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Ding J, Liu Z, Liu S, Xie X, Yin Q, Lu W, Wang W, Zhang Y. Preparation and anti-tumor ability evaluation of anti-PD-L1 conjugated curcumin in colon cancer. Int J Biol Macromol 2025; 306:141563. [PMID: 40037453 DOI: 10.1016/j.ijbiomac.2025.141563] [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: 08/30/2024] [Revised: 02/22/2025] [Accepted: 02/25/2025] [Indexed: 03/06/2025]
Abstract
Immune checkpoint inhibitors have been approved for various solid tumor treatments but have shown poor efficacy on colon cancer. Curcumin has been proven as an anti-tumor agent that inhibits cell cycle and tumor cell proliferation. Moreover, curcumin has also been reported to have the ability to inhibit PD-L1 expression, which might benefit the therapeutic efficacy of immune checkpoint inhibitors. Therefore, we proposed using antibody-drug conjugate (ADC) could effectively inhibit tumor proliferation and reverse the immunosuppression in colon cancer. We prepared an anti-PD-L1 conjugated curcumin with a ROS-responsive linker of phenylboronic acid carbamate, which provides chemo-drug active targeting ability and tumor environment-responsive release. Both in vitro and in vivo data confirm the improved cytotoxicity of anti-PD-L1-PBA-Cur and inhibited cell invasion. More importantly, the PD-L1 expression on the tumor surface was significantly reduced after being treated with ADC. The in vivo inhibition of tumor progression and PD-L1 expression was confirmed in both subcutaneous and in-suit mouse models. This study provides an effective colon treatment strategy with the advantages of high tumor targeting efficiency and immunopotentiation potential.
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Affiliation(s)
- Jie Ding
- Department of Gastrointestinal Surgery, Guizhou Provincial People's Hospital, Guiyang 550002, China; NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang 550002, China; School of Medicine, Guizhou University, Guiyang 550002, China.
| | - Zhenhua Liu
- Department of Hepatobiliary Surgery, Guizhou Provincial People's Hospital, Guiyang 550002, China
| | - Sheng Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha 550002, China
| | - Xueqing Xie
- Department of Gastrointestinal Surgery, Guizhou Provincial People's Hospital, Guiyang 550002, China; NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang 550002, China
| | - Qingling Yin
- Department of Gastrointestinal Surgery, Guizhou Provincial People's Hospital, Guiyang 550002, China; NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang 550002, China
| | - Wei Lu
- Zunyi Medical University, Zunyi 563000, China
| | - Wanchuan Wang
- Department of Anus and Intestine Surgery, The Six Affilated Hospital, School of Medicine, South China University of Technology, Foshan 528200, China.
| | - Yi Zhang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, China; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Dongre P, Ramesh M, Govindaraju T, Inamdar MS. Asrij/OCIAD1 depletion reduces inflammatory microglial activation and ameliorates Aβ pathology in an Alzheimer's disease mouse model. J Neuroinflammation 2025; 22:89. [PMID: 40114191 PMCID: PMC11924864 DOI: 10.1186/s12974-025-03415-5] [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: 01/19/2025] [Accepted: 03/10/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles, neuroinflammation, and glial activation. Asrij/OCIAD1 (Ovarian Carcinoma Immunoreactive Antigen Domain containing protein 1) is an AD-associated factor. Increased Asrij levels in the brains of AD patients and mouse models are linked to the severity of neurodegeneration. However, the contribution of Asrij to AD progression and whether reducing Asrij levels is sufficient to mitigate Aβ pathology in vivo is unclear. METHODS To explore the impact of Asrij on AD pathology, we deleted asrij in the APP/PS1 mouse model of AD and analyzed the effects on AD hallmarks. We used the Morris water maze and open field test to assess behavioral performance. Using immunohistochemistry and biochemical analyses, we evaluated Aβ plaque load, neuronal and synaptic damage, and gliosis. Further, we utilized confocal microscopy imaging, flow cytometry, and RNA sequencing analysis to comprehensively investigate changes in microglial responses to Aβ pathology upon Asrij depletion. RESULTS Asrij depletion ameliorates cognitive impairments, Aβ deposition, neuronal and synaptic damage, and reactive astrogliosis in the AD mouse. Notably, Asrij-deficient microglia exhibit reduced plaque-associated proliferation and decreased phagocytic activation. Transcriptomic analyses of AD microglia reveal upregulation of energy metabolism pathways and downregulation of innate immunity and inflammatory pathways upon Asrij depletion. Mechanistically, loss of Asrij increases mitochondrial activity and impedes the acquisition of a pro-inflammatory disease-associated microglia (DAM) state. Reduced levels of proinflammatory cytokines and decreased STAT3 and NF-κB activation indicate protective changes in AD microglia. Taken together, our results suggest that increased Asrij levels reported in AD, may suppress microglial metabolic activity and promote inflammatory microglial activation, thereby exacerbating AD pathology. CONCLUSIONS In summary, we show that Asrij depletion ameliorates Aβ pathology, neuronal and synaptic damage, gliosis, and improves behavioral performance in APP/PS1 mice. This supports that Asrij exacerbates the AD pathology. Mechanistically, Asrij is critical for the development of DAM and promotes neuroinflammatory signaling activation in microglia, thus restricting neuroprotective microglial responses. Hence, reducing Asrij in this context may help retard AD. Our work positions Asrij as a critical molecular regulator that links microglial dysfunction to AD pathogenesis.
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Affiliation(s)
- Prathamesh Dongre
- Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bangalore, Karnataka, 560064, India
| | - Madhu Ramesh
- Bioorganic Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bangalore, Karnataka, 560064, India
| | - Thimmaiah Govindaraju
- Bioorganic Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bangalore, Karnataka, 560064, India.
| | - Maneesha S Inamdar
- Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bangalore, Karnataka, 560064, India.
- Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore, Karnataka, 560065, India.
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Yin YF, Jia QY, Yao HF, Zhu YH, Zheng JH, Duan ZH, Hu CY, Sun YW, Liu DJ, Huo YM, Liu W. OCIAD2 promotes pancreatic cancer progression through the AKT signaling pathway. Gene 2024; 927:148735. [PMID: 38944166 DOI: 10.1016/j.gene.2024.148735] [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: 11/29/2023] [Revised: 05/18/2024] [Accepted: 06/11/2024] [Indexed: 07/01/2024]
Abstract
BACKGROUND OCIAD2（Ovarian carcinoma immunoreactive antigen-like protein 2） is a protein reported in various cancers. However, the role of OCIAD2 has not been explored in pan-cancer datasets. The purpose of this research lies in analyzing the expression level and prognostic-related value of OCIAD2 in different human cancers, as well as revealing the underlying mechanism in specific cancer type (pancreatic adenocarcinoma, PAAD). METHODS The correlation between OCIAD2 expression level and clinical relevance in different human cancers was investigated from bioinformatical perspective (GTEx and TCGA). The OCIAD2 expression level and clinical significance in PAAD were explored in GEO datasets and tissue microarray. Functional experiments were used to determine the OCIAD2 cell functions in vitro and in vivo. GSEA, western blot and immunohistochemistry were used to uncover the potential mechanism. RESULTS OCIAD2 expression level was closely correlated with clinical relevance in many cancer types through pan-cancer analysis, and we found OCIAD2 was highly expressed in PAAD and associated with poorer prognosis. OCIAD2 acted as the promotor of Warburg effect and influenced PAAD cells proliferation, migration and apoptosis. Mechanistically, OCIAD2 upregulation may boost glycolysis in PAAD via activating the AKT signaling pathway in PAAD. CONCLUSIONS In PAAD, OCIAD2 promotes Warburg effect via AKT signaling pathway and targeting cancer cells metabolic reprogramming could be a potential treatment.
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Affiliation(s)
- Yi-Fan Yin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, PR China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Qin-Yuan Jia
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, PR China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Hong-Fei Yao
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, PR China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Yu-Heng Zhu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, PR China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Jia-Hao Zheng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, PR China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Zong-Hao Duan
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, PR China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Cheng-Yu Hu
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Yong-Wei Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, PR China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - De-Jun Liu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, PR China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China.
| | - Yan-Miao Huo
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, PR China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China.
| | - Wei Liu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, PR China; Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China.
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Xie P, Wu M, Wang H, Zhang B, Zhang Z, Yan J, Yu M, Yu Q, Zhao Y, Huang D, Xu M, Xu W, Li H, Xu Y, Xiao Y, Guo L. GOLM1 dictates acquired Lenvatinib resistance by a GOLM1-CSN5 positive feedback loop upon EGFR signaling activation in hepatocellular carcinoma. Oncogene 2024; 43:3108-3120. [PMID: 39251847 DOI: 10.1038/s41388-024-03153-7] [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: 02/24/2024] [Revised: 08/24/2024] [Accepted: 09/02/2024] [Indexed: 09/11/2024]
Abstract
Lenvatinib is a multiple receptor tyrosine kinases inhibitor (TKI) authorized for first-line treatment of hepatocellular carcinoma (HCC). However, Lenvatinib resistance is common in HCC clinical treatment, highlighting the urgent need to understand mechanisms of resistance. Here, we identified Golgi membrane protein 1 (GOLM1), a type II transmembrane protein originally located in the Golgi apparatus, as a novel regulator of Lenvatinib resistance. We found GOLM1 was overexpressed in Lenvatinib resistant human HCC cell lines, blood and HCC samples. Additionally, GOLM1 overexpression contributes to Lenvatinib resistance and HCC progression in vitro and in vivo. Mechanistically, GOLM1 upregulates CSN5 expression through EGFR-STAT3 pathway. Reversely, CSN5 deubiquitinates and stabilizes GOLM1 protein by inhibiting ubiquitin-proteasome pathway of GOLM1. Furthermore, clinical specimens of HCC showed a positive correlation between the activation of the GOLM1-EGFR-STAT3-CSN5 axis. Finally, GOLM1 knockdown was found to act in synergy with Lenvatinib in subcutaneous and orthotopic mouse model. Overall, these findings identify a mechanism of resistance to Lenvatinib treatment for HCC, highlight an effective predictive biomarker of Lenvatinib response in HCC and show that targeting GOLM1 may improve the clinical benefit of Lenvatinib.
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Affiliation(s)
- Peiyi Xie
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China
| | - Mengyuan Wu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China
| | - Hui Wang
- Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, PR China
| | - Bo Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China
| | - Zihao Zhang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China
| | - Jiuliang Yan
- Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, PR China
| | - Mincheng Yu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China
| | - Qiang Yu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China
| | - Yufei Zhao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China
| | - Da Huang
- Department of Thyroid Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, PR China
| | - Min Xu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China
| | - Wenxin Xu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China
| | - Hui Li
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China.
- Shanghai Medical College and Zhongshan Hospital Immunotherapy Technology Translational Research Center, Shanghai, 200031, PR China.
| | - Yongfeng Xu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China.
| | - Yongsheng Xiao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China.
| | - Lei Guo
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China.
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Feng Z, Liu S, Su M, Song C, Lin C, Zhao F, Li Y, Zeng X, Zhu Y, Hou Y, Ren C, Zhang H, Yi P, Ji Y, Wang C, Li H, Ma M, Luo L, Li L. TANGO6 regulates cell proliferation via COPI vesicle-mediated RPB2 nuclear entry. Nat Commun 2024; 15:2371. [PMID: 38490996 PMCID: PMC10943085 DOI: 10.1038/s41467-024-46720-y] [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: 11/02/2022] [Accepted: 03/01/2024] [Indexed: 03/18/2024] Open
Abstract
Coat protein complex I (COPI) vesicles mediate the retrograde transfer of cargo between Golgi cisternae and from the Golgi to the endoplasmic reticulum (ER). However, their roles in the cell cycle and proliferation are unclear. This study shows that TANGO6 associates with COPI vesicles via two transmembrane domains. The TANGO6 N- and C-terminal cytoplasmic fragments capture RNA polymerase II subunit B (RPB) 2 in the cis-Golgi during the G1 phase. COPI-docked TANGO6 carries RPB2 to the ER and then to the nucleus. Functional disruption of TANGO6 hinders the nuclear entry of RPB2, which accumulates in the cytoplasm, causing cell cycle arrest in the G1 phase. The conditional depletion or overexpression of TANGO6 in mouse hematopoietic stem cells results in compromised or expanded hematopoiesis. Our study results demonstrate that COPI vesicle-associated TANGO6 plays a role in the regulation of cell cycle progression by directing the nuclear transfer of RPB2, making it a potential target for promoting or arresting cell expansion.
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Affiliation(s)
- Zhi Feng
- Research center of Stem cells and Ageing, Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, 400714, PR China
| | - Shengnan Liu
- Institute of Developmental Biology and Regenerative Medicine, Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Southwest University, Chongqing, 400715, PR China
| | - Ming Su
- Research center of Stem cells and Ageing, Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, 400714, PR China
| | - Chunyu Song
- Institute of Developmental Biology and Regenerative Medicine, Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Southwest University, Chongqing, 400715, PR China
| | - Chenyu Lin
- Institute of Developmental Biology and Regenerative Medicine, Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Southwest University, Chongqing, 400715, PR China
| | - Fangying Zhao
- Institute of Developmental Biology and Regenerative Medicine, Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Southwest University, Chongqing, 400715, PR China
| | - Yang Li
- Research center of Stem cells and Ageing, Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, 400714, PR China
| | - Xianyan Zeng
- Institute of Life Sciences, Laboratory of Developmental Biology, Department of Cell Biology and Genetics, Chongqing Medical University, Chongqing, 400016, PR China
| | - Yong Zhu
- Institute of Life Sciences, Laboratory of Developmental Biology, Department of Cell Biology and Genetics, Chongqing Medical University, Chongqing, 400016, PR China
| | - Yu Hou
- Institute of Life Sciences, Laboratory of Developmental Biology, Department of Cell Biology and Genetics, Chongqing Medical University, Chongqing, 400016, PR China
| | - Chunguang Ren
- Institute of Life Sciences, Laboratory of Developmental Biology, Department of Cell Biology and Genetics, Chongqing Medical University, Chongqing, 400016, PR China
| | - Huan Zhang
- Institute of Life Sciences, Laboratory of Developmental Biology, Department of Cell Biology and Genetics, Chongqing Medical University, Chongqing, 400016, PR China
| | - Ping Yi
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, PR China
| | - Yong Ji
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine; Key Laboratory of Targeted Intervention of Cardiovascular Disease; Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, 211166, PR China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150076, Heilongjiang, PR China
| | - Chao Wang
- MOE Key Laboratory for Membraneless Organelles & Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, PR China
| | - Hongtao Li
- Institute of Developmental Biology and Regenerative Medicine, Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Southwest University, Chongqing, 400715, PR China
| | - Ming Ma
- Institute of Developmental Biology and Regenerative Medicine, Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Southwest University, Chongqing, 400715, PR China
| | - Lingfei Luo
- Institute of Developmental Biology and Regenerative Medicine, Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Southwest University, Chongqing, 400715, PR China.
| | - Li Li
- Research center of Stem cells and Ageing, Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, 400714, PR China.
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Wu J, Ma L, Gong Q, Chen Y, Chen L, Shi C. NEAR-INFRARED DYE IR-780 ALLEVIATES HEMATOPOIETIC SYSTEM DAMAGE BY PROMOTING HEMATOPOIETIC STEM CELLS INTO QUIESCENCE. Shock 2024; 61:442-453. [PMID: 38411611 DOI: 10.1097/shk.0000000000002317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2024]
Abstract
ABSTRACT Potential radiation exposure is a general concern, but there still lacks radioprotective countermeasures. Here, we found a small molecular near-infrared dye IR-780, which promoted hematopoietic stem cells (HSCs) into quiescence to resist stress. When mice were treated with IR-780 before stress, increased HSC quiescence and better hematopoietic recovery were observed in mice in stress conditions. However, when given after radiation, IR-780 did not show obvious benefit. Transplantation assay and colony-forming assay were carried out to determine self-renewal ability and repopulation capacity of HSCs. Furthermore, IR-780 pretreatment reduced the generation of reactive oxygen species (ROS) and DNA damage in HSCs after radiation. In homeostasis, the percentage of Lineage - , Sca-1 + , and c-Kit + cells and long-term HSCs (LT-HSCs) were improved, and more HSCs were in G0 state after administration of IR-780. Further investigations showed that IR-780 selectively accumulated in mitochondria membrane potential high LT-HSCs (MMP-high LT-HSCs). Finally, IR-780 promoted human CD34 + HSC reconstruction ability in NOD-Prkdc scid Il2rg null mice after transplantation and improved repopulation capacity in vitro culture. Our research showed that IR-780 selectively entered MMP-high LT-HSCs and promoted them into dormancy, thus reducing hematopoietic injury and improving regeneration capacity. This novel approach might hold promise as a potential countermeasure for radiation injury.
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Affiliation(s)
- Jie Wu
- Institute of Rocket Force Medicine, State Key of Trauma and Chemical Poisoning Third Military Medical University (Army Medical University), Chongqing, China
| | - Le Ma
- Institute of Rocket Force Medicine, State Key of Trauma and Chemical Poisoning Third Military Medical University (Army Medical University), Chongqing, China
| | - Qiang Gong
- Department of Hematology, Southwest Hospital, First Affiliated Hospital of the Army Medical University, Chongqing, China
| | - Yan Chen
- Institute of Rocket Force Medicine, State Key of Trauma and Chemical Poisoning Third Military Medical University (Army Medical University), Chongqing, China
| | - Long Chen
- Institute of Rocket Force Medicine, State Key of Trauma and Chemical Poisoning Third Military Medical University (Army Medical University), Chongqing, China
| | - Chunmeng Shi
- Institute of Rocket Force Medicine, State Key of Trauma and Chemical Poisoning Third Military Medical University (Army Medical University), Chongqing, China
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Lu Y, Yang L, Shen M, Zhang Z, Wang S, Chen F, Chen N, Xu Y, Zeng H, Chen M, Chen S, Wang F, Hu M, Wang J. Tespa1 facilitates hematopoietic and leukemic stem cell maintenance by restricting c-Myc degradation. Leukemia 2023; 37:1039-1047. [PMID: 36997676 PMCID: PMC10169665 DOI: 10.1038/s41375-023-01880-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 03/13/2023] [Accepted: 03/16/2023] [Indexed: 05/11/2023]
Abstract
Hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) have robust self-renewal potential, which is responsible for sustaining normal and malignant hematopoiesis, respectively. Although considerable efforts have been made to explore the regulation of HSC and LSC maintenance, the underlying molecular mechanism remains obscure. Here, we observe that the expression of thymocyte-expressed, positive selection-associated 1 (Tespa1) is markedly increased in HSCs after stresses exposure. Of note, deletion of Tespa1 results in short-term expansion but long-term exhaustion of HSCs in mice under stress conditions due to impaired quiescence. Mechanistically, Tespa1 can interact with CSN subunit 6 (CSN6), a subunit of COP9 signalosome, to prevent ubiquitination-mediated degradation of c-Myc protein in HSCs. As a consequence, forcing c-Myc expression improves the functional defect of Tespa1-null HSCs. On the other hand, Tespa1 is identified to be highly enriched in human acute myeloid leukemia (AML) cells and is essential for AML cell growth. Furthermore, using MLL-AF9-induced AML model, we find that Tespa1 deficiency suppresses leukemogenesis and LSC maintenance. In summary, our findings reveal the important role of Tespa1 in promoting HSC and LSC maintenance and therefore provide new insights on the feasibility of hematopoietic regeneration and AML treatment.
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Affiliation(s)
- Yukai Lu
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
- Frontier Medical Training Brigade, Third Military Medical University, Xinjiang, 831200, China
| | - Lijing Yang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Mingqiang Shen
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Zihao Zhang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Song Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Fang Chen
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Naicheng Chen
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Yang Xu
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Hao Zeng
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Mo Chen
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Shilei Chen
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Fengchao Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Mengjia Hu
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.
- Chinese PLA Center for Disease Control and Prevention, Beijing, 100071, China.
| | - Junping Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.
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8
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de Morree A, Rando TA. Regulation of adult stem cell quiescence and its functions in the maintenance of tissue integrity. Nat Rev Mol Cell Biol 2023; 24:334-354. [PMID: 36922629 PMCID: PMC10725182 DOI: 10.1038/s41580-022-00568-6] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2022] [Indexed: 03/18/2023]
Abstract
Adult stem cells are important for mammalian tissues, where they act as a cell reserve that supports normal tissue turnover and can mount a regenerative response following acute injuries. Quiescent stem cells are well established in certain tissues, such as skeletal muscle, brain, and bone marrow. The quiescent state is actively controlled and is essential for long-term maintenance of stem cell pools. In this Review, we discuss the importance of maintaining a functional pool of quiescent adult stem cells, including haematopoietic stem cells, skeletal muscle stem cells, neural stem cells, hair follicle stem cells, and mesenchymal stem cells such as fibro-adipogenic progenitors, to ensure tissue maintenance and repair. We discuss the molecular mechanisms that regulate the entry into, maintenance of, and exit from the quiescent state in mice. Recent studies revealed that quiescent stem cells have a discordance between RNA and protein levels, indicating the importance of post-transcriptional mechanisms, such as alternative polyadenylation, alternative splicing, and translation repression, in the control of stem cell quiescence. Understanding how these mechanisms guide stem cell function during homeostasis and regeneration has important implications for regenerative medicine.
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Affiliation(s)
- Antoine de Morree
- Department of Neurology and Neurological Science, Stanford University School of Medicine, Stanford, CA, USA.
- Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.
| | - Thomas A Rando
- Department of Neurology and Neurological Science, Stanford University School of Medicine, Stanford, CA, USA.
- Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA.
- Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
- Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA, USA.
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9
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Hu M, Chen N, Chen M, Chen F, Lu Y, Xu Y, Yang L, Zeng H, Shen M, Chen X, Chen S, Wang F, Wang S, Wang J. Transcription factor Nkx2-3 maintains the self-renewal of hematopoietic stem cells by regulating mitophagy. Leukemia 2023:10.1038/s41375-023-01907-y. [PMID: 37095209 DOI: 10.1038/s41375-023-01907-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 04/12/2023] [Accepted: 04/17/2023] [Indexed: 04/26/2023]
Abstract
Hematopoietic stem cells (HSCs) reside at the top of the hematopoietic hierarchy, exhibiting a unique capacity to self-renew and differentiate into all blood cells throughout the lifetime. However, how to prevent HSC exhaustion during long-term hematopoietic output is not fully understood. Here, we show that the homeobox transcription factor Nkx2-3 is required for HSC self-renewal by preserving metabolic fitness. We found that Nkx2-3 is preferentially expressed in HSCs with excessive regenerative potential. Mice with conditional deletion of Nkx2-3 displayed a reduced HSC pool and long-term repopulating capacity as well as increased sensitivity to irradiation and 5-flurouracil treatment due to impaired HSC quiescence. In contrast, overexpression of Nkx2-3 improved HSC function both in vitro and in vivo. Furthermore, mechanistic studies revealed that Nkx2-3 can directly control the transcription of the critical mitophagy regulator ULK1, which is essential for sustaining metabolic homeostasis in HSCs by clearing activated mitochondria. More importantly, a similar regulatory role of NKX2-3 was observed in human cord blood-derived HSCs. In conclusion, our data demonstrate an important role of the Nkx2-3/ULK1/mitophagy axis in regulating the self-renewal of HSCs, therefore providing a promising strategy to improve the function of HSCs in the clinic.
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Affiliation(s)
- Mengjia Hu
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
- Chinese PLA Center for Disease Control and Prevention, Beijing, 100071, China
| | - Naicheng Chen
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Mo Chen
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Fang Chen
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Yukai Lu
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Yang Xu
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Lijing Yang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Hao Zeng
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Mingqiang Shen
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Xuehong Chen
- Department of Obstetrics and Gynecology, Liangping District Maternal and Child Health Care Hospital, Chongqing, 405200, China
| | - Shilei Chen
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Fengchao Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China
| | - Song Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.
| | - Junping Wang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China.
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10
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Wang L, Zeng X, Yang G, Liu G, Pan Y. Pan-cancer analyses of Jab1/COPS5 reveal oncogenic role and clinical outcome in human cancer. Heliyon 2022; 8:e12553. [PMID: 36643321 PMCID: PMC9834752 DOI: 10.1016/j.heliyon.2022.e12553] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 11/30/2022] [Accepted: 12/15/2022] [Indexed: 12/25/2022] Open
Abstract
Jab1/COPS5 is associated with the progression of some cancers, however, its role in most cancers is still unclear.This study systematically explored the action and clinical application value of Jab1/COPS5 in different tumors based on large clinical data. We first identified by differential and survival analysis that Jab1/COPS5 was highly expressed as a high-risk gene in most cancers and was closely related to prognostic survival of patients based on the TCGA, GEO and CPTAC databases. Mutation analysis suggested that missense mutations were the main mutation type of Jab1. TMB and MSI were positively correlated with Jab1/COPS5 in most tumors, and patients with Jab1/COPS5 mutations had a poorer prognosis in prostate adenocarcinoma. By immune infiltration analysis, Jab1/COPS5 expression was positively correlated with the infiltration of CD8+ T cells in thymoma and uveal melanoma, and Jab1/COPS5 expression in testicular germ cell tumors was negatively correlated with the infiltration of cancer-associated fibroblasts. Correlation and enrichment analysis suggested that ARMC1, TCEB1 and UBE2V2 were positively correlated with Jab1/COPS5 expression and involved in multiple biological effects. In summary, this study systematically investigated the role of Jab1/COPS5 in different tumors, providing a theoretical basis for Jab1/COPS5 as a new biomarker in unresearched cancers and paving the way for targeted therapy and drug development.
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Affiliation(s)
- Liping Wang
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Xiaojiao Zeng
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Gui Yang
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Guohong Liu
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Yunbao Pan
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
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11
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Sinha S, Sinha A, Dongre P, Kamat K, Inamdar MS. Organelle dysfunction upon asrij depletion causes aging-like changes in mouse hematopoietic stem cells. Aging Cell 2022; 21:e13570. [PMID: 35289070 PMCID: PMC9009118 DOI: 10.1111/acel.13570] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 01/04/2022] [Accepted: 02/01/2022] [Indexed: 12/03/2022] Open
Abstract
Aging of the blood system is characterized by increased hematopoietic stem cells (HSCs) and myeloid‐biased differentiation leading to higher propensity for hematological malignancies. Unraveling cell‐intrinsic mechanisms regulating HSC aging could aid reversal or slowing of aging. Asrij/OCIAD1 is an evolutionarily conserved regulator of hematopoiesis and governs mitochondrial, endosomal, and proteasomal function in mammalian stem cells. Asrij deletion in mice causes loss of HSC quiescence, myeloid skewing, reduced p53 and increased DNA damage, features attributed to aged HSCs. Mechanistically, Asrij controls p53 ubiquitination and degradation and AKT/STAT5 activation. Asrij localizes to endosomes and mitochondria. As decline in organelle structure and function are common hallmarks of aging, we asked whether Asrij regulates organelle function in aged HSCs. We find that chronologically aged wild‐type (WT) HSCs had reduced Asrij levels. Expectedly, young asrij KO mice had reduced AcH4K16 levels; however, transcriptome analysis of KO HSCs showed a modest overlap of gene expression with aged WT HSCs. Further, analysis of organelle structure and function in asrij KO mice revealed significant changes, namely damaged mitochondria, elevated ROS; impaired endosomal trafficking seen by increased cleaved Notch1, reduced Rab5; and reduced 26S proteasome activity. Pharmacological correction of mitochondrial and proteasome activity in asrij KO mice restored HSC and myeloid cell frequencies. Furthermore, lysophosphatidic acid‐induced Asrij upregulation in aged WT mice rescued mitochondrial and proteasome activity and restored HSC frequency. Our results highlight a new role for Asrij in preventing HSC aging by regulating organelle homeostasis and will help decipher organelle dynamics in HSC longevity.
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Affiliation(s)
- Saloni Sinha
- Jawaharlal Nehru Centre for Advanced Scientific Research Bangalore India
| | - Alice Sinha
- Jawaharlal Nehru Centre for Advanced Scientific Research Bangalore India
| | - Prathamesh Dongre
- Jawaharlal Nehru Centre for Advanced Scientific Research Bangalore India
| | - Kajal Kamat
- Jawaharlal Nehru Centre for Advanced Scientific Research Bangalore India
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12
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Chen Z, Guo Q, Song G, Hou Y. Molecular regulation of hematopoietic stem cell quiescence. Cell Mol Life Sci 2022; 79:218. [PMID: 35357574 PMCID: PMC11072845 DOI: 10.1007/s00018-022-04200-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 02/07/2022] [Accepted: 02/07/2022] [Indexed: 12/19/2022]
Abstract
Hematopoietic stem cells (HSCs) are primarily dormant in a cell-cycle quiescence state to preserve their self-renewal capacity and long-term maintenance, which is essential for the homeostasis of hematopoietic system. Dysregulation of quiescence causes HSC dysfunction and may result in aberrant hematopoiesis (e.g., myelodysplastic syndrome and bone marrow failure syndromes) and leukemia transformation. Accumulating evidence indicates that both intrinsic molecular networks and extrinsic signals regulate HSC quiescence, including cell-cycle regulators, transcription factors, epigenetic factors, and niche factors. Further, the transition between quiescence and activation of HSCs is a continuous developmental path driven by cell metabolism (e.g., protein synthesis, glycolysis, oxidative phosphorylation, and autophagy). Elucidating the complex regulatory networks of HSC quiescence will expand the knowledge of HSC hemostasis and benefit for clinical HSC use. Here, we review the current understanding and progression on the molecular and metabolic regulation of HSC quiescence, providing a more complete picture regarding the mechanisms of HSC quiescence maintenance.
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Affiliation(s)
- Zhe Chen
- Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, China
- Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Qian Guo
- Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, China
- Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Guanbin Song
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
| | - Yu Hou
- Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, China.
- Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
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13
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CDK19 regulates the proliferation of hematopoietic stem cells and acute myeloid leukemia cells by suppressing p53-mediated transcription of p21. Leukemia 2022; 36:956-969. [PMID: 35110726 DOI: 10.1038/s41375-022-01512-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 01/07/2022] [Accepted: 01/21/2022] [Indexed: 02/06/2023]
Abstract
The cell cycle progression of hematopoietic stem cells (HSCs) and acute myeloid leukemia (AML) cells is precisely controlled by multiple regulatory factors. However, the underlying mechanisms are not fully understood. Here, we find that cyclin-dependent kinase 19 (CDK19), not its paralogue CDK8, is relatively enriched in mouse HSCs, and its expression is more significantly increased than CDK8 after proliferative stresses. Furthermore, SenexinB (a CDK8/19 inhibitor) treatment impairs the proliferation and self-renewal ability of HSCs. Moreover, overexpression of CDK19 promotes HSC function better than CDK8 overexpression. Using CDK19 knockout mice, we observe that CDK19-/- HSCs exhibit similar phenotypes to those of cells treated with SenexinB. Interestingly, the p53 signaling pathway is significantly activated in HSCs lacking CDK19 expression. Further investigations show that CDK19 can interact with p53 to inhibit p53-mediated transcription of p21 in HSCs and treatment with a specific p53 inhibitor (PFTβ) partially rescues the defects of CDK19-null HSCs. Importantly, SenexinB treatment markedly inhibits the proliferation of AML cells. Collectively, our findings indicate that CDK19 is involved in regulating HSC and AML cell proliferation via the p53-p21 pathway, revealing a new mechanism underlying cell cycle regulation in normal and malignant hematopoietic cells.
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14
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Srebf1c preserves hematopoietic stem cell function and survival as a switch of mitochondrial metabolism. Stem Cell Reports 2022; 17:599-615. [PMID: 35148846 PMCID: PMC9039836 DOI: 10.1016/j.stemcr.2022.01.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 01/13/2022] [Accepted: 01/13/2022] [Indexed: 01/25/2023] Open
Abstract
Mitochondria are fundamental but complex determinants for hematopoietic stem cell (HSC) maintenance. However, the factors involved in the regulation of mitochondrial metabolism in HSCs and the underlying mechanisms have not been fully elucidated. Here, we identify sterol regulatory element binding factor-1c (Srebf1c) as a key factor in maintaining HSC biology under both steady-state and stress conditions. Srebf1c knockout (Srebf1c-/-) mice display increased phenotypic HSCs and less HSC quiescence. In addition, Srebf1c deletion compromises the function and survival of HSCs in competitive transplantation or following chemotherapy and irradiation. Mechanistically, SREBF1c restrains the excessive activation of mammalian target of rapamycin (mTOR) signaling and mitochondrial metabolism in HSCs by regulating the expression of tuberous sclerosis complex 1 (Tsc1). Our study demonstrates that Srebf1c plays an important role in regulating HSC fate via the TSC1-mTOR-mitochondria axis.
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15
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Hu M, Lu Y, Wang S, Zhang Z, Qi Y, Chen N, Shen M, Chen F, Chen M, Yang L, Chen S, Zeng D, Wang F, Su Y, Xu Y, Wang J. CD63 acts as a functional marker in maintaining hematopoietic stem cell quiescence through supporting TGFβ signaling in mice. Cell Death Differ 2022; 29:178-191. [PMID: 34363017 PMCID: PMC8738745 DOI: 10.1038/s41418-021-00848-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 02/07/2023] Open
Abstract
Hematopoietic stem cell (HSC) fate is tightly controlled by various regulators, whereas the underlying mechanism has not been fully uncovered due to the high heterogeneity of these populations. In this study, we identify tetraspanin CD63 as a novel functional marker of HSCs in mice. We show that CD63 is unevenly expressed on the cell surface in HSC populations. Importantly, HSCs with high CD63 expression (CD63hi) are more quiescent and have more robust self-renewal and myeloid differentiation abilities than those with negative/low CD63 expression (CD63-/lo). On the other hand, using CD63 knockout mice, we find that loss of CD63 leads to reduced HSC numbers in the bone marrow. In addition, CD63-deficient HSCs exhibit impaired quiescence and long-term repopulating capacity, accompanied by increased sensitivity to irradiation and 5-fluorouracil treatment. Further investigations demonstrate that CD63 is required to sustain TGFβ signaling activity through its interaction with TGFβ receptors I and II, thereby playing an important role in regulating the quiescence of HSCs. Collectively, our data not only reveal a previously unrecognized role of CD63 but also provide us with new insights into HSC heterogeneity.
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Affiliation(s)
- Mengjia Hu
- grid.410570.70000 0004 1760 6682State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Yukai Lu
- grid.410570.70000 0004 1760 6682State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Song Wang
- grid.410570.70000 0004 1760 6682State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Zihao Zhang
- grid.410570.70000 0004 1760 6682State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Yan Qi
- grid.410570.70000 0004 1760 6682State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Naicheng Chen
- grid.410570.70000 0004 1760 6682State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Mingqiang Shen
- grid.410570.70000 0004 1760 6682State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Fang Chen
- grid.410570.70000 0004 1760 6682State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Mo Chen
- grid.410570.70000 0004 1760 6682State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Lijing Yang
- grid.410570.70000 0004 1760 6682State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Shilei Chen
- grid.410570.70000 0004 1760 6682State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Dongfeng Zeng
- grid.410570.70000 0004 1760 6682Department of Hematology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Fengchao Wang
- grid.410570.70000 0004 1760 6682State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Yongping Su
- grid.410570.70000 0004 1760 6682State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Yang Xu
- grid.410570.70000 0004 1760 6682State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Junping Wang
- grid.410570.70000 0004 1760 6682State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
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16
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Hong J, Shiba-Ishii A, Kim Y, Noguchi M, Sakamoto N. Ovarian carcinoma immunoreactive antigen domain 2 controls mitochondrial apoptosis in lung adenocarcinoma. Cancer Sci 2021; 112:5114-5126. [PMID: 34628698 PMCID: PMC8645747 DOI: 10.1111/cas.15160] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/30/2021] [Accepted: 10/01/2021] [Indexed: 12/24/2022] Open
Abstract
Ovarian carcinoma immunoreactive antigen domain 2 (OCIAD2) has been reported to show significantly higher expression in invasive lung adenocarcinoma than in lung adenocarcinoma in situ, and its abnormal expression is associated with poorer prognosis of the patients. However, the cellular function of OCIAD2 in this tumor remains poorly understood. In the present study, we first validated that OCIAD2 showed higher expression in human lung adenocarcinoma tissues or cell lines than in normal lung tissue or immortalized normal bronchial epithelial cells. OCIAD2 was localized predominantly at the mitochondrial membrane in lung adenocarcinoma cells. Interestingly, suppression of OCIAD2 led to loss of mitochondrial structure and a reduction in the number of mitochondria. Moreover, OCIAD2 suppression led to downregulation of cellular growth, proliferation, migration, and invasion, and upregulation of mitochondria‐related apoptosis. We also showed that OCIAD2 suppression induced a decrease in mitochondrial membrane potential and release of cytochrome c. Transcriptional profiling using RNA sequencing revealed a total of 137 genes whose expression was commonly altered after OCIAD2 knockdown in three lung adenocarcinoma cell lines (A549, HCC827, and PC9). Pathway enrichment analysis of those genes demonstrated significant enrichment in apoptotic signaling or endoplasmic reticulum (ER) stress pathways. Our data suggest that OCIAD2 inhibits the mitochondria‐initiated apoptosis and thus promotes the survival of lung cancer cells. Therefore, OCIAD2 may be an effective target for treatment of lung adenocarcinoma.
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Affiliation(s)
- Jeongmin Hong
- Doctoral Program in Biomedical Science, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan
| | - Aya Shiba-Ishii
- Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Yunjung Kim
- Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Masayuki Noguchi
- Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Noriaki Sakamoto
- Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
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17
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Ray A, Kamat K, Inamdar MS. A Conserved Role for Asrij/OCIAD1 in Progenitor Differentiation and Lineage Specification Through Functional Interaction With the Regulators of Mitochondrial Dynamics. Front Cell Dev Biol 2021; 9:643444. [PMID: 34295888 PMCID: PMC8290362 DOI: 10.3389/fcell.2021.643444] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 06/14/2021] [Indexed: 11/24/2022] Open
Abstract
Mitochondria are highly dynamic organelles whose activity is an important determinant of blood stem and progenitor cell state. Mitochondrial morphology is maintained by continuous fission and fusion and affects stem cell proliferation, differentiation, and aging. However, the mechanism by which mitochondrial morphology and dynamics regulate cell differentiation and lineage choice remains incompletely understood. Asrij/OCIAD1 is a conserved protein that governs mitochondrial morphology, energy metabolism and human embryonic stem cell (hESC) differentiation. To investigate the in vivo relevance of these properties, we compared hESC phenotypes with those of Drosophila hematopoiesis, where Asrij is shown to regulate blood progenitor maintenance by conserved mechanisms. In concordance with hESC studies, we found that Drosophila Asrij also localizes to mitochondria of larval blood cells and its depletion from progenitors results in elongated mitochondria. Live imaging of asrij knockdown hemocytes and of OCIAD1 knockout hESCs showed reduced mitochondrial dynamics. Since key regulators of mitochondrial dynamics actively regulate mitochondrial morphology, we hypothesized that mitochondrial fission and fusion may control progenitor maintenance or differentiation in an Asrij-dependent manner. Knockdown of the fission regulator Drp1 in Drosophila lymph gland progenitors specifically suppressed crystal cell differentiation whereas depletion of the fusion regulator Marf (Drosophila Mitofusin) increased the same with concomitant upregulation of Notch signaling. These phenotypes were stronger in anterior progenitors and were exacerbated by Asrij depletion. Asrij is known to suppress Notch signaling and crystal cell differentiation. Our analysis reveals that synergistic interactions of Asrij with Drp1 and Marf have distinct impacts on lymph gland progenitor mitochondrial dynamics and crystal cell differentiation. Taken together, using invertebrate and mammalian model systems we demonstrate a conserved role for Asrij/OCIAD1 in linking mitochondrial dynamics and progenitor differentiation. Our study sets the stage for deciphering how regulators of mitochondrial dynamics may contribute to functional heterogeneity and lineage choice in vertebrate blood progenitors.
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Affiliation(s)
- Arindam Ray
- Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India
| | - Kajal Kamat
- Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India
| | - Maneesha S Inamdar
- Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India
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Dunphy K, Dowling P, Bazou D, O’Gorman P. Current Methods of Post-Translational Modification Analysis and Their Applications in Blood Cancers. Cancers (Basel) 2021; 13:1930. [PMID: 33923680 PMCID: PMC8072572 DOI: 10.3390/cancers13081930] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/04/2021] [Accepted: 04/14/2021] [Indexed: 12/12/2022] Open
Abstract
Post-translational modifications (PTMs) add a layer of complexity to the proteome through the addition of biochemical moieties to specific residues of proteins, altering their structure, function and/or localization. Mass spectrometry (MS)-based techniques are at the forefront of PTM analysis due to their ability to detect large numbers of modified proteins with a high level of sensitivity and specificity. The low stoichiometry of modified peptides means fractionation and enrichment techniques are often performed prior to MS to improve detection yields. Immuno-based techniques remain popular, with improvements in the quality of commercially available modification-specific antibodies facilitating the detection of modified proteins with high affinity. PTM-focused studies on blood cancers have provided information on altered cellular processes, including cell signaling, apoptosis and transcriptional regulation, that contribute to the malignant phenotype. Furthermore, the mechanism of action of many blood cancer therapies, such as kinase inhibitors, involves inhibiting or modulating protein modifications. Continued optimization of protocols and techniques for PTM analysis in blood cancer will undoubtedly lead to novel insights into mechanisms of malignant transformation, proliferation, and survival, in addition to the identification of novel biomarkers and therapeutic targets. This review discusses techniques used for PTM analysis and their applications in blood cancer research.
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Affiliation(s)
- Katie Dunphy
- Department of Biology, National University of Ireland, W23 F2K8 Maynooth, Ireland; (K.D.); (P.D.)
| | - Paul Dowling
- Department of Biology, National University of Ireland, W23 F2K8 Maynooth, Ireland; (K.D.); (P.D.)
| | - Despina Bazou
- Department of Haematology, Mater Misericordiae University Hospital, D07 WKW8 Dublin, Ireland;
| | - Peter O’Gorman
- Department of Haematology, Mater Misericordiae University Hospital, D07 WKW8 Dublin, Ireland;
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19
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Samsa WE, Mamidi MK, Hausman BS, Bashur LA, Greenfield EM, Zhou G. The master developmental regulator Jab1/Cops5/Csn5 is essential for proper bone growth and survival in mice. Bone 2021; 143:115733. [PMID: 33157284 PMCID: PMC7769967 DOI: 10.1016/j.bone.2020.115733] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 09/29/2020] [Accepted: 11/02/2020] [Indexed: 11/29/2022]
Abstract
Jab1, also known as Csn5/Cops5, is a key subunit of the COP9 Signalosome, a highly conserved macromolecular complex. We previously reported that the conditional knockout of Jab1 in mouse limb buds and chondrocytes results in severely shortened limbs and neonatal lethal chondrodysplasia, respectively. In this study, we further investigated the specific role of Jab1 in osteoblast differentiation and postnatal bone growth by characterizing a novel mouse model, the Osx-cre; Jab1flox/flox conditional knockout (Jab1 cKO) mouse, in which Jab1 is deleted in osteoblast precursor cells. Jab1 cKO mutant mice appeared normal at birth, but developed progressive dwarfism. Inevitably, all mutant mice died prior to weaning age. The histological and micro-computed tomography analysis of mutant long bones revealed severely altered bone microarchitecture, with a significant reduction in trabecular thickness. Moreover, Jab1 cKO mouse tibiae had a drastic decrease in mineralization near the epiphyseal growth plates, and Jab1 cKO mice also developed spontaneous fractures near the tibiofibular junction. Additionally, our cell culture studies demonstrated that Jab1 deletion in osteoblast precursors led to decreased mineralization and a reduced response to TGFβ and BMP signaling. Moreover, an unbiased reporter screen also identified decreased TGFβ activity in Jab1-knockdown osteoblasts. Thus, Jab1 is necessary for proper osteoblast differentiation and postnatal bone growth, likely in part through its positive regulation of the TGFβ and BMP signaling pathways in osteoblast progenitor cells.
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Affiliation(s)
- William E Samsa
- Department of Orthopaedics, Case Western Reserve University, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Murali K Mamidi
- Department of Orthopaedics, Case Western Reserve University, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Bryan S Hausman
- Department of Orthopaedics, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Lindsay A Bashur
- Department of Orthopaedics, Case Western Reserve University, Cleveland, OH 44106, USA
| | | | - Guang Zhou
- Department of Orthopaedics, Case Western Reserve University, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
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20
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Expression, Purification and Crystallization of Asrij, A Novel Scaffold Transmembrane Protein. J Membr Biol 2021; 254:65-74. [PMID: 33433647 DOI: 10.1007/s00232-020-00166-7] [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: 10/23/2020] [Accepted: 12/17/2020] [Indexed: 10/22/2022]
Abstract
Asrij/OCIAD1 is a scaffold transmembrane protein belonging to the Ovarian Carcinoma Immunoreactive Antigen Domain containing protein family. In Drosophila and mouse models, Asrij localizes at the endosomal and mitochondrial membrane and is shown to regulate the stemness of hematopoietic stem cells. Interaction of Asrij with ADP Ribosylation Factor 1 (Arf1) is shown to be crucial for hematopoietic niche function and prohemocyte maintenance. Here, we report the heterologous expression, standardization of detergents and purification methodologies for crystallization of Asrij/OCIAD1. To probe the activity of bacterially expressed Asrij, we developed a protein complementation assay and conclusively show that Asrij and Arf1 physically interact. Further, we find that sophorolipids improve the solubility and monodispersibility of Asrij. Hence, we propose that sophorolipids could be novel additives for stabilization of membrane proteins. To our knowledge, this is the first study detailing methodology for the production and crystallization of a heterologously expressed scaffold membrane protein and will be widely applicable to understand membrane protein structure and function.
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21
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Luo M, Li JF, Yang Q, Zhang K, Wang ZW, Zheng S, Zhou JJ. Stem cell quiescence and its clinical relevance. World J Stem Cells 2020; 12:1307-1326. [PMID: 33312400 PMCID: PMC7705463 DOI: 10.4252/wjsc.v12.i11.1307] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/28/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Quiescent state has been observed in stem cells (SCs), including in adult SCs and in cancer SCs (CSCs). Quiescent status of SCs contributes to SC self-renewal and conduces to averting SC death from harsh external stimuli. In this review, we provide an overview of intrinsic mechanisms and extrinsic factors that regulate adult SC quiescence. The intrinsic mechanisms discussed here include the cell cycle, mitogenic signaling, Notch signaling, epigenetic modification, and metabolism and transcriptional regulation, while the extrinsic factors summarized here include microenvironment cells, extracellular factors, and immune response and inflammation in microenvironment. Quiescent state of CSCs has been known to contribute immensely to therapeutic resistance in multiple cancers. The characteristics and the regulation mechanisms of quiescent CSCs are discussed in detail. Importantly, we also outline the recent advances and controversies in therapeutic strategies targeting CSC quiescence.
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Affiliation(s)
- Meng Luo
- Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Jin-Fan Li
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Qi Yang
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Kun Zhang
- Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Zhan-Wei Wang
- Department of Breast Surgery, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313003, Zhejiang Province, China
| | - Shu Zheng
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Jiao-Jiao Zhou
- Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
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22
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OCIAD1 is a host mitochondrial substrate of the hepatitis C virus NS3-4A protease. PLoS One 2020; 15:e0236447. [PMID: 32697788 PMCID: PMC7375614 DOI: 10.1371/journal.pone.0236447] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 07/06/2020] [Indexed: 12/15/2022] Open
Abstract
The hepatitis C virus (HCV) nonstructural protein 3-4A (NS3-4A) protease is a key component of the viral replication complex and the target of protease inhibitors used in current clinical practice. By cleaving and thereby inactivating selected host factors it also plays a role in the persistence and pathogenesis of hepatitis C. Here, we describe ovarian cancer immunoreactive antigen domain containing protein 1 (OCIAD1) as a novel cellular substrate of the HCV NS3-4A protease. OCIAD1 was identified by quantitative proteomics involving stable isotopic labeling using amino acids in cell culture coupled with mass spectrometry. It is a poorly characterized membrane protein believed to be involved in cancer development. OCIAD1 is cleaved by the NS3-4A protease at Cys 38, close to a predicted transmembrane segment. Cleavage was observed in heterologous expression systems, the replicon and cell culture-derived HCV systems, as well as in liver biopsies from patients with chronic hepatitis C. NS3-4A proteases from diverse hepacivirus species efficiently cleaved OCIAD1. The subcellular localization of OCIAD1 on mitochondria was not altered by NS3-4A-mediated cleavage. Interestingly, OCIAD2, a homolog of OCIAD1 with a cysteine residue in a similar position and identical subcellular localization, was not cleaved by NS3-4A. Domain swapping experiments revealed that the sequence surrounding the cleavage site as well as the predicted transmembrane segment contribute to substrate selectivity. Overexpression as well as knock down and rescue experiments did not affect the HCV life cycle in vitro, raising the possibility that OCIAD1 may be involved in the pathogenesis of hepatitis C in vivo.
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23
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Chignon A, Bon-Baret V, Boulanger MC, Li Z, Argaud D, Bossé Y, Thériault S, Arsenault BJ, Mathieu P. Single-cell expression and Mendelian randomization analyses identify blood genes associated with lifespan and chronic diseases. Commun Biol 2020; 3:206. [PMID: 32358504 PMCID: PMC7195437 DOI: 10.1038/s42003-020-0937-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 04/10/2020] [Indexed: 12/13/2022] Open
Abstract
The human lifespan is a heritable trait, which is intricately linked to the development of disorders. Here, we show that genetic associations for the parental lifespan are enriched in open chromatin of blood cells. By using blood expression quantitative trait loci (eQTL) derived from 31,684 samples, we identified for the lifespan 125 cis- and 559 trans-regulated expressed genes (eGenes) enriched in adaptive and innate responses. Analysis of blood single-cell expression data showed that eGenes were enriched in dendritic cells (DCs) and the modelling of cell ligand-receptor interactions predicted crosstalk between DCs and a cluster of monocytes with a signature of cytotoxicity. In two-sample Mendelian randomization (MR), we identified 16 blood cis-eGenes causally associated with the lifespan. In MR, the majority of cis-eGene-disorder association pairs had concordant effects with the lifespan. The present work underlined that the lifespan is linked with the immune response and identifies eGenes associated with the lifespan and disorders.
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Affiliation(s)
- Arnaud Chignon
- Laboratory of Cardiovascular Pathobiology, Department of Surgery, Quebec Heart and Lung Institute/Research Center, Laval University, Quebec, QC, Canada
| | - Valentin Bon-Baret
- Laboratory of Cardiovascular Pathobiology, Department of Surgery, Quebec Heart and Lung Institute/Research Center, Laval University, Quebec, QC, Canada
| | - Marie-Chloé Boulanger
- Laboratory of Cardiovascular Pathobiology, Department of Surgery, Quebec Heart and Lung Institute/Research Center, Laval University, Quebec, QC, Canada
| | - Zhonglin Li
- Laboratory of Cardiovascular Pathobiology, Department of Surgery, Quebec Heart and Lung Institute/Research Center, Laval University, Quebec, QC, Canada
| | - Deborah Argaud
- Laboratory of Cardiovascular Pathobiology, Department of Surgery, Quebec Heart and Lung Institute/Research Center, Laval University, Quebec, QC, Canada
| | - Yohan Bossé
- Department of Molecular Medicine, Laval University, Quebec, QC, Canada
| | - Sébastien Thériault
- Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec, QC, Canada
| | | | - Patrick Mathieu
- Laboratory of Cardiovascular Pathobiology, Department of Surgery, Quebec Heart and Lung Institute/Research Center, Laval University, Quebec, QC, Canada.
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Geertsma HM, Rousseaux MWC. Convergent systems-based approaches identify a role for OCIAD1 in Alzheimer's disease. EBioMedicine 2020; 52:102627. [PMID: 31981980 PMCID: PMC6976923 DOI: 10.1016/j.ebiom.2020.102627] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 01/02/2020] [Indexed: 12/16/2022] Open
Affiliation(s)
- Haley M Geertsma
- Neuroscience Program, University of Ottawa, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Canada
| | - Maxime W C Rousseaux
- Department of Cellular and Molecular Medicine, University of Ottawa, Canada; University of Ottawa Brain and Mind Research Institute, Canada; Ottawa Institute of Systems Biology, Canada.
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25
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Li X, Wang L, Cykowski M, He T, Liu T, Chakranarayan J, Rivera A, Zhao H, Powell S, Xia W, Wong STC. OCIAD1 contributes to neurodegeneration in Alzheimer's disease by inducing mitochondria dysfunction, neuronal vulnerability and synaptic damages. EBioMedicine 2020; 51:102569. [PMID: 31931285 PMCID: PMC6957876 DOI: 10.1016/j.ebiom.2019.11.030] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 11/10/2019] [Accepted: 11/19/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Hyperamyloidosis in the brain is known as the earliest neuropathological change and a unique etiological factor in Alzheimer's disease (AD), while progressive neurodegeneration in certain vulnerable brain regions forms the basis of clinical syndromes. It is not clear how early hyperamyloidosis is implicated in progressive neurodegeneration and what factors contribute to the selective brain vulnerability in AD. METHODS Bioinformatics and experimental neurobiology methods were integrated to identify novel factors involved in the hyperamyloidosis-induced brain vulnerability in AD. We first examined neurodegeneration-specific gene signatures from sporadic AD patients and synaptic protein changes in young transgenic AD mice. Then, we systematically assessed the association of a top candidate gene with AD and investigated its mechanistic role in neurodegeneration. FINDINGS We identified the ovary-orientated protein OCIAD1 (Ovarian-Carcinoma-Immunoreactive-Antigen-Domain-Containing-1) as a neurodegeneration-associated factor for AD. Higher levels of OCIAD1, found in vulnerable brain areas and dystrophic neurites, were correlated with disease severity. Multiple early AD pathological events, particularly Aβ/GSK-3β signaling, elevate OCIAD1, which in turn interacts with BCL-2 to impair mitochondrial function and facilitates mitochondria-associated neuronal injury. Notably, elevated OCIAD1 by Aβ increases cell susceptibility to other AD pathological challenges. INTERPRETATION Our findings suggest that OCIAD1 contributes to neurodegeneration in AD by impairing mitochondria function, and subsequently leading to neuronal vulnerability, and synaptic damages. FUNDING Ting Tsung & Wei Fong Chao Foundation, John S Dunn Research Foundation, Cure Alzheimer's Fund, and NIH R01AG057635 to STCW.
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Affiliation(s)
- Xuping Li
- Ting Tsung & Wei Fong Chao Center for BRAIN, Weill Cornell Medicine, Houston Methodist Research Institute, 6670 Bertner Ave, Houston, TX 77030, USA.
| | - Lin Wang
- Department of Informatics Development, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Matthew Cykowski
- Departments of Pathology and Genome Medicine, Weill Cornell Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Tiancheng He
- Department of Informatics Development, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Timothy Liu
- Ting Tsung & Wei Fong Chao Center for BRAIN, Weill Cornell Medicine, Houston Methodist Research Institute, 6670 Bertner Ave, Houston, TX 77030, USA
| | - Joshua Chakranarayan
- Ting Tsung & Wei Fong Chao Center for BRAIN, Weill Cornell Medicine, Houston Methodist Research Institute, 6670 Bertner Ave, Houston, TX 77030, USA
| | - Andreana Rivera
- Departments of Pathology and Genome Medicine, Weill Cornell Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Hong Zhao
- Ting Tsung & Wei Fong Chao Center for BRAIN, Weill Cornell Medicine, Houston Methodist Research Institute, 6670 Bertner Ave, Houston, TX 77030, USA
| | - Suzanne Powell
- Departments of Pathology and Genome Medicine, Weill Cornell Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Weiming Xia
- Ting Tsung & Wei Fong Chao Center for BRAIN, Weill Cornell Medicine, Houston Methodist Research Institute, 6670 Bertner Ave, Houston, TX 77030, USA; Geriatric Research Education Clinical Center, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA 01730, USA; Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA
| | - Stephen T C Wong
- Ting Tsung & Wei Fong Chao Center for BRAIN, Weill Cornell Medicine, Houston Methodist Research Institute, 6670 Bertner Ave, Houston, TX 77030, USA; Department of Informatics Development, Houston Methodist Hospital, Houston, TX 77030, USA; Departments of Pathology and Genome Medicine, Weill Cornell Medicine, Houston Methodist Hospital, Houston, TX 77030, USA; Departments of Radiology, Weill Cornell Medicine, Houston Methodist Hospital, Houston, TX 77030, USA.
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