The human endogenous retrovirus type W envelope glycoprotein(ERVWE1),located at chromosome 7q21–22,has been implicated in the pathophysiology of schizophrenia.Our previous studies have shown elevated ERVWE1 expressio...The human endogenous retrovirus type W envelope glycoprotein(ERVWE1),located at chromosome 7q21–22,has been implicated in the pathophysiology of schizophrenia.Our previous studies have shown elevated ERVWE1 expression in schizophrenia patients.Growing evidence suggests that autophagy dysfunction contributes to schizophrenia,yet the relationship between ERVWE1 and autophagy remains unclear.In this study,bioinformatics analysis of the human prefrontal cortex RNA microarray dataset(GSE53987)revealed that differentially expressed genes were predominantly enriched in autophagy-related pathways.Clinical data further demonstrated that serum levels of microtubuleassociated protein 1 light chain 3β(LC3B),a key marker of macroautophagy,were significantly elevated in schizophrenia patients compared to controls,and positively correlated with ERVWE1 expression.Cellular and molecular experiments suggested that ERVWE1 promoted macroautophagy by increasing the LC3B II/I ratio,enhancing autophagosome formation,and reducing sequestosome 1(SQSTM1)expression via upregulation of NADPH oxidase activator 1(NOXA1).Concurrently,NOXA1 downregulated the expression of key micromitophagy-related genes,including PTEN-induced kinase 1(PINK1),Parkin RBR E3 ubiquitin-protein ligase(Parkin),and the pyruvate dehydrogenase E1 subunitα1(PDHA1).As a result,ERVWE1,via NOXA1,inhibited micromitophagy by suppressing the expression of PINK1,Parkin,and PDHA1,thereby leading to impaired production of mitochondrialderived vesicles(MDVs).Mechanistically,ERVWE1 enhanced NOXA1 transcription by upregulating upstream transcription factor 2(USF2).In conclusion,ERVWE1 promotes macroautophagy and inhibits micromitophagy through USF2-NOXA1 axis,providing novel mechanistic insight into the role autophagy dysregulation in schizophrenia.These findings suggest that targeting autophagy pathways may offer novel therapeutic strategies for schizophrenia treatment.展开更多
Human endogenous retroviruses(HERVs) are retroviruses that infected human genome millions of years ago and have persisted throughout human evolution. About 8% of our genome is composed of HERVs, most of which are nonf...Human endogenous retroviruses(HERVs) are retroviruses that infected human genome millions of years ago and have persisted throughout human evolution. About 8% of our genome is composed of HERVs, most of which are nonfunctional because of epigenetic control or deactivating mutations. However, a correlation between HERVs and human cancer has been described and many tumors, such as melanoma, breast cancer, germ cell tumors, renal cancer or ovarian cancer, express HERV proteins, mainly HERV-K(HML6) and HERV-K(HML2). Although the causative role of HERVs in cancer is controversial, data from animal models demonstrated that endogenous retroviruses are potentially oncogenic. HERV protein expression in human cells generates an immune response by activating innate and adaptive immunities. Some HERV-derived peptides have antigenic properties. For example, HERV-K(HML-6) encodes the HER-K MEL peptide recognized by CD8+ lymphocytes. In addition, HERVs are twoedged immunomodulators. HERVs show immunosuppressive activity. The presence of genomic retroviral elements in host-cell cytosol may activate an interferon type I response. Therefore, targeting HERVs through cellular vaccines or immunomodulatory drugs combined with checkpoint inhibitors is attracting interest because they could be active in human tumors.展开更多
Human endogenous retroviruses(HERVs)were formed via ancient integration of exogenous retroviruses into the human genome and are considered to be viral“fossils”.The human genome is embedded with a considerable amount...Human endogenous retroviruses(HERVs)were formed via ancient integration of exogenous retroviruses into the human genome and are considered to be viral“fossils”.The human genome is embedded with a considerable amount of HERVs,witnessing the long-term evolutionary history of the viruses and the host.Most HERVs have lost coding capability during selection but still function in terms of HERV-mediated regulation of host gene expression.In this review,we summarize the roles of HERV activation in response to viral infections and diseases,and emphasize the potential use of HERVs as biomedicine markers in the early diagnosis of diseases such as cancer,which provides a new perspective for the clinical application of HERVs.展开更多
Human endogenous retroviruses (HERVs) represent footprints of previous retroviral infections. They are integrated within the human germ line and constitute approximately 8% of our genome. They have the potential to ha...Human endogenous retroviruses (HERVs) represent footprints of previous retroviral infections. They are integrated within the human germ line and constitute approximately 8% of our genome. They have the potential to harm, given their capacity to alter the cellular metabolism, and could be involved in various pathological processes. This revision intends to highlight the importance of HERVs in health and disease, and the increasing interest of the scientific community in their biology. In this overview, we will present a brief summary of the structure and physiological function of HERVs and an analysis of their role in schizophrenia, a paradigm of mental illness, particularly stressing the importance of HERV research to explore the more basic mechanisms disrupted in this psychiatric condition.展开更多
The association between transcriptional activation of HERV and the develop- ment of schizophrenia was investigated. Nested RT-PCR was used to detect the preval- ence of HERV env RNA in the PBMCs of individuals with re...The association between transcriptional activation of HERV and the develop- ment of schizophrenia was investigated. Nested RT-PCR was used to detect the preval- ence of HERV env RNA in the PBMCs of individuals with recent-onset of schizophrenia and normal persons from central and southern China. β-actin gene was used as an internal control. HERV env homologous sequences were found in the PBMCs of 8 of 28 (28.6%) individuals with recent-onset schizophrenia, while no env sequences were identified in any of the PBMCs obtained from 24 normal person (P<0.001). The results suggested that transcriptional activation of HERV might be associated with the develop- pment of schizophr- enia in at least some patients.展开更多
Human endogenous retroviruses(HERVs) are the remains of ancient retroviruses that invaded our ancestors’ germline cell and were integrated into the genome. The expression of HERVs has always been a cause for concern ...Human endogenous retroviruses(HERVs) are the remains of ancient retroviruses that invaded our ancestors’ germline cell and were integrated into the genome. The expression of HERVs has always been a cause for concern because of its association with various cancers and diseases. However, few previous studies have focused on specific activation of HERVs by viral infections. Our previous study has shown that dengue virus type 2(DENV-2) infection induces the transcription of a large number of abnormal HERVs loci;therefore, the purpose of this study was to explore the relationship between exogenous viral infection and HERV activation further. In this study, we retrieved and reanalyzed published data on 21 transcriptomes of human cells infected with various viruses. We found that infection with different viruses could induce transcriptional activation of HERV loci. Through the comparative analysis of all viral datasets, we identified 43 key HERV loci that were up-regulated by DENV-2, influenza A virus, influenza B virus, Zika virus, measles virus, and West Nile virus infections. Furthermore, the neighboring genes of these HERVs were simultaneously up-regulated, and almost all such neighboring genes were interferon-stimulated genes(ISGs), which are enriched in the host’s antiviral immune response pathways. Our data supported the hypothesis that activation of HERVs, probably via an interferon-mediated mechanism, plays an important role in innate immunity against viral infections.展开更多
Human endogenous retroviruses(HERVs)are remnants of ancient retroviral infections that have become permanently integrated into the human genome,collectively accounting for approximately 8%of the human DNA.A typical fu...Human endogenous retroviruses(HERVs)are remnants of ancient retroviral infections that have become permanently integrated into the human genome,collectively accounting for approximately 8%of the human DNA.A typical full-length HERV provirus consists of four primary genes:gag,pro,pol,and env,flanked by two long terminal repeats(LTRs).Although some of the HERV proviruses remain intact,the majority of HERVs have undergone truncation,insertions,deletions,or point mutations over evolutionary time.-Recent studies have revealed that epigenetic reprogramming,a hallmark of both cellular senescence and premature aging,can lead to the activation of HERVs[1].This reactivation has also been observed across a range of aging-related diseases,including immunosenescence,neurodegenerative diseases,and certain types of cancer.These findings suggest that HERVs may not only be consequences of aging but also active contributors to aging-related cellular dysfunction.In this perspective,we review emerging evidence linking HERVs to cellular senescence and aging-related diseases,highlight their potential utility as biomarkers and diagnostic indicators,and address both the opportunities and challenges in translating this knowledge into clinical applications.展开更多
基金supported by the National Natural Science Foundation of China(No.82272321)the Stanley Foundation from the Stanley Medical Research Institute(SMRI),United States(No.06R-1366)。
文摘The human endogenous retrovirus type W envelope glycoprotein(ERVWE1),located at chromosome 7q21–22,has been implicated in the pathophysiology of schizophrenia.Our previous studies have shown elevated ERVWE1 expression in schizophrenia patients.Growing evidence suggests that autophagy dysfunction contributes to schizophrenia,yet the relationship between ERVWE1 and autophagy remains unclear.In this study,bioinformatics analysis of the human prefrontal cortex RNA microarray dataset(GSE53987)revealed that differentially expressed genes were predominantly enriched in autophagy-related pathways.Clinical data further demonstrated that serum levels of microtubuleassociated protein 1 light chain 3β(LC3B),a key marker of macroautophagy,were significantly elevated in schizophrenia patients compared to controls,and positively correlated with ERVWE1 expression.Cellular and molecular experiments suggested that ERVWE1 promoted macroautophagy by increasing the LC3B II/I ratio,enhancing autophagosome formation,and reducing sequestosome 1(SQSTM1)expression via upregulation of NADPH oxidase activator 1(NOXA1).Concurrently,NOXA1 downregulated the expression of key micromitophagy-related genes,including PTEN-induced kinase 1(PINK1),Parkin RBR E3 ubiquitin-protein ligase(Parkin),and the pyruvate dehydrogenase E1 subunitα1(PDHA1).As a result,ERVWE1,via NOXA1,inhibited micromitophagy by suppressing the expression of PINK1,Parkin,and PDHA1,thereby leading to impaired production of mitochondrialderived vesicles(MDVs).Mechanistically,ERVWE1 enhanced NOXA1 transcription by upregulating upstream transcription factor 2(USF2).In conclusion,ERVWE1 promotes macroautophagy and inhibits micromitophagy through USF2-NOXA1 axis,providing novel mechanistic insight into the role autophagy dysregulation in schizophrenia.These findings suggest that targeting autophagy pathways may offer novel therapeutic strategies for schizophrenia treatment.
文摘Human endogenous retroviruses(HERVs) are retroviruses that infected human genome millions of years ago and have persisted throughout human evolution. About 8% of our genome is composed of HERVs, most of which are nonfunctional because of epigenetic control or deactivating mutations. However, a correlation between HERVs and human cancer has been described and many tumors, such as melanoma, breast cancer, germ cell tumors, renal cancer or ovarian cancer, express HERV proteins, mainly HERV-K(HML6) and HERV-K(HML2). Although the causative role of HERVs in cancer is controversial, data from animal models demonstrated that endogenous retroviruses are potentially oncogenic. HERV protein expression in human cells generates an immune response by activating innate and adaptive immunities. Some HERV-derived peptides have antigenic properties. For example, HERV-K(HML-6) encodes the HER-K MEL peptide recognized by CD8+ lymphocytes. In addition, HERVs are twoedged immunomodulators. HERVs show immunosuppressive activity. The presence of genomic retroviral elements in host-cell cytosol may activate an interferon type I response. Therefore, targeting HERVs through cellular vaccines or immunomodulatory drugs combined with checkpoint inhibitors is attracting interest because they could be active in human tumors.
基金supported by the National Science and Technology Major Project(Grant No.2018ZX10301101)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA13010500)the CAS Pioneer Hundred Talents Program to JC。
文摘Human endogenous retroviruses(HERVs)were formed via ancient integration of exogenous retroviruses into the human genome and are considered to be viral“fossils”.The human genome is embedded with a considerable amount of HERVs,witnessing the long-term evolutionary history of the viruses and the host.Most HERVs have lost coding capability during selection but still function in terms of HERV-mediated regulation of host gene expression.In this review,we summarize the roles of HERV activation in response to viral infections and diseases,and emphasize the potential use of HERVs as biomedicine markers in the early diagnosis of diseases such as cancer,which provides a new perspective for the clinical application of HERVs.
文摘Human endogenous retroviruses (HERVs) represent footprints of previous retroviral infections. They are integrated within the human germ line and constitute approximately 8% of our genome. They have the potential to harm, given their capacity to alter the cellular metabolism, and could be involved in various pathological processes. This revision intends to highlight the importance of HERVs in health and disease, and the increasing interest of the scientific community in their biology. In this overview, we will present a brief summary of the structure and physiological function of HERVs and an analysis of their role in schizophrenia, a paradigm of mental illness, particularly stressing the importance of HERV research to explore the more basic mechanisms disrupted in this psychiatric condition.
文摘The association between transcriptional activation of HERV and the develop- ment of schizophrenia was investigated. Nested RT-PCR was used to detect the preval- ence of HERV env RNA in the PBMCs of individuals with recent-onset of schizophrenia and normal persons from central and southern China. β-actin gene was used as an internal control. HERV env homologous sequences were found in the PBMCs of 8 of 28 (28.6%) individuals with recent-onset schizophrenia, while no env sequences were identified in any of the PBMCs obtained from 24 normal person (P<0.001). The results suggested that transcriptional activation of HERV might be associated with the develop- pment of schizophr- enia in at least some patients.
基金This work was supported by the China Ministry of Science and Technology Key Research&Development Program(No.2016YFC1200800)the National Natural Science Foundation of China(No.91631110)the National Mega Project on Major Infectious Disease Prevention(No.2017ZX10103005-005)。
文摘Human endogenous retroviruses(HERVs) are the remains of ancient retroviruses that invaded our ancestors’ germline cell and were integrated into the genome. The expression of HERVs has always been a cause for concern because of its association with various cancers and diseases. However, few previous studies have focused on specific activation of HERVs by viral infections. Our previous study has shown that dengue virus type 2(DENV-2) infection induces the transcription of a large number of abnormal HERVs loci;therefore, the purpose of this study was to explore the relationship between exogenous viral infection and HERV activation further. In this study, we retrieved and reanalyzed published data on 21 transcriptomes of human cells infected with various viruses. We found that infection with different viruses could induce transcriptional activation of HERV loci. Through the comparative analysis of all viral datasets, we identified 43 key HERV loci that were up-regulated by DENV-2, influenza A virus, influenza B virus, Zika virus, measles virus, and West Nile virus infections. Furthermore, the neighboring genes of these HERVs were simultaneously up-regulated, and almost all such neighboring genes were interferon-stimulated genes(ISGs), which are enriched in the host’s antiviral immune response pathways. Our data supported the hypothesis that activation of HERVs, probably via an interferon-mediated mechanism, plays an important role in innate immunity against viral infections.
基金the National Natural Science Foundation of China(grant number 32470151 to J.C.).
文摘Human endogenous retroviruses(HERVs)are remnants of ancient retroviral infections that have become permanently integrated into the human genome,collectively accounting for approximately 8%of the human DNA.A typical full-length HERV provirus consists of four primary genes:gag,pro,pol,and env,flanked by two long terminal repeats(LTRs).Although some of the HERV proviruses remain intact,the majority of HERVs have undergone truncation,insertions,deletions,or point mutations over evolutionary time.-Recent studies have revealed that epigenetic reprogramming,a hallmark of both cellular senescence and premature aging,can lead to the activation of HERVs[1].This reactivation has also been observed across a range of aging-related diseases,including immunosenescence,neurodegenerative diseases,and certain types of cancer.These findings suggest that HERVs may not only be consequences of aging but also active contributors to aging-related cellular dysfunction.In this perspective,we review emerging evidence linking HERVs to cellular senescence and aging-related diseases,highlight their potential utility as biomarkers and diagnostic indicators,and address both the opportunities and challenges in translating this knowledge into clinical applications.
