SARS-CoV-2 N protein enhances the anti-apoptotic activity of MCL-1 to promote viral replication  

作　　者：Pan Pan Weiwei Ge Zhiwei Lei Wei luo Yuqing Liu Zhanwen Guan Lumiao Chen Zhenyang Yu Miaomiao Shen Dingwen Hu Qi Xiang Wenbiao Wang Pin Wan Mingfu Tian Yang Yu Zhen Luo Xulin Chen Heng Xiao Qiwei Zhang Xujing Liang Xin Chen Yongkui Li Jianguo Wu 

机构地区：[1]The First Affiliated Hospital of Jinan University,510632,Guangzhou,China [2]Foshan Institute of Medical Microbiology,528315,Foshan,China [3]Guangdong Provincial Key Laboratory of Virology,Institute of Medical Microbiology,Jinan University,510632,Guangzhou,China [4]State Key Laboratory of Virology,College of Life Sciences,Wuhan University,430072,Wuhan,China [5]The First People’s Hospital of Foshan,528315,Foshan,China

出　　处：《Signal Transduction and Targeted Therapy》2023年第6期3055-3069,共15页信号转导与靶向治疗（英文）

基　　金：supported by the National Natural Science Foundation of China(81730061 to J.W.,82072834 to X.C.,32100697 to L.Z.and 32200117 to P.P.);China Postdoctoral Science Foundation(2020M683177 to P.P.,2020T130046ZX to P.P.);Open Research Fund Program of the State Key Laboratory of Virology of China(2021KF003 to P.P.);Open Research Fund Program of Guangdong Provincial Key Laboratory of Virology(2022KF003 to P.P.);R&D Program of Guangzhou Laboratory(SRPG22-006 to Q.Z.)。

摘　　要：Viral infection in respiratory tract usually leads to cell death,impairing respiratory function to cause severe disease.However,the diversity of clinical manifestations of SARS-CoV-2 infection increases the complexity and difficulty of viral infection prevention,and especially the high-frequency asymptomatic infection increases the risk of virus transmission.Studying how SARS-CoV-2 affects apoptotic pathway may help to understand the pathological process of its infection.Here,we uncovered SARS-CoV-2 imployed a distinct anti-apoptotic mechanism via its N protein.We found SARS-CoV-2 virus-like particles(trVLP)suppressed cell apoptosis,but the trVLP lacking N protein didn’t.Further study verified that N protein repressed cell apoptosis in cultured cells,human lung organoids and mice.Mechanistically,N protein specifically interacted with anti-apoptotic protein MCL-1,and recruited a deubiquitinating enzyme USP15 to remove the K63-linked ubiquitination of MCL-1,which stabilized this protein and promoted it to hijack Bak in mitochondria.Importantly,N protein promoted the replications of IAV,DENV and ZIKV,and exacerbated death of IAV-infected mice,all of which could be blocked by a MCL-1 specific inhibitor,S63845.Altogether,we identifed a distinct anti-apoptotic function of the N protein,through which it promoted viral replication.These may explain how SARS-CoV-2 effectively replicates in asymptomatic individuals without cuasing respiratory dysfunction,and indicate a risk of enhanced coinfection with other viruses.We anticipate that abrogating the N/MCL-1-dominated apoptosis repression is conducive to the treatments of SARS-CoV-2 infection as well as coinfections with other viruses.

关 键 词：APO PREVENTION promoted 

分 类 号：R563.1[医药卫生—呼吸系统]