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 ...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.展开更多
Dear Editor,The current pandemic of beta-coronavirus(SARS-CoV-2)has exerted devastating influence on almost all countries,resulting in the disease named COVID-19.1 Coronavirus possesses the largest RNA genome among al...Dear Editor,The current pandemic of beta-coronavirus(SARS-CoV-2)has exerted devastating influence on almost all countries,resulting in the disease named COVID-19.1 Coronavirus possesses the largest RNA genome among all the RNA viruses.Its genome encodes about 29 proteins(Supplementary Fig.S1).The subcellular distributions of the viral proteins have yet been reported for SARS-CoV-2.It is important to investigate the viral proteins’locations in cells because the subcellular distribution information not only helps us in understanding how viruses interact with the host cells but also provides clues in fighting against the viral infection.Therefore,we cloned all the genes of SARS-CoV-2 into vectors for expression in mammalian cells and used immunofluorescent assay(IFA)to examine the viral proteins’subcellular location.Except for the NSP11 that is only 14 aa long,we expressed all other 28 viral proteins in HEp-2 or Caco-2 cells and found a diversity of protein distribution in cells,suggesting a complicated interaction of SARSCoV-2 with host cells to achieve a successful infection.展开更多
As a highly pathogenic human coronavirus,SARS-CoV-2 has to counteract an intricate network of antiviral host responses to establish infection and spread.The nucleic acid-induced stress response is an essential compone...As a highly pathogenic human coronavirus,SARS-CoV-2 has to counteract an intricate network of antiviral host responses to establish infection and spread.The nucleic acid-induced stress response is an essential component of antiviral defense and is closely related to antiviral innate immunity.However,whether SARS-CoV-2 regulates the stress response pathway to achieve immune evasion remains elusive.In this study,SARS-CoV-2 NSP5 and N protein were found to attenuate antiviral stress granule(avSG)formation.Moreover,NSP5 and N suppressed IFN expression induced by infection of Sendai virus or transfection of a synthetic mimic of dsRNA,poly(I:C),inhibiting TBK1 and IRF3 phosphorylation,and restraining the nuclear translocalization of IRF3.Furthermore,HEK293T cells with ectopic expression of NSP5 or N protein were less resistant to vesicular stomatitis virus infection.Mechanistically,NSP5 suppressed avSG formation and disrupted RIG-I–MAVS complex to attenuate the RIG-I–mediated antiviral immunity.In contrast to the multiple targets of NSP5,the N protein specifically targeted cofactors upstream of RIG-I.The N protein interacted with G3BP1 to prevent avSG formation and to keep the cofactors G3BP1 and PACT from activating RIG-I.Additionally,the N protein also affected the recognition of dsRNA by RIG-I.This study revealed the intimate correlation between SARS-CoV-2,the stress response,and innate antiviral immunity,shedding light on the pathogenic mechanism of COVID-19.展开更多
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 ...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.展开更多
基金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)+3 种基金grants from the Natural Science Foundation of China(81930039,31730026,81525012)awarded to C.G.,and 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.,and grants from the Key Research and Development Project of Shandong Province(2020SFXGFY08).
文摘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supported by an NIH/NIAID SC1AI112785(Q.T.)an NIH/DE R01DE028583-01(subaward to Q.T.)+1 种基金National Institute on Minority Health and Health Disparities of the National Institutes of Health under Award Number G12MD007597(Q.T.)by grants from COVID-19 emergency tackling research project of Shandong University(Grant No.2020XGB03 to P.-H.W).
文摘Dear Editor,The current pandemic of beta-coronavirus(SARS-CoV-2)has exerted devastating influence on almost all countries,resulting in the disease named COVID-19.1 Coronavirus possesses the largest RNA genome among all the RNA viruses.Its genome encodes about 29 proteins(Supplementary Fig.S1).The subcellular distributions of the viral proteins have yet been reported for SARS-CoV-2.It is important to investigate the viral proteins’locations in cells because the subcellular distribution information not only helps us in understanding how viruses interact with the host cells but also provides clues in fighting against the viral infection.Therefore,we cloned all the genes of SARS-CoV-2 into vectors for expression in mammalian cells and used immunofluorescent assay(IFA)to examine the viral proteins’subcellular location.Except for the NSP11 that is only 14 aa long,we expressed all other 28 viral proteins in HEp-2 or Caco-2 cells and found a diversity of protein distribution in cells,suggesting a complicated interaction of SARSCoV-2 with host cells to achieve a successful infection.
基金This work was supported by grants from the Key Research and Development Program of Shandong Province(2020CXGC011305 to P.-H.W)grants from the Natural Science Foundation of Shandong Province(ZR2020QC085 to P.-H.W)+7 种基金grants from the Natural Science Foundation of Jiangsu Province(BK20200225 to P.-H.W)grants from the Natural Science Foundation of China(82101856 to P.-H.W)grants from the National Key R&D Program of China(2021YFC2701203 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)Future Scholar Program of Shandong University,and the Natural Science Foundation of China(81901604)awarded to Y.Zgrants from the Key Research and Development Project of Shandong Province(2020SFXGFY08).
文摘As a highly pathogenic human coronavirus,SARS-CoV-2 has to counteract an intricate network of antiviral host responses to establish infection and spread.The nucleic acid-induced stress response is an essential component of antiviral defense and is closely related to antiviral innate immunity.However,whether SARS-CoV-2 regulates the stress response pathway to achieve immune evasion remains elusive.In this study,SARS-CoV-2 NSP5 and N protein were found to attenuate antiviral stress granule(avSG)formation.Moreover,NSP5 and N suppressed IFN expression induced by infection of Sendai virus or transfection of a synthetic mimic of dsRNA,poly(I:C),inhibiting TBK1 and IRF3 phosphorylation,and restraining the nuclear translocalization of IRF3.Furthermore,HEK293T cells with ectopic expression of NSP5 or N protein were less resistant to vesicular stomatitis virus infection.Mechanistically,NSP5 suppressed avSG formation and disrupted RIG-I–MAVS complex to attenuate the RIG-I–mediated antiviral immunity.In contrast to the multiple targets of NSP5,the N protein specifically targeted cofactors upstream of RIG-I.The N protein interacted with G3BP1 to prevent avSG formation and to keep the cofactors G3BP1 and PACT from activating RIG-I.Additionally,the N protein also affected the recognition of dsRNA by RIG-I.This study revealed the intimate correlation between SARS-CoV-2,the stress response,and innate antiviral immunity,shedding light on the pathogenic mechanism of COVID-19.
基金supported by National Institute on Minority Health and Health Disparities of the National Institutes of Health under Award Number G12MD007597,and by grants from COVID-19 emergency tackling research project of Shandong University(Grant No.2020XGB03 to P.-H.W.)。
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)+5 种基金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).
文摘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.
