摘要
Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has quickly spread worldwide and has affected more than 10 million individuals.A typical feature of COVID-19 is the suppression of type I and III interferon(IFN)-mediated antiviral immunity.However,the molecular mechanism by which SARS-CoV-2 evades antiviral immunity remains elusive.Here,we reported that the SARS-CoV-2 membrane(M)protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway mediated by RIG-I/MDA-5–MAVS signaling.In addition,the SARS-CoV-2 M protein suppresses type I and III IFN induction stimulated by SeV infection or poly(I:C)transfection.Mechanistically,the SARS-CoV-2 M protein interacts with RIG-I,MAVS,and TBK1,thus preventing the formation of the multiprotein complex containing RIG-I,MAVS,TRAF3,and TBK1 and subsequently impeding the phosphorylation,nuclear translocation,and activation of IRF3.Consequently,ectopic expression of the SARS-CoV-2 M protein facilitates the replication of vesicular stomatitis virus.Taken together,these results indicate that the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling,which subsequently attenuates antiviral immunity and enhances viral replication.This study provides insight into the interpretation of SARS-CoV-2-induced antiviral immune suppression and illuminates the pathogenic mechanism of COVID-19.
基金
This work was supported by grants from the COVID-19 emergency tackling research project of Shandong University(Grant No.2020XGB03 to P.-H.W)
grants from the Natural Science Foundation of Jiangsu Province(SBK2020042706 to P.-H.W)
grants from the Natural Science Foundation of China(81930039,31730026,81525012)awarded to C.G.
the Fundamental Research Funds of Shandong University(21510078614099)
the Fundamental Research Funds of Cheeloo College of Medicine(21510089393109)
China Postdoctoral Science Foundation(2018M642662)
the Natural Science Foundation of China(81901604)awarded to Y.Z.
grants from the Key Research and Development Project of Shandong Province(2020SFXGFY08).
