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

作　　者：Dongyan Zhang Xiulin Wu Xing Xue Wenshi Li Ping Zhou Zhao Lv Kexin Zhao Fan Zhu 

机构地区：[1]State Key Laboratory of Virology and Department of Medical Microbiology,School of Basic Medical Sciences,Wuhan University,Wuhan,430071,China [2]Hubei Province Key Laboratory of Allergy&Immunology,Wuhan University,Wuhan,430071,China

出　　处：《Virologica Sinica》2024年第1期31-43,共13页中国病毒学（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.82272321 and 81971943);Fundamental Research Funds for the Central Universities(2042023kf0230);the Stanley Foundation from the Stanley Medical Research Institute(SMRI),United States(No.06R-1366).

摘　　要：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.

关 键 词：ERVW-1 Glutathione peroxidase 4(GPX4) Solute carrier family 3 member 2(SLC3A2) Ferroptosis SCHIZOPHRENIA 

分 类 号：R373[医药卫生—病原生物学]