, Luo K, Wu Z, Tu X, Yin P, Lou Z. SUMOylation of HNRNPA2B1 modulates RPA dynamics during unperturbed replication and genotoxic stress responses. Mol Cell 2023; 83:539-555.e7. [PMID: 36702126 PMCID: PMC9975078 DOI: 10.1016/j.molcel.2023.01.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 11/17/2022] [Accepted: 01/03/2023] [Indexed: 01/26/2023]
Abstract
Replication protein A (RPA) is a major regulator of eukaryotic DNA metabolism involved in multiple essential cellular processes. Maintaining appropriate RPA dynamics is crucial for cells to prevent RPA exhaustion, which can lead to replication fork breakage and replication catastrophe. However, how cells regulate RPA availability during unperturbed replication and in response to stress has not been well elucidated. Here, we show that HNRNPA2B1SUMO functions as an endogenous inhibitor of RPA during normal replication. HNRNPA2B1SUMO associates with RPA through recognizing the SUMO-interacting motif (SIM) of RPA to inhibit RPA accumulation at replication forks and impede local ATR activation. Declining HNRNPA2SUMO induced by DNA damage will release nuclear soluble RPA to localize to chromatin and enable ATR activation. Furthermore, we characterize that HNRNPA2B1 hinders homologous recombination (HR) repair via limiting RPA availability, thus conferring sensitivity to PARP inhibitors. These findings establish HNRNPA2B1 as a critical player in RPA-dependent surveillance networks.
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Affiliation(s)
- Shouhai Zhu
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Jing Hou
- Department of Breast Surgery, Guizhou Provincial People's Hospital, Guiyang, Guizhou 550002, China
| | - Huanyao Gao
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Qi Hu
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
| | - Jake A Kloeber
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA; Mayo Clinic Medical Scientist Training Program, Mayo Clinic, Rochester, MN 55905, USA
| | - Jinzhou Huang
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Fei Zhao
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Qin Zhou
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Kuntian Luo
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Zheming Wu
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Xinyi Tu
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Ping Yin
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA
| | - Zhenkun Lou
- Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
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50
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Wang W, Lu J, Yang WC, Spear ED, Michaelis S, Matunis MJ. Analysis of a degron-containing reporter protein GFP-CL1 reveals a role for SUMO1 in cytosolic protein quality control. J Biol Chem 2023; 299:102851. [PMID: 36587767 PMCID: PMC9898758 DOI: 10.1016/j.jbc.2022.102851] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 12/30/2022] Open
Abstract
Misfolded proteins are recognized and degraded through protein quality control (PQC) pathways, which are essential for maintaining proteostasis and normal cellular functions. Defects in PQC can result in disease, including cancer, cardiovascular disease, and neurodegeneration. The small ubiquitin-related modifiers (SUMOs) were previously implicated in the degradation of nuclear misfolded proteins, but their functions in cytoplasmic PQC are unclear. Here, in a systematic screen of SUMO protein mutations in the budding yeast Saccharomyces cerevisiae, we identified a mutant allele (Smt3-K38A/K40A) that sensitizes cells to proteotoxic stress induced by amino acid analogs. Smt3-K38A/K40A mutant strains also exhibited a defect in the turnover of a soluble PQC model substrate containing the CL1 degron (NES-GFP-Ura3-CL1) localized in the cytoplasm, but not the nucleus. Using human U2OS SUMO1- and SUMO2-KO cell lines, we observed a similar SUMO-dependent pathway for degradation of the mammalian degron-containing PQC reporter protein, GFP-CL1, also only in the cytoplasm but not the nucleus. Moreover, we found that turnover of GFP-CL1 in the cytoplasm was uniquely dependent on SUMO1 but not the SUMO2 paralogue. Additionally, we showed that turnover of GFP-CL1 in the cytoplasm is dependent on the AAA-ATPase, Cdc48/p97. Cellular fractionation studies and analysis of a SUMO1-GFP-CL1 fusion protein revealed that SUMO1 promotes cytoplasmic misfolded protein degradation by maintaining substrate solubility. Collectively, our findings reveal a conserved and previously unrecognized role for SUMO1 in regulating cytoplasmic PQC and provide valuable insights into the roles of sumoylation in PQC-associated diseases.
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Affiliation(s)
- Wei Wang
- Department of Biochemistry and Molecular Biology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Jian Lu
- Department of Biochemistry and Molecular Biology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Wei-Chih Yang
- Department of Biochemistry and Molecular Biology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Eric D Spear
- Department of Cell Biology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA
| | - Susan Michaelis
- Department of Cell Biology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA
| | - Michael J Matunis
- Department of Biochemistry and Molecular Biology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA.
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