摘要
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
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)
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.Z
grants from the Key Research and Development Project of Shandong Province(2020SFXGFY08).