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Zhang W, Huang C, Yao H, Yang S, Jiapaer Z, Song J, Wang X. Retrotransposon: an insight into neurological disorders from perspectives of neurodevelopment and aging. Transl Neurodegener 2025; 14:14. [PMID: 40128823 PMCID: PMC11934714 DOI: 10.1186/s40035-025-00471-y] [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: 05/23/2024] [Accepted: 01/21/2025] [Indexed: 03/26/2025] Open
Abstract
Neurological disorders present considerable challenges in diagnosis and treatment due to their complex and diverse etiology. Retrotransposons are a type of mobile genetic element that are increasingly revealed to play a role in these diseases. This review provides a detailed overview of recent developments in the study of retrotransposons in neurodevelopment, neuroaging, and neurological diseases. Retrotransposons, including long interspersed nuclear elements-1, Alu, SINE-VNTR-Alu, and endogenous retrovirus, play important regulatory roles in the development and aging of the nervous system. They have also been implicated in the pathological processes of several neurological diseases, including Alzheimer's disease, X-linked dystonia-parkinsonism, amyotrophic lateral sclerosis, autism spectrum disorder, and schizophrenia. Retrotransposons provide a new perspective for understanding the molecular mechanisms underlying neurological diseases and provide insights into diagnostic and therapeutic strategies of these diseases.
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Affiliation(s)
- Wenchuan Zhang
- School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chenxuan Huang
- School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Haiyang Yao
- School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shangzhi Yang
- School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zeyidan Jiapaer
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science & Technology, Xinjiang University, Xinjiang, China.
| | - Juan Song
- Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Xianli Wang
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Jia C, Zhang M, Wu X, Zhang X, Lv Z, Zhao K, Zhang J, Su Y, Zhu F. HERV-W Env Induces Neuron Pyroptosis via the NLRP3-CASP1-GSDMD Pathway in Recent-Onset Schizophrenia. Int J Mol Sci 2025; 26:520. [PMID: 39859234 PMCID: PMC11765033 DOI: 10.3390/ijms26020520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/01/2025] [Accepted: 01/05/2025] [Indexed: 01/30/2025] Open
Abstract
HERVs (Human endogenous retroviruses) are remnants of ancient exogenous retroviruses that have integrated into the human genome, particularly in germ-line cells. Among these, the envelope protein gene HERV-W env (Human endogenous retroviruses W family envelope protein), located on chromosome 7 and primarily expressed in the human placenta, has been closely linked to various neuropsychiatric disorders, including schizophrenia, as well as autoimmune diseases and cancer. Recent studies have highlighted the abnormal expression of cytokines as a key factor in the pathophysiology of schizophrenia. Notably, elevated serum levels of IL-1β (interleukin 1 beta) in schizophrenia, a cytokine associated with inflammation, are a characteristic feature of pyroptosis-a form of pro-inflammatory programmed cell death. Although previous research has observed significant upregulation of pyroptosis-related genes such as CASP1 (Caspase-1), NLRP3 (NLR family pyrin domain containing 3), and IL1B (interleukin 1 beta) in the serum of schizophrenia patients, and extensive neuron pyroptosis has been documented in various neuropsychiatric disorders, including Alzheimer's disease, epilepsy, and multiple sclerosis, the occurrence of neuron pyroptosis in schizophrenia remains uncertain. Furthermore, the mechanisms underlying pyroptosis in schizophrenia and its potential connection with HERV-W env have yet to be fully elucidated. In this study, we found that the expression levels of pyroptosis-related genes, specifically CASP1, GSDMD (Gasdermin D), and IL1B, were significantly elevated in patients with schizophrenia compared to healthy controls. Furthermore, our analysis revealed a strong positive correlation between HERV-W env expression and the levels of CASP1/GSDMD/IL1B in these patients. Experimental evidence further demonstrated that HERV-W env promoted the activation of Caspase-1 and the cleavage of Gasdermin D, leading to increased release of LDH (lactate dehydrogenase) and IL-1β. Importantly, inhibitors targeting NLRP3, CASP1, and GSDMD significantly reduced the releases of LDH and IL-1β induced by HERV-W env, whereas BID (BH3 interacting domain death agonist) inhibitors did not have a notable effect. This suggests that HERV-W env induces CASP1-GSDMD-dependent pyroptosis through the NLRP3-CASP1-GSDMD signaling pathway. As pyroptosis is increasingly recognized for its connection to neurodegenerative diseases, this study provides insights into the molecular mechanisms of neuronal pyroptosis mediated by the NLRP3 inflammasome in the context of HERV-W env. Additionally, it explores the potential facilitation of HERV-W env in the development of schizophrenia via pyroptosis, proposing that certain pyroptosis indicators could serve as potential biomarkers for schizophrenia. Based on our existing research results and the findings of previous researchers, we infer that HERV-W env acts as a bridge in the onset and progression of schizophrenia. Furthermore, HERV-W env may serve as a potential target for the clinical treatment of schizophrenia, suggesting that monoclonal antibody therapy targeting HERV-W env could represent a novel approach to managing this disease.
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Affiliation(s)
- Chen Jia
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Mengqi Zhang
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Xiulin Wu
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Xu Zhang
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Zhao Lv
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Kexin Zhao
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Jiahang Zhang
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Yaru Su
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Fan Zhu
- State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
- Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University, Wuhan 430071, China
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Li W, Xue X, Li X, Wu X, Zhou P, Xia Y, Zhang J, Zhang M, Zhu F. Ancestral retrovirus envelope protein ERVWE1 upregulates circ_0001810, a potential biomarker for schizophrenia, and induces neuronal mitochondrial dysfunction via activating AK2. Cell Biosci 2024; 14:138. [PMID: 39543767 PMCID: PMC11566632 DOI: 10.1186/s13578-024-01318-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 10/31/2024] [Indexed: 11/17/2024] Open
Abstract
BACKGROUND Increasingly studies highlight the crucial role of the ancestral retrovirus envelope protein ERVWE1 in the pathogenic mechanisms of schizophrenia, a severe psychiatric disorder affecting approximately 1% of the global population. Recent studies also underscore the significance of circular RNAs (circRNAs), crucial for neurogenesis and synaptogenesis, in maintaining neuronal functions. However, the precise relationship between ERVWE1 and circRNAs in the etiology of schizophrenia remains elusive. RESULTS This study observed elevated levels of hsa_circ_0001810 (circ_0001810) in the blood samples of schizophrenia patients, displaying a significant positive correlation with ERVWE1 expression. Interestingly, in vivo studies demonstrated that ERVWE1 upregulated circ_0001810 in neuronal cells. Circ_0001810, acting as a competing endogenous RNA (ceRNA), bound to miR-1197 and facilitated the release of adenylate kinase 2 (AK2). The bioinformatics analysis of the schizophrenia datasets revealed increased levels of AK2 and enrichment of mitochondrial dynamics. Notably, miR-1197 was reduced in schizophrenia patients, while AK2 levels were increased. Additionally, AK2 showed positive correlations with ERVWE1 and circ_0001810. Further studies demonstrated that AK2 led to mitochondrial dysfunction, characterized by loss of intracellular ATP, mitochondrial depolarization, and disruption of mitochondrial dynamics. Our comprehensive investigation suggested that ERVWE1 influenced ATP levels, promoted mitochondrial depolarization, and disrupted mitochondrial dynamics through the circ_0001810/AK2 pathway. CONCLUSIONS Circ_0001810 and AK2 were increased in schizophrenia and positively correlated with ERVWE1. Importantly, ERVWE1 triggered mitochondrial dysfunction through circ_0001810/miR-1197/AK2 pathway. Recent focus on the impact of mitochondrial dynamics on schizophrenia development had led to our discovery of a novel mechanism by which ERVWE1 contributed to the etiology of schizophrenia, particularly through mitochondrial dynamics. Moreover, these findings collectively proposed that circ_0001810 might serve as a potential blood-based biomarker for schizophrenia. Consistent with our previous theories, ERVWE1 is increasingly recognized as a promising therapeutic target for schizophrenia.
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Affiliation(s)
- Wenshi Li
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Xing Xue
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Xuhang Li
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Xiulin Wu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Ping Zhou
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Yaru Xia
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Jiahang Zhang
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Mengqi Zhang
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Science, Wuhan University, Wuhan, 430071, China.
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Boda VK, Yasmen N, Jiang J, Li W. Pathophysiological significance and modulation of the transient receptor potential canonical 3 ion channel. Med Res Rev 2024; 44:2510-2544. [PMID: 38715347 PMCID: PMC11452291 DOI: 10.1002/med.22048] [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: 01/08/2024] [Revised: 04/11/2024] [Accepted: 04/23/2024] [Indexed: 05/12/2024]
Abstract
Transient receptor potential canonical 3 (TRPC3) protein belongs to the TRP family of nonselective cation channels. Its activation occurs by signaling through a G protein-coupled receptor (GPCR) and a phospholipase C-dependent (PLC) pathway. Perturbations in the expression of TRPC3 are associated with a plethora of pathophysiological conditions responsible for disorders of the cardiovascular, immune, and central nervous systems. The recently solved cryo-EM structure of TRPC3 provides detailed inputs about the underlying mechanistic aspects of the channel, which in turn enables more efficient ways of designing small-molecule modulators. Pharmacologically targeting TRPC3 in animal models has demonstrated great efficacy in treating diseases including cancers, neurological disorders, and cardiovascular diseases. Despite extensive scientific evidence supporting some strong correlations between the expression and activity of TRPC3 and various pathophysiological conditions, therapeutic strategies based on its pharmacological modulations have not led to clinical trials. The development of small-molecule TRPC3 modulators with high safety, sufficient brain penetration, and acceptable drug-like profiles remains in progress. Determining the pathological mechanisms for TRPC3 involvement in human diseases and understanding the requirements for a drug-like TRPC3 modulator will be valuable in advancing small-molecule therapeutics to future clinical trials. In this review, we provide an overview of the origin and activation mechanism of TRPC3 channels, diseases associated with irregularities in their expression, and new development in small-molecule modulators as potential therapeutic interventions for treating TRPC3 channelopathies.
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Affiliation(s)
- Vijay K. Boda
- Department of Pharmaceutical Sciences, and Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
| | - Nelufar Yasmen
- Department of Pharmaceutical Sciences, and Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
| | - Jianxiong Jiang
- Department of Pharmaceutical Sciences, and Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
| | - Wei Li
- Department of Pharmaceutical Sciences, and Drug Discovery Center, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
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Perron H. A tale of a hidden family of genetic immigrants. Microbes Infect 2024:105387. [PMID: 38944111 DOI: 10.1016/j.micinf.2024.105387] [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: 04/20/2024] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 07/01/2024]
Abstract
Though not usual for the editors of a scientific journal to ask that a story be told to its readers, this special issue is offering an opportunity to pay tribute to all those who have made it possible for a long scientific journey to open up many research avenues, to access the discoveries of what was not known and to the understanding of what was unveiled in the field of human endogenous retroviruses. In particular, and beyond a simple fortuitous association, to show their pathogenic involvement in certain diseases whose causality has been the subject of numerous and variable hypotheses.
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Affiliation(s)
- Hervé Perron
- GeNeuro, 3 chemin du Pré-Fleuri, 1228 Plan-les-ouates, Geneva, Switzerland; Geneuro-Innovation, 60A, Avenue Rockefeller, 69008 Lyon, France.
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Zhang D, Wu X, Xue X, Li W, Zhou P, Lv Z, Zhao K, Zhu F. Ancient dormant virus remnant ERVW-1 drives ferroptosis via degradation of GPX4 and SLC3A2 in schizophrenia. Virol Sin 2024; 39:31-43. [PMID: 37690733 PMCID: PMC10877354 DOI: 10.1016/j.virs.2023.09.001] [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: 05/04/2023] [Accepted: 09/06/2023] [Indexed: 09/12/2023] Open
Abstract
Human endogenous retroviruses (HERVs) are remnants of retroviral infections in human germline cells from millions of years ago. Among these, ERVW-1 (also known as HERV-W-ENV, ERVWE1, or ENVW) encodes the envelope protein of the HERV-W family, which contributes to the pathophysiology of schizophrenia. Additionally, neuropathological studies have revealed cell death and disruption of iron homeostasis in the brains of individuals with schizophrenia. Here, our bioinformatics analysis showed that differentially expressed genes in the human prefrontal cortex RNA microarray dataset (GSE53987) were mainly related to ferroptosis and its associated pathways. Clinical data demonstrated significantly lower expression levels of ferroptosis-related genes, particularly Glutathione peroxidase 4 (GPX4) and solute carrier family 3 member 2 (SLC3A2), in schizophrenia patients compared to normal controls. Further in-depth analyses revealed a significant negative correlation between ERVW-1 expression and the levels of GPX4/SLC3A2 in schizophrenia. Studies indicated that ERVW-1 increased iron levels, malondialdehyde (MDA), and transferrin receptor protein 1 (TFR1) expression while decreasing glutathione (GSH) levels and triggering the loss of mitochondrial membrane potential, suggesting that ERVW-1 can induce ferroptosis. Ongoing research has shown that ERVW-1 reduced the expression of GPX4 and SLC3A2 by inhibiting their promoter activities. Moreover, Ferrostatin-1 (Fer-1), the ferroptosis inhibitor, reversed the iron accumulation and mitochondrial membrane potential loss, as well as restored the expressions of ferroptosis markers GSH, MDA, and TFR1 induced by ERVW-1. In conclusion, ERVW-1 could promote ferroptosis by downregulating the expression of GPX4 and SLC3A2, revealing a novel mechanism by which ERVW-1 contributes to neuronal cell death in schizophrenia.
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Affiliation(s)
- Dongyan Zhang
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Xiulin Wu
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Xing Xue
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Wenshi Li
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Ping Zhou
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Zhao Lv
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Kexin Zhao
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Fan Zhu
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China; Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan, 430071, China.
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Wu X, Liu L, Xue X, Li X, Zhao K, Zhang J, Li W, Yao W, Ding S, Jia C, Zhu F. Captive ERVWE1 triggers impairment of 5-HT neuronal plasticity in the first-episode schizophrenia by post-transcriptional activation of HTR1B in ALKBH5-m6A dependent epigenetic mechanisms. Cell Biosci 2023; 13:213. [PMID: 37990254 PMCID: PMC10664518 DOI: 10.1186/s13578-023-01167-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 11/07/2023] [Indexed: 11/23/2023] Open
Abstract
BACKGROUND Abnormalities in the 5-HT system and synaptic plasticity are hallmark features of schizophrenia. Previous studies suggest that the human endogenous retrovirus W family envelope (ERVWE1) is an influential risk factor for schizophrenia and inversely correlates with 5-HT4 receptor in schizophrenia. To our knowledge, no data describes the effect of ERVWE1 on 5-HT neuronal plasticity. N6-methyladenosine (m6A) regulates gene expression and impacts synaptic plasticity. Our research aims to systematically investigate the effects of ERVWE1 on 5-HT neuronal plasticity through m6A modification in schizophrenia. RESULTS HTR1B, ALKBH5, and Arc exhibited higher levels in individuals with first-episode schizophrenia compared to the controls and showed a strong positive correlation with ERVWE1. Interestingly, HTR1B was also correlated with ALKBH5 and Arc. Further analyses confirmed that ALKBH5 may be an independent risk factor for schizophrenia. In vitro studies, we discovered that ERVWE1 enhanced HTR1B expression, thereby activating the ERK-ELK1-Arc pathway and reducing the complexity and spine density of 5-HT neurons. Furthermore, ERVWE1 reduced m6A levels through ALKBH5 demethylation. ERVWE1 induced HTR1B upregulation by improving its mRNA stability in ALKBH5-m6A-dependent epigenetic mechanisms. Importantly, ALKBH5 mediated the observed alterations in 5-HT neuronal plasticity induced by ERVWE1. CONCLUSIONS Overall, HTR1B, Arc, and ALKBH5 levels were increased in schizophrenia and positively associated with ERVWE1. Moreover, ALKBH5 was a novel risk gene for schizophrenia. ERVWE1 impaired 5-HT neuronal plasticity in ALKBH5-m6A dependent mechanism by the HTR1B-ERK-ELK1-Arc pathway, which may be an important contributor to aberrant synaptic plasticity in schizophrenia.
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Affiliation(s)
- Xiulin Wu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | | | - Xing Xue
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Xuhang Li
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Kexin Zhao
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Jiahang Zhang
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Wenshi Li
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Wei Yao
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Shuang Ding
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Chen Jia
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan, 430071, China.
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Wang Q, Shi Y, Bian Q, Zhang N, Wang M, Wang J, Li X, Lai L, Zhao Z, Yu H. Molecular mechanisms of syncytin-1 in tumors and placental development related diseases. Discov Oncol 2023; 14:104. [PMID: 37326913 DOI: 10.1007/s12672-023-00702-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 05/25/2023] [Indexed: 06/17/2023] Open
Abstract
Human endogenous retroviruses (HERVs) have evolved from exogenous retroviruses and account for approximately 8% of the human genome. A growing number of findings suggest that the abnormal expression of HERV genes is associated with schizophrenia, multiple sclerosis, endometriosis, breast cancer, bladder cancer and other diseases. HERV-W env (syncytin-1) is a membrane glycoprotein which plays an important role in placental development. It includes embryo implantation, fusion of syncytiotrophoblasts and of fertilized eggs, and immune response. The abnormal expression of syncytin-1 is related to placental development-related diseases such as preeclampsia, infertility, and intrauterine growth restriction, as well as tumors such as neuroblastoma, endometrial cancer, and endometriosis. This review mainly focused on the molecular interactions of syncytin-1 in placental development-related diseases and tumors, to explore whether syncytin-1 can be an emerging biological marker and potential therapeutic target.
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Affiliation(s)
- Qianqian Wang
- Department of Biochemistry, Jining Medical University, 133 Hehua Road, Jining, 272067, Shandong, People's Republic of China
| | - Ying Shi
- Department of Biochemistry, Jining Medical University, 133 Hehua Road, Jining, 272067, Shandong, People's Republic of China
| | - Qiang Bian
- Collaborative Innovation Center, Jining Medical University, Jining, 272067, Shandong, People's Republic of China
- Department of Pathophysiology, Weifang Medical University, Weifang, 261053, Shandong, People's Republic of China
| | - Naibin Zhang
- Department of Biochemistry, Jining Medical University, 133 Hehua Road, Jining, 272067, Shandong, People's Republic of China
| | - Meng Wang
- Department of Biochemistry, Jining Medical University, 133 Hehua Road, Jining, 272067, Shandong, People's Republic of China
| | - Jianing Wang
- Department of Biochemistry, Jining Medical University, 133 Hehua Road, Jining, 272067, Shandong, People's Republic of China
| | - Xuan Li
- Department of Biochemistry, Jining Medical University, 133 Hehua Road, Jining, 272067, Shandong, People's Republic of China
| | - Luhao Lai
- Collaborative Innovation Center, Jining Medical University, Jining, 272067, Shandong, People's Republic of China
| | - Zhankui Zhao
- The Affiliated Hospital of Jining Medical University, Jining Medical University, 89 Guhuai Road, Jining, 272029, Shandong, People's Republic of China.
| | - Honglian Yu
- Department of Biochemistry, Jining Medical University, 133 Hehua Road, Jining, 272067, Shandong, People's Republic of China.
- Collaborative Innovation Center, Jining Medical University, Jining, 272067, Shandong, People's Republic of China.
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Xue X, Wu X, Liu L, Liu L, Zhu F. ERVW-1 Activates ATF6-Mediated Unfolded Protein Response by Decreasing GANAB in Recent-Onset Schizophrenia. Viruses 2023; 15:1298. [PMID: 37376599 PMCID: PMC10304270 DOI: 10.3390/v15061298] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 05/27/2023] [Accepted: 05/29/2023] [Indexed: 06/29/2023] Open
Abstract
Schizophrenia, a mental disorder, afflicts 1% of the worldwide population. The dysregulation of homeostasis in the endoplasmic reticulum (ER) has been implicated in schizophrenia. Moreover, recent studies indicate that ER stress and the unfolded protein response (UPR) are linked to this mental disorder. Our previous research has verified that endogenous retrovirus group W member 1 envelope (ERVW-1), a risk factor for schizophrenia, is elevated in individuals with schizophrenia. Nevertheless, no literature is available regarding the underlying relationship between ER stress and ERVW-1 in schizophrenia. The aim of our research was to investigate the molecular mechanism connecting ER stress and ERVW-1 in schizophrenia. Here, we employed Gene Differential Expression Analysis to predict differentially expressed genes (DEGs) in the human prefrontal cortex of schizophrenic patients and identified aberrant expression of UPR-related genes. Subsequent research indicated that the UPR gene called XBP1 had a positive correlation with ATF6, BCL-2, and ERVW-1 in individuals with schizophrenia using Spearman correlation analysis. Furthermore, results from the enzyme-linked immunosorbent assay (ELISA) suggested increased serum protein levels of ATF6 and XBP1 in schizophrenic patients compared with healthy controls, exhibiting a strong correlation with ERVW-1 using median analysis and Mann-Whitney U analysis. However, serum GANAB levels were decreased in schizophrenic patients compared with controls and showed a significant negative correlation with ERVW-1, ATF6, and XBP1 in schizophrenic patients. Interestingly, in vitro experiments verified that ERVW-1 indeed increased ATF6 and XBP1 expression while decreasing GANAB expression. Additionally, the confocal microscope experiment suggested that ERVW-1 could impact the shape of the ER, leading to ER stress. GANAB was found to participate in ER stress regulated by ERVW-1. In conclusion, ERVW-1 induced ER stress by suppressing GANAB expression, thereby upregulating the expression of ATF6 and XBP1 and ultimately contributing to the development of schizophrenia.
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Affiliation(s)
- Xing Xue
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; (X.X.); (X.W.); (L.L.)
| | - Xiulin Wu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; (X.X.); (X.W.); (L.L.)
| | - Lijuan Liu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; (X.X.); (X.W.); (L.L.)
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, China
| | | | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; (X.X.); (X.W.); (L.L.)
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, China
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Stricker E, Peckham-Gregory EC, Scheurer ME. HERVs and Cancer-A Comprehensive Review of the Relationship of Human Endogenous Retroviruses and Human Cancers. Biomedicines 2023; 11:936. [PMID: 36979914 PMCID: PMC10046157 DOI: 10.3390/biomedicines11030936] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/03/2023] [Accepted: 03/10/2023] [Indexed: 03/30/2023] Open
Abstract
Genomic instability and genetic mutations can lead to exhibition of several cancer hallmarks in affected cells such as sustained proliferative signaling, evasion of growth suppression, activated invasion, deregulation of cellular energetics, and avoidance of immune destruction. Similar biological changes have been observed to be a result of pathogenic viruses and, in some cases, have been linked to virus-induced cancers. Human endogenous retroviruses (HERVs), once external pathogens, now occupy more than 8% of the human genome, representing the merge of genomic and external factors. In this review, we outline all reported effects of HERVs on cancer development and discuss the HERV targets most suitable for cancer treatments as well as ongoing clinical trials for HERV-targeting drugs. We reviewed all currently available reports of the effects of HERVs on human cancers including solid tumors, lymphomas, and leukemias. Our review highlights the central roles of HERV genes, such as gag, env, pol, np9, and rec in immune regulation, checkpoint blockade, cell differentiation, cell fusion, proliferation, metastasis, and cell transformation. In addition, we summarize the involvement of HERV long terminal repeat (LTR) regions in transcriptional regulation, creation of fusion proteins, expression of long non-coding RNAs (lncRNAs), and promotion of genome instability through recombination.
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Affiliation(s)
- Erik Stricker
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77047, USA
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77047, USA
| | | | - Michael E. Scheurer
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77047, USA
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77047, USA
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11
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Li X, Wu X, Li W, Yan Q, Zhou P, Xia Y, Yao W, Zhu F. HERV-W ENV Induces Innate Immune Activation and Neuronal Apoptosis via linc01930/cGAS Axis in Recent-Onset Schizophrenia. Int J Mol Sci 2023; 24:3000. [PMID: 36769337 PMCID: PMC9917391 DOI: 10.3390/ijms24033000] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/27/2023] [Accepted: 01/31/2023] [Indexed: 02/08/2023] Open
Abstract
Schizophrenia is a severe neuropsychiatric disorder affecting about 1% of individuals worldwide. Increased innate immune activation and neuronal apoptosis are common findings in schizophrenia. Interferon beta (IFN-β), an essential cytokine in promoting and regulating innate immune responses, causes neuronal apoptosis in vitro. However, the precise pathogenesis of schizophrenia is unknown. Recent studies indicate that a domesticated endogenous retroviral envelope glycoprotein of the W family (HERV-W ENV, also called ERVWE1 or syncytin 1), derived from the endogenous retrovirus group W member 1 (ERVWE1) locus on chromosome 7q21.2, has a high level in schizophrenia. Here, we found an increased serum IFN-β level in schizophrenia and showed a positive correlation with HERV-W ENV. In addition, serum long intergenic non-protein coding RNA 1930 (linc01930), decreased in schizophrenia, was negatively correlated with HERV-W ENV and IFN-β. In vitro experiments showed that linc01930, mainly in the nucleus and with noncoding functions, was repressed by HERV-W ENV through promoter activity suppression. Further studies indicated that HERV-W ENV increased IFN-β expression and neuronal apoptosis by restraining the expression of linc01930. Furthermore, HERV-W ENV enhanced cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes protein (STING) expression and interferon regulatory factor 3 (IRF3) phosphorylation in neuronal cells. Notably, cGAS interacted with HERV-W ENV and triggered IFN-β expression and neuronal apoptosis caused by HERV-W ENV. Moreover, Linc01930 participated in the increased neuronal apoptosis and expression level of cGAS and IFN-β induced by HERV-W ENV. To summarize, our results suggested that linc01930 and IFN-β might be novel potential blood-based biomarkers in schizophrenia. The totality of these results also showed that HERV-W ENV facilitated antiviral innate immune response, resulting in neuronal apoptosis through the linc01930/cGAS/STING pathway in schizophrenia. Due to its monoclonal antibody GNbAC1 application in clinical trials, we considered HERV-W ENV might be a reliable therapeutic choice for schizophrenia.
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Affiliation(s)
- Xuhang Li
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, Wuhan 430071, China
| | - Xiulin Wu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, Wuhan 430071, China
| | - Wenshi Li
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, Wuhan 430071, China
| | - Qiujin Yan
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, Wuhan 430071, China
| | - Ping Zhou
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, Wuhan 430071, China
| | - Yaru Xia
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, Wuhan 430071, China
| | - Wei Yao
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, Wuhan 430071, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, Wuhan 430071, China
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, China
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12
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Wu X, Yan Q, Liu L, Xue X, Yao W, Li X, Li W, Ding S, Xia Y, Zhang D, Zhu F. Domesticated HERV-W env contributes to the activation of the small conductance Ca 2+-activated K + type 2 channels via decreased 5-HT4 receptor in recent-onset schizophrenia. Virol Sin 2023; 38:9-22. [PMID: 36007838 PMCID: PMC10006216 DOI: 10.1016/j.virs.2022.08.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 08/17/2022] [Indexed: 11/25/2022] Open
Abstract
The human endogenous retroviruses type W family envelope (HERV-W env) gene is located on chromosome 7q21-22. Our previous studies show that HERV-W env is elevated in schizophrenia and HERV-W env can increase calcium influx. Additionally, the 5-HTergic system and particularly 5-hydroxytryptamine (5-HT) receptors play a prominent role in the pathogenesis and treatment of schizophrenia. 5-hydroxytryptamine receptor 4 (5-HT4R) agonist can block calcium channels. However, the underlying relationship between HERV-W env and 5-HT4R in the etiology of schizophrenia has not been revealed. Here, we used enzyme-linked immunosorbent assay to detect the concentration of HERV-W env and 5-HT4R in the plasma of patients with schizophrenia and we found that there were decreased levels of 5-HT4R and a negative correlation between 5-HT4R and HERV-W env in schizophrenia. Overexpression of HERV-W env decreased the transcription and protein levels of 5-HT4R but increased small conductance Ca2+-activated K+ type 2 channels (SK2) expression levels. Further studies revealed that HERV-W env could interact with 5-HT4R. Additionally, luciferase assay showed that an essential region (-364 to -176 from the transcription start site) in the SK2 promoter was required for HERV-W env-induced SK2 expression. Importantly, 5-HT4R participated in the regulation of SK2 expression and promoter activity. Electrophysiological recordings suggested that HERV-W env could increase SK2 channel currents and the increase of SK2 currents was inhibited by 5-HT4R. In conclusion, HERV-W env could activate SK2 channels via decreased 5-HT4R, which might exhibit a novel mechanism for HERV-W env to influence neuronal activity in schizophrenia.
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Affiliation(s)
- Xiulin Wu
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Qiujin Yan
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | | | - Xing Xue
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Wei Yao
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Xuhang Li
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Wenshi Li
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Shuang Ding
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Yaru Xia
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Dongyan Zhang
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Fan Zhu
- State Key Laboratory of Virology and Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China; Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan, 430071, China.
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13
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Yao W, Zhou P, Yan Q, Wu X, Xia Y, Li W, Li X, Zhu F. ERVWE1 Reduces Hippocampal Neuron Density and Impairs Dendritic Spine Morphology through Inhibiting Wnt/JNK Non-Canonical Pathway via miR-141-3p in Schizophrenia. Viruses 2023; 15:168. [PMID: 36680208 PMCID: PMC9863209 DOI: 10.3390/v15010168] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/26/2022] [Accepted: 01/03/2023] [Indexed: 01/09/2023] Open
Abstract
Human endogenous retroviruses (HERVs) are remnants of ancestral germline infections by exogenous retroviruses. Human endogenous retroviruses W family envelope gene (HERV-W env, also called ERVWE1), located on chromosome 7q21-22, encodes an envelope glycoprotein from the HERV-W family. Mounting evidence suggests that aberrant expression of ERVWE1 involves the etiology of schizophrenia. Moreover, the genetic and morphological studies indicate that dendritic spine deficits may contribute to the onset of schizophrenia. Here, we reported that ERVWE1 changed the density and morphology of the dendritic spine through inhibiting Wingless-type (Wnt)/c-Jun N-terminal kinases (JNK) non-canonical pathway via miR-141-3p in schizophrenia. In this paper, we found elevated levels of miR-141-3p and a significant positive correlation with ERVWE1 in schizophrenia. Moreover, serum Wnt5a and actin-related protein 2 (Arp2) levels decreased and demonstrated a significant negative correlation with ERVWE1 in schizophrenia. In vitro experiments disclosed that ERVWE1 up-regulated miR-141-3p expression by interacting with transcription factor (TF) Yin Yang 1 (YY1). YY1 modulated miR-141-3p expression by binding to its promoter. The luciferase assay revealed that YY1 enhanced the promoter activity of miR-141-3p. Using the miRNA target prediction databases and luciferase reporter assays, we demonstrated that miR-141-3p targeted Wnt5a at its 3' untranslated region (3' UTR). Furthermore, ERVWE1 suppressed the expression of Arp2 through non-canonical pathway, Wnt5a/JNK signaling pathway. In addition, ERVWE1 inhibited Wnt5a/JNK/Arp2 signal pathway through miR-141-3p. Finally, functional assays showed that ERVWE1 induced the abnormalities in hippocampal neuron morphology and spine density through inhibiting Wnt/JNK non-canonical pathway via miR-141-3p in schizophrenia. Our findings indicated that miR-141-3p, Wnt5a, and Arp2 might be potential clinical blood-based biomarkers or therapeutic targets for schizophrenia. Our work also provided new insight into the role of ERVWE1 in schizophrenia pathogenesis.
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Affiliation(s)
- Wei Yao
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Ping Zhou
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Qiujin Yan
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Xiulin Wu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Yaru Xia
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Wenshi Li
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Xuhang Li
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, China
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Sahu S, Singh B, Kumar Rai A. Human endogenous retrovirus regulates the initiation and progression of cancers (Review). Mol Clin Oncol 2022; 17:143. [PMID: 36157315 PMCID: PMC9468830 DOI: 10.3892/mco.2022.2576] [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: 05/18/2022] [Accepted: 06/22/2022] [Indexed: 11/05/2022] Open
Abstract
The expression of genes is altered in various diseases and is responsible for the disease's initiation, progression and pathology. Several other genes, predominantly inactivated, may become activated in a given condition and contribute to the initiation and progression of the disease. Similarly, human endogenous viruses (HERVs) are an incomplete, non-productive and inactive viral sequence present in the heterochromatin of the human genome, and are often referred to as junk DNA. HERVs were inserted into the host genome millions of years ago. However, they were silenced due to multiple mutations and recombination that occurred over time. However, their expression is increased in cancers due to either epigenetic or transcriptional dysregulation. Some of the HERVs having intact open reading frames have been reported to express virus-like particles, functional peptides and proteins involved in tumorigenesis. To summarize, there is involvement of different HERVs in the initiation and progression of several cancers. The present review aims to provide concise information on HERV and its involvement in the initiation and progression of multiple types of cancer.
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Affiliation(s)
- Srishti Sahu
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj, Uttar Pradesh 211004, India
| | - Bharat Singh
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj, Uttar Pradesh 211004, India
| | - Ambak Kumar Rai
- Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Prayagraj, Uttar Pradesh 211004, India
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15
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Yan Q, Wu X, Zhou P, Zhou Y, Li X, Liu Z, Tan H, Yao W, Xia Y, Zhu F. HERV-W Envelope Triggers Abnormal Dopaminergic Neuron Process through DRD2/PP2A/AKT1/GSK3 for Schizophrenia Risk. Viruses 2022; 14:145. [PMID: 35062349 PMCID: PMC8777930 DOI: 10.3390/v14010145] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/08/2022] [Accepted: 01/10/2022] [Indexed: 12/13/2022] Open
Abstract
An increasing number of studies have begun considering human endogenous retroviruses (HERVs) as potential pathogenic phenomena. Our previous research suggests that HERV-W Envelope (HERV-W ENV), a HERV-W family envelope protein, is elevated in schizophrenia patients and contributes to the pathophysiology of schizophrenia. The dopamine (DA) hypothesis is the cornerstone in research and clinical practice related to schizophrenia. Here, we found that the concentration of DA and the expression of DA receptor D2 (DRD2) were significantly higher in schizophrenia patients than in healthy individuals. Intriguingly, there was a positive correlation between HERV-W ENV and DA concentration. Depth analyses showed that there was a marked consistency between HERV-W ENV and DRD2 in schizophrenia. Studies in vitro indicated that HERV-W ENV could increase the DA concentration by regulating DA metabolism and induce the expression of DRD2. Co-IP assays and laser confocal scanning microscopy indicated cellular colocalization and a direct interaction between DRD2 and HERV-W ENV. Additionally, HERV-W ENV caused structural and functional abnormalities of DA neurons. Further studies showed that HERV-W ENV could trigger the PP2A/AKT1/GSK3 pathway via DRD2. A whole-cell patch-clamp analysis suggested that HERV-W ENV enhanced sodium influx through DRD2. In conclusion, we uncovered a relationship between HERV-W ENV and the dopaminergic system in the DA neurons. Considering that GNbAC1, a selective monoclonal antibody to the MSRV-specific epitope, has been promised as a therapy for treating type 1 diabetes and multiple sclerosis (MS) in clinical trials, understanding the precise function of HERV-W ENV in the dopaminergic system may provide new insights into the treatment of schizophrenia.
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Affiliation(s)
- Qiujin Yan
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; (Q.Y.); (X.W.); (P.Z.); (Y.Z.); (X.L.); (W.Y.); (Y.X.)
| | - Xiulin Wu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; (Q.Y.); (X.W.); (P.Z.); (Y.Z.); (X.L.); (W.Y.); (Y.X.)
| | - Ping Zhou
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; (Q.Y.); (X.W.); (P.Z.); (Y.Z.); (X.L.); (W.Y.); (Y.X.)
| | - Yan Zhou
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; (Q.Y.); (X.W.); (P.Z.); (Y.Z.); (X.L.); (W.Y.); (Y.X.)
| | - Xuhang Li
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; (Q.Y.); (X.W.); (P.Z.); (Y.Z.); (X.L.); (W.Y.); (Y.X.)
| | - Zhongchun Liu
- Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan 430060, China; (Z.L.); (H.T.)
| | - Huawei Tan
- Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan 430060, China; (Z.L.); (H.T.)
| | - Wei Yao
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; (Q.Y.); (X.W.); (P.Z.); (Y.Z.); (X.L.); (W.Y.); (Y.X.)
| | - Yaru Xia
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; (Q.Y.); (X.W.); (P.Z.); (Y.Z.); (X.L.); (W.Y.); (Y.X.)
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; (Q.Y.); (X.W.); (P.Z.); (Y.Z.); (X.L.); (W.Y.); (Y.X.)
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, China
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16
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Farina AR, Cappabianca LA, Zelli V, Sebastiano M, Mackay AR. Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting. World J Stem Cells 2021; 13:685-736. [PMID: 34367474 PMCID: PMC8316860 DOI: 10.4252/wjsc.v13.i7.685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.
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Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Lucia Annamaria Cappabianca
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Veronica Zelli
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Michela Sebastiano
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy.
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Fu Y, Zhuang X, Xia X, Li X, Xiao K, Liu X. Correlation Between Promoter Hypomethylation and Increased Expression of Syncytin-1 in Non-Small Cell Lung Cancer. Int J Gen Med 2021; 14:957-965. [PMID: 33776474 PMCID: PMC7989540 DOI: 10.2147/ijgm.s294392] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 02/19/2021] [Indexed: 12/15/2022] Open
Abstract
Introduction Syncytin-1 is a human endogenous retroviral (HERVW) envelope protein, which has been implicated in trophoblast and cancer cell fusions as well as in immunomodulatory functions. We investigated syncytin-1 expression and promoter methylation in non-small cell lung cancer (NSCLC) and the adjacent, para-carcinoma tissues. In addition, the correlation to patient survival differentiation of between 5-year survival and death group was analyzed. Methods Survival ratio was calculated by Kaplan-Meier survival curve. Death risk assessment was executed by Cox risk regression model. The 5ʹ-LTR methylation level of HERVW promoter was detected by EpiTYPER method. Results Syncytin-1 expression in NSCLC tissue was found to be significantly higher than in para-carcinoma tissues. Moreover, the 5-year survival group has a lower syncytin-1 expression than the death group. Clinical stage and the percentage of syncytin-1 positive cells were top risk factors according to Cox ratio risk regression model analysis. While the methylation level of the 5ʹ-LTR in HERVW gene promoter was relatively lower in NSCLC than para-carcinoma tissues, the methylation status of a CpG-2 site overlapping the Oct-1 binding site was found to be an important element potentially involved in the epigenetic regulation of HERVW gene expression. Conclusion These findings suggest that syncytin-1 could be a biomarker for the diagnosis/prognosis of NSCLC, and further studies are required to elucidate the exact role of syncytin-1 in the development of NSCLC as well as the underlying molecular mechanism for syncytin-1 function and regulation.
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Affiliation(s)
- Yang Fu
- Department of Reproductive Medicine Center, Jinan Maternity and Child Care Hospital, Jinan, 250001, People's Republic of China
| | - Xuewei Zhuang
- Department of Clinical Laboratory Medicine, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250031, People's Republic of China.,Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People's Republic of China
| | - Xiyan Xia
- Department of Microbial Immune, Jinan Vocational College of Nursing, Jinan, 250012, People's Republic of China
| | - Xiaohui Li
- Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People's Republic of China
| | - Ke Xiao
- Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People's Republic of China
| | - Xiaojing Liu
- Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People's Republic of China
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Endogenous Retroviruses Activity as a Molecular Signature of Neurodevelopmental Disorders. Int J Mol Sci 2019; 20:ijms20236050. [PMID: 31801288 PMCID: PMC6928979 DOI: 10.3390/ijms20236050] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 11/26/2019] [Accepted: 11/28/2019] [Indexed: 12/20/2022] Open
Abstract
Human endogenous retroviruses (HERVs) are genetic elements resulting from relics of ancestral infection of germline cells, now recognized as cofactors in the etiology of several complex diseases. Here we present a review of findings supporting the role of the abnormal HERVs activity in neurodevelopmental disorders. The derailment of brain development underlies numerous neuropsychiatric conditions, likely starting during prenatal life and carrying on during subsequent maturation of the brain. Autism spectrum disorders, attention deficit hyperactivity disorders, and schizophrenia are neurodevelopmental disorders that arise clinically during early childhood or adolescence, currently attributed to the interplay among genetic vulnerability, environmental risk factors, and maternal immune activation. The role of HERVs in human embryogenesis, their intrinsic responsiveness to external stimuli, and the interaction with the immune system support the involvement of HERVs in the derailed neurodevelopmental process. Although definitive proofs that HERVs are involved in neurobehavioral alterations are still lacking, both preclinical models and human studies indicate that the abnormal expression of ERVs could represent a neurodevelopmental disorders-associated biological trait in affected individuals and their parents.
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19
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Chen Y, Yan Q, Zhou P, Li S, Zhu F. HERV-W env regulates calcium influx via activating TRPC3 channel together with depressing DISC1 in human neuroblastoma cells. J Neurovirol 2019; 25:101-113. [PMID: 30397826 DOI: 10.1007/s13365-018-0692-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 10/06/2018] [Accepted: 10/24/2018] [Indexed: 12/11/2022]
Abstract
The activation and involvement of human endogenous retroviruses W family envelope gene (HERV-W env, also called ERVWE1) have been reported in several neuropsychiatric disorders, including schizophrenia, as well as in multiple sclerosis (MS). Dysregulation of intracellular calcium content is also involved in the pathogenesis of these diseases. Our previous studies showed that HERV-W env overexpression results in activation of small conductance Ca2+-activated K+ channel protein 3 (SK3), a potential risk factor for schizophrenia. In the present study, we aimed to elucidate the relationship between HERV-W env and calcium signaling in schizophrenia. Our results showed that HERV-W env could induce Ca2+ influx in two human neuroblastoma cell lines and upregulate the expression and activation of TRPC3 in cells. The abnormal increase in intracellular Ca2+ concentration was inhibited by addition of the TRPC3 channel blocker pyr3, demonstrating that the Ca2+ influx induced by HERV-W env was TRPC3-dependent. Further experiments showed that HERV-W env overexpression downregulated DISC1, while knockdown of DISC1 promoted activation of TRPC3 without affecting TRPC3 expression. In conclusion, HERV-W env induced Ca2+ influx in human neuroblastoma cells by activating the TRPC3 channel through directly regulating its expression or downregulating DISC1, which could also increase TRPC3 activation without affecting TRPC3 expression. These findings provide new insights into how HERV-W env affects neuronal activity and contributes to the pathogenesis of schizophrenia.
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Affiliation(s)
- Yatang Chen
- Department of Medical Microbiology, School of Medicine, Wuhan University, 185 Donghu Road, Wuhan, 430071, People's Republic of China
| | - Qiujin Yan
- Department of Medical Microbiology, School of Medicine, Wuhan University, 185 Donghu Road, Wuhan, 430071, People's Republic of China
| | - Ping Zhou
- Department of Medical Microbiology, School of Medicine, Wuhan University, 185 Donghu Road, Wuhan, 430071, People's Republic of China
| | - Shan Li
- Department of Integrated Medicine, Dongfeng Hospital, Hubei University of Medicine, Hubei, 442000, People's Republic of China
| | - Fan Zhu
- Department of Medical Microbiology, School of Medicine, Wuhan University, 185 Donghu Road, Wuhan, 430071, People's Republic of China.
- Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University, Wuhan, 430071, People's Republic of China.
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20
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Chang X, Lima LDA, Liu Y, Li J, Li Q, Sleiman PMA, Hakonarson H. Common and Rare Genetic Risk Factors Converge in Protein Interaction Networks Underlying Schizophrenia. Front Genet 2018; 9:434. [PMID: 30323833 PMCID: PMC6172705 DOI: 10.3389/fgene.2018.00434] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Accepted: 09/12/2018] [Indexed: 11/25/2022] Open
Abstract
Hundreds of genomic loci have been identified with the recent advances of schizophrenia in genome-wide association studies (GWAS) and sequencing studies. However, the functional interactions among those genes remain largely unknown. We developed a network-based approach to integrate multiple genetic risk factors, which lead to the discovery of new susceptibility genes and causal sub-networks, or pathways in schizophrenia. We identified significantly and consistently over-represented pathways in the largest schizophrenia GWA studies, which are highly relevant to synaptic plasticity, neural development and signaling transduction, such as long-term potentiation, neurotrophin signaling pathway, and the ERBB signaling pathway. We also demonstrated that genes targeted by common SNPs are more likely to interact with genes harboring de novo mutations (DNMs) in the protein-protein interaction (PPI) network, suggesting a mutual interplay of both common and rare variants in schizophrenia. We further developed an edge-based search algorithm to identify the top-ranked gene modules associated with schizophrenia risk. Our results suggest that the N-methyl-D-aspartate receptor (NMDAR) interactome may play a leading role in the pathology of schizophrenia, as it is highly targeted by multiple types of genetic risk factors.
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Affiliation(s)
- Xiao Chang
- The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Leandro de Araujo Lima
- The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Yichuan Liu
- The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Jin Li
- The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States.,Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Qingqin Li
- Janssen Research & Development, LLC, Titusville, NJ, United States
| | - Patrick M A Sleiman
- The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States.,Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.,Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Hakon Hakonarson
- The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States.,Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.,Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
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21
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Grandi N, Tramontano E. HERV Envelope Proteins: Physiological Role and Pathogenic Potential in Cancer and Autoimmunity. Front Microbiol 2018; 9:462. [PMID: 29593697 PMCID: PMC5861771 DOI: 10.3389/fmicb.2018.00462] [Citation(s) in RCA: 159] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 02/27/2018] [Indexed: 12/29/2022] Open
Abstract
Human endogenous retroviruses (HERVs) are relics of ancient infections accounting for about the 8% of our genome. Despite their persistence in human DNA led to the accumulation of mutations, HERVs are still contributing to the human transcriptome, and a growing number of findings suggests that their expression products may have a role in various diseases. Among HERV products, the envelope proteins (Env) are currently highly investigated for their pathogenic properties, which could likely be participating to several disorders with complex etiology, particularly in the contexts of autoimmunity and cancer. In fact, HERV Env proteins have been shown, on the one side, to trigger both innate and adaptive immunity, prompting inflammatory, cytotoxic and apoptotic reactions; and, on the other side, to prevent the immune response activation, presenting immunosuppressive properties and acting as immune downregulators. In addition, HERV Env proteins have been shown to induce abnormal cell-cell fusion, possibly contributing to tumor development and metastasizing processes. Remarkably, even highly defective HERV env genes and alternative env splicing variants can provide further mechanisms of pathogenesis. A well-known example is the HERV-K(HML2) env gene that, depending on the presence or the absence of a 292-bp deletion, can originate two proteins of different length (Np9 and Rec) proposed to have oncogenic properties. The understanding of their involvement in complex pathological disorders made HERV Env proteins potential targets for therapeutic interventions. Of note, a monoclonal antibody directed against a HERV-W Env is currently under clinical trial as therapeutic approach for multiple sclerosis, representing the first HERV-based treatment. The present review will focus on the current knowledge of the HERV Env expression, summarizing its role in human physiology and its possible pathogenic effects in various cancer and autoimmune disorders. It moreover analyzes HERV Env possible exploitation for the development of innovative therapeutic strategies.
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Affiliation(s)
- Nicole Grandi
- Laboratory of Molecular Virology, Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy
| | - Enzo Tramontano
- Laboratory of Molecular Virology, Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy
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22
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Liu C, Liu L, Wang X, Liu Y, Wang M, Zhu F. HBV X Protein induces overexpression of HERV-W env through NF-κB in HepG2 cells. Virus Genes 2017; 53:797-806. [PMID: 28639221 DOI: 10.1007/s11262-017-1479-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 06/13/2017] [Indexed: 10/19/2022]
Abstract
Human endogenous retrovirus W family (HERV-W) envelope (env) at chromosome 7 is highly expressed in the placenta and possesses fusogenic activity in trophoblast development. HERV-W env has been found to be overexpressed in some cancers and immune diseases. Viral transactivators can induce the overexpression of HERV-W env in human cell lines. Hepatitis B virus X protein (HBx) is believed to be a multifunctional oncogenic protein. Here, we reported that HBx could increase the promoter activity of HERV-W env and upregulate the mRNA levels of non-spliced and spliced HERV-W env and also its protein in human hepatoma HepG2 cells. Interestingly, we found that the inhibition of nuclear factor κB (NF-κB) using shRNA targeting NF-κB/p65 or PDTC (an inhibitor of NF-κB) could attenuate the upregulation of HERV-W env induced by HBx. These suggested that HBx might upregulate the expression of HERV-W env through NF-κB in HepG2 cells. This study might provide a new insight in HBV-associated liver diseases including HCC.
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Affiliation(s)
- Cong Liu
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, People's Republic of China
| | - Lijuan Liu
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, People's Republic of China
| | - Xiuling Wang
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, People's Republic of China
| | - Youyi Liu
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, People's Republic of China
| | - Miao Wang
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, People's Republic of China
| | - Fan Zhu
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, People's Republic of China.
- Hubei Province Key Laboratory of Allergy and Immunology, Wuhan, 430071, Hubei Province, People's Republic of China.
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23
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Human leukemia antigen-A*0201-restricted epitopes of human endogenous retrovirus W family envelope (HERV-W env) induce strong cytotoxic T lymphocyte responses. Virol Sin 2017; 32:280-289. [PMID: 28840564 DOI: 10.1007/s12250-017-3984-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 07/20/2017] [Indexed: 12/29/2022] Open
Abstract
Human endogenous retrovirus W family (HERV-W) envelope (env) has been reported to be related to several human diseases, including autoimmune disorders, and it could activate innate immunity. However, there are no reports investigating whether human leukemia antigen (HLA)-A*0201+ restriction is involved in the immune response caused by HERV-W env in neuropsychiatric diseases. In the present study, HERV-W env-derived epitopes presented by HLA-A*0201 are described with the potential for use in adoptive immunotherapy. Five peptides displaying HLA-A*0201-binding motifs were predicted using SYFEPITHI and BIMAS, and synthesized. A CCK-8 assay showed peptides W, Q and T promoted lymphocyte proliferation. Stimulation of peripheral blood mononuclear cells from HLA-A*0201+ donors with each of these peptides induced peptide-specific CD8+ T cells. High numbers of IFN-γ-secreting T cells were also detectable after several weekly stimulations with W, Q and T. Besides lysis of HERV-W env-loaded target cells, specific apoptosis was also observed. These data demonstrate that human T cells can be sensitized toward HERV-W env peptides (W, Q and T) and, moreover, pose a high killing potential toward HERV-W env-expressing U251 cells. In conclusion, peptides W Q and T, which are HERV-W env antigenic epitopes, have both antigenicity and immunogenicity, and can cause strong T cell immune responses. Our data strengthen the view that HERV-W env should be considered as an autoantigen that can induce autoimmunity in neuropsychiatric diseases, such as multiple sclerosis and schizophrenia. These data might provide an experimental foundation for a HERV-W env peptide vaccine and new insight into the treatment of neuropsychiatric diseases.
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24
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Grandi N, Tramontano E. Type W Human Endogenous Retrovirus (HERV-W) Integrations and Their Mobilization by L1 Machinery: Contribution to the Human Transcriptome and Impact on the Host Physiopathology. Viruses 2017; 9:v9070162. [PMID: 28653997 PMCID: PMC5537654 DOI: 10.3390/v9070162] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 06/08/2017] [Accepted: 06/20/2017] [Indexed: 01/07/2023] Open
Abstract
Human Endogenous Retroviruses (HERVs) are ancient infection relics constituting ~8% of our DNA. While HERVs’ genomic characterization is still ongoing, impressive amounts of data have been obtained regarding their general expression across tissues. Among HERVs, one of the most studied is the W group, which is the sole HERV group specifically mobilized by the long interspersed element-1 (LINE-1) machinery, providing a source of novel insertions by retrotransposition of HERV-W processed pseudogenes, and comprising a member encoding a functional envelope protein coopted for human placentation. The HERV-W group has been intensively investigated for its putative role in several diseases, such as cancer, inflammation, and autoimmunity. Despite major interest in the link between HERV-W expression and human pathogenesis, no conclusive correlation has been demonstrated so far. In general, (i) the absence of a proper identification of the specific HERV-W sequences expressed in a given condition; and (ii) the lack of studies attempting to connect the various observations in the same experimental conditions are the major problems preventing the definitive assessment of the HERV-W impact on human physiopathology. In this review, we summarize the current knowledge on the HERV-W group presence within the human genome and its expression in physiological tissues as well as in the main pathological contexts.
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Affiliation(s)
- Nicole Grandi
- Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato SS554, 09042 Monserrato, Cagliari, Italy.
| | - Enzo Tramontano
- Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato SS554, 09042 Monserrato, Cagliari, Italy.
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), 09042 Monserrato, Cagliari, Italy.
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25
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Xiao R, Li S, Cao Q, Wang X, Yan Q, Tu X, Zhu Y, Zhu F. Human endogenous retrovirus W env increases nitric oxide production and enhances the migration ability of microglia by regulating the expression of inducible nitric oxide synthase. Virol Sin 2017; 32:216-225. [PMID: 28656540 PMCID: PMC6598877 DOI: 10.1007/s12250-017-3997-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 05/26/2017] [Indexed: 01/21/2023] Open
Abstract
Human endogenous retrovirus W env (HERV-W env) plays a critical role in many neuropsychological diseases such as schizophrenia and multiple sclerosis (MS). These diseases are accompanied by immunological reactions in the central nervous system (CNS). Microglia are important immunocytes in brain inflammation that can produce a gasotransmitter-nitric oxide (NO). NO not only plays a role in the function of neuronal cells but also participates in the pathogenesis of various neuropsychological diseases. In this study, we reported increased NO production in CHME-5 microglia cells after they were transfected with HERV-W env. Moreover, HERV-W env increased the expression and function of human inducible nitric oxide synthase (hiNOS) and enhanced the promoter activity of hiNOS. Microglial migration was also enhanced. These data revealed that HERV-W env might contribute to increase NO production and microglial migration ability in neuropsychological disorders by regulating the expression of inducible NOS. Results from this study might lead to the identification of novel targets for the treatment of neuropsychological diseases, including neuroinflammatory diseases, stroke, and neurodegenerative diseases.
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Affiliation(s)
- Ran Xiao
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, China
| | - Shan Li
- Department of Integrated Medicine, Dongfeng Hospital, Hubei University of Medicine, Wuhan, 442000, China
| | - Qian Cao
- Department of Neurology Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Xiuling Wang
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, China
| | - Qiujin Yan
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, China
| | - Xiaoning Tu
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, China
| | - Ying Zhu
- The State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China
| | - Fan Zhu
- Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, China.
- Hubei Province Key Laboratory of Allergy and Immunology, Wuhan, 430071, China.
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26
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Suntsova M, Garazha A, Ivanova A, Kaminsky D, Zhavoronkov A, Buzdin A. Molecular functions of human endogenous retroviruses in health and disease. Cell Mol Life Sci 2015; 72:3653-75. [PMID: 26082181 PMCID: PMC11113533 DOI: 10.1007/s00018-015-1947-6] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2015] [Revised: 05/29/2015] [Accepted: 06/03/2015] [Indexed: 12/13/2022]
Abstract
Human endogenous retroviruses (HERVs) and related genetic elements form 504 distinct families and occupy ~8% of human genome. Recent success of high-throughput experimental technologies facilitated understanding functional impact of HERVs for molecular machinery of human cells. HERVs encode active retroviral proteins, which may exert important physiological functions in the body, but also may be involved in the progression of cancer and numerous human autoimmune, neurological and infectious diseases. The spectrum of related malignancies includes, but not limits to, multiple sclerosis, psoriasis, lupus, schizophrenia, multiple cancer types and HIV. In addition, HERVs regulate expression of the neighboring host genes and modify genomic regulatory landscape, e.g., by providing regulatory modules like transcription factor binding sites (TFBS). Indeed, recent bioinformatic profiling identified ~110,000 regulatory active HERV elements, which formed at least ~320,000 human TFBS. These and other peculiarities of HERVs might have played an important role in human evolution and speciation. In this paper, we focus on the current progress in understanding of normal and pathological molecular niches of HERVs, on their implications in human evolution, normal physiology and disease. We also review the available databases dealing with various aspects of HERV genetics.
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Affiliation(s)
- Maria Suntsova
- Group for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, 117997, Russia.
- Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117198, Russia.
| | - Andrew Garazha
- Group for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, 117997, Russia.
- Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, 117198, Russia.
| | - Alena Ivanova
- Group for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, 117997, Russia.
- Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.
| | - Dmitry Kaminsky
- Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.
| | - Alex Zhavoronkov
- Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.
- Department of Translational and Regenerative Medicine, Moscow Institute of Physics and Technology, 9 Institutskiy per., Dolgoprudny, Moscow, 141700, Russia.
| | - Anton Buzdin
- Group for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, 117997, Russia.
- Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.
- National Research Centre "Kurchatov Institute", Centre for Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, 1, Akademika Kurchatova sq., Moscow, 123182, Russia.
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27
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Slokar G, Hasler G. Human Endogenous Retroviruses as Pathogenic Factors in the Development of Schizophrenia. Front Psychiatry 2015; 6:183. [PMID: 26793126 PMCID: PMC4707225 DOI: 10.3389/fpsyt.2015.00183] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 12/15/2015] [Indexed: 11/13/2022] Open
Abstract
Schizophrenia is a complex disorder, characterized by the interplay between genetic and environmental factors. Human endogenous retroviruses (HERVs), genetic elements that originated from infections by exogenous retroviruses millions of years ago, comprise ~8% of the human genome. Here, we provide a comprehensive review of accumulating evidence, detailing HERV aberrancies associated with schizophrenia. Studies examining the genome, transcriptome, and proteome of individuals with schizophrenia provide data that support the association of these viral elements with the disorder. Molecular differences can be found within the central nervous system and peripheral tissues. However, additional studies are needed to substantiate the reported link and to address several discrepancies among previous investigations. We further discuss potentially relevant pathogenic mechanisms to the development of schizophrenia.
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Affiliation(s)
- Gorjan Slokar
- Psychiatric University Hospital, University of Bern , Bern , Switzerland
| | - Gregor Hasler
- Psychiatric University Hospital, University of Bern , Bern , Switzerland
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28
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Emmer A, Staege MS, Kornhuber ME. The retrovirus/superantigen hypothesis of multiple sclerosis. Cell Mol Neurobiol 2014; 34:1087-96. [PMID: 25138639 PMCID: PMC11488904 DOI: 10.1007/s10571-014-0100-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Accepted: 08/09/2014] [Indexed: 12/21/2022]
Abstract
The pathogenesis of multiple sclerosis (MS) is as yet unknown. Commonly, MS is assumed to be due to an autoimmune inflammation of the central nervous system (CNS). Neurodegeneration is regarded to be a secondary reaction. This concept is increasingly being challenged. Human endogenous retroviruses (HERV) that could be locally activated in the CNS have been proposed as an alternative concept. HERV-encoded envelope proteins (env) can act as strong immune stimulators (superantigens). Thus, slow disease progression following neurodegeneration might be induced by re-activation of HERV expression directly, while relapses in parallel to inflammation might be secondary to the expression of HERV-encoded superantigens. It has been shown previously that T-cell superantigens are capable to induce a cellular inflammatory reaction in the CNS of experimental animals similar to that in MS. Furthermore, B-cell superantigens have been shown to activate blood leucocytes in vitro to produce immunoglobulin in an oligoclonal manner. It remains to be established, whether the outlined hypothesis accords with all known features of MS. Furthermore, anti-HERV agents may be taken into consideration to enrich and improve MS therapy.
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Affiliation(s)
- Alexander Emmer
- Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany,
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