Human endogenous retrovirus W family envelope protein (ERVWE1) regulates macroautophagy activation and micromitophagy inhibition via NOXA1 in schizophrenia

Jiahang Zhang; Huiling Wang; Xing Xue; Xiulin Wu; Wenshi Li; Zhao Lv; Yaru Su; Mengqi Zhang; Kexin Zhao; Xu Zhang; Chen Jia; Fan Zhu

doi:10.1016/j.virs.2025.05.007

June 2025

. doi: 10.1016/j.virs.2025.05.007

Citation: Jiahang Zhang, Huiling Wang, Xing Xue, Xiulin Wu, Wenshi Li, Zhao Lv, Yaru Su, Mengqi Zhang, Kexin Zhao, Xu Zhang, Chen Jia, Fan Zhu. Human endogenous retrovirus W family envelope protein (ERVWE1) regulates macroautophagy activation and micromitophagy inhibition via NOXA1 in schizophrenia .VIROLOGICA SINICA, 2025, 40(3) : 401-418. http://dx.doi.org/10.1016/j.virs.2025.05.007

精神分裂症中人内源性逆转录病毒W家族包膜蛋白(ERVWE1)通过NOXA1激活巨自噬和抑制线粒体微自噬

张嘉航 ^a ,
王惠玲 ^b ,
薛行 ^a ,
吴秀林 ^a ,
李雯诗 ^a ,
吕朝 ^a ,
苏亚茹 ^a ,
张梦琪 ^a ,
赵珂鑫 ^a ,
张旭 ^a ,
贾琛 ^a ,
朱帆 ^a,c,,

a 武汉大学基础医学院医学微生物学系, 病毒学与生物安全国家重点实验室;
b 武汉大学人民医院精神科;
c 武汉大学基础医学院医学微生物学系, 湖北省过敏与免疫学重点实验室

通讯作者： 朱帆, fanzhu@whu.edu.cn
收稿日期： 2025-01-26
录用日期： 2025-05-22

摘要

位于染色体7q21-22的内源性逆转录病毒W家族包膜蛋白（Human endogenous retrovirus type W envelope glycoprotein，ERVWE1）被认为与精神分裂症的病理生理学密切相关。本课题组之前的研究显示，精神分裂症患者体内的ERVWE1表达升高。越来越多的证据表明，自噬功能障碍是导致精神分裂症的因素之一，但ERVWE1与自噬之间的关系仍不清楚。在这项研究中，对人类前额叶皮层的基因芯片（GSE53987）进行的生物信息学分析表明，差异表达基因主要富集在自噬相关通路中。临床数据进一步表明，与对照组相比，精神分裂症患者血清中微管相关蛋白1轻链3β（Microtubule-associated protein 1 light chain 3β, LC3B）的水平显著升高，而LC3B是巨自噬的关键标志物，并且与ERVWE1的表达呈显著正相关。细胞和分子实验表明，ERVWE1通过上调NADPH氧化酶激活剂1（NADPH oxidase activator 1，NOXA1）增加LC3B II/I比值、减少p62蛋白（Sequestosome 1，SQSTM1）的表达和增强自噬体的形成来促进巨自噬。同时，NOXA1下调了与线粒体微自噬相关的关键基因表达，包括PTEN诱导的激酶1（PTEN-induced kinase 1，PINK1）、Parkin RBR E3泛素蛋白连接酶（Parkin RBR E3 ubiquitin-protein ligase，Parkin）和丙酮酸脱氢酶E1亚基α 1（Pyruvate dehydrogenase E1 subunit α 1，PDHA1），这意味着ERVWE1通过NOXA1抑制了PINK1、Parkin和PDHA1的表达，导致线粒体衍生囊泡（Mitochondrial-derived vesicles，MDV）的生成受损，从而抑制线粒体微自噬。从机制上讲，ERVWE1通过上调上游转录因子2（Upstream transcription factor 2，USF2）促进了NOXA1的表达。总之，ERVWE1通过USF2-NOXA1轴激活巨自噬并抑制线粒体微自噬，为自噬失调在精神分裂症中的作用提供了新的机制认识。这些发现表明，以自噬通路为靶点可能为精神分裂症的治疗提供新的策略。
- 人内源性逆转录病毒（Human endogenous retroviruses，HERVs）
- , ERVWE1
- , NADPH氧化酶激活剂1（NADPH oxidase activator 1，NOXA1）
- , 巨自噬
- , 线粒体微自噬
- , 精神分裂症

Human endogenous retrovirus W family envelope protein (ERVWE1) regulates macroautophagy activation and micromitophagy inhibition via NOXA1 in schizophrenia

Jiahang Zhang ^a ,
Huiling Wang ^b ,
Xing Xue ^a ,
Xiulin Wu ^a ,
Wenshi Li ^a ,
Zhao Lv ^a ,
Yaru Su ^a ,
Mengqi Zhang ^a ,
Kexin Zhao ^a ,
Xu Zhang ^a ,
Chen Jia ^a ,
Fan Zhu ^a,c,,

a. State Key Laboratory of Virology and Biosafety, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China;
b. Department of Psychiatry, Renmin Hospital of Wuhan University, Jiefang Road No. 238, Wuhan 430060, China;
c. Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China

Corresponding author: Fan Zhu, fanzhu@whu.edu.cn
Received Date: 26 January 2025
Accepted Date: 22 May 2025

Abstract

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 microtubule-associated 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 subunit α 1 (PDHA1). As a result, ERVWE1, via NOXA1, inhibited micromitophagy by suppressing the expression of PINK1, Parkin, and PDHA1, thereby leading to impaired production of mitochondrial-derived 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.
- Human endogenous retroviruses (HERVs)
- , ERVWE1
- , NADPH oxidase activator 1 (NOXA1)
- , Macroautophagy
- , Micromitophagy
- , Schizophrenia

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