HERV-W ENV Induces Innate Immune Activation and Neuronal Apoptosis via linc01930/cGAS Axis in Recent-Onset Schizophrenia

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.

Ancient dormant virus remnant ERVW-1 drives ferroptosis via degradation of GPX4 and SLC3A2 in schizophrenia

“…ELISA of blood samples revealed higher ERVW-1 levels in schizophrenia patients ( Fig. 2 D), consistent with our previous study ( Huang et al., 2011 ; Li et al., 2023 ; Wang et al., 2018 ; Wu et al., 2023 ; Xia et al., 2021 ; Yan et al., 2022 ; Yao et al., 2023 ). Furthermore, Spearman's analysis showed that ERVW-1 negatively correlated with GPX4 ( Fig.…”

“…Emerging evidence indicates that ERVW-1 is associated with a variety of diseases, including autoimmune diseases ( Mameli et al., 2007 ), cancers ( Yu et al., 2014 ; Zhou et al., 2021 ), and neuropsychiatric disorders ( Kury et al., 2018 ; Wang et al., 2018 ). Notably, previous research has shown that ERVW-1 is abnormally elevated in patients with schizophrenia ( Huang et al., 2011 ; Li et al., 2023 ; Wu et al., 2023 ; Xia et al., 2021 ; Yan et al., 2022 ; Yao et al., 2023 ).…”

“…human cytomegalovirus ( Illescas-Montes et al., 2019 ) and hepatitis B virus ( Liu et al., 2017 )), and internal factors such as aging-associated processes ( Nevalainen et al., 2018 ) and epigenetics changes ( Garcia-Montojo et al., 2018 ). Activated HERVs may be involved in certain diseases, such as certain cancers ( Jansz et al., 2021 ; Yu et al., 2013 ), autoimmune diseases ( Posso-Osorio et al., 2021 ), and neuropsychiatric disorders ( Li et al., 2023 ; Yao et al., 2023 ).…”

HERVs and Cancer—A Comprehensive Review of the Relationship of Human Endogenous Retroviruses and Human Cancers

“…As the first treatment targeting a human endogenous retrovirus (HERV) protein enters into phase III clinical trials to combat multiple sclerosis (MS) progression [ 1 ], HERVs are becoming increasingly promising targets in cancer diagnostics and therapies. Previously, HERVs have been identified as involved in the progression of complex diseases such as MS [ 1 , 2 ], schizophrenia [ 3 , 4 ], and type 1 diabetes [ 5 , 6 ]. Lessons learned from these phenotypes have illuminated the potential for HERVs to impact human cancer development and treatment options.…”

Molecular Research on Mental Disorders

“…Limited knowledge of the pathophysiology of schizophrenia is also reflected in the lack of endogenous disease markers. As a result, Li et al [ 2 ] sought new markers of schizophrenia. They attributed a special role to the linc01930/cCAS axis.…”