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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.

Dear Editor, The COVID-19 pandemic worldwide is caused by a novel coronavirus SARS-CoV-2 (the severe acute respiratory syndrome coronavirus 2). 1 After viral invasion into the host cells, the~30 kb viral genome RNA injected is translated into structural and nonstructural proteins to replicate viral genome and assemble more viral particles. Many copies of nucleocapsid (N) protein can bind to viral genome RNA and pack it into~100 nm particles, assisting membrane (M) and envelope (E) proteins to efficiently assemble the viral envelope. 2 The exact molecular mechanism by which N protein packs up the viral genome still remains elusive. An N protein of SARS-CoV-2 consists of an N-terminal RNAbinding domain (NTD) and a C-terminal dimerization domain (CTD) and shares~90% sequence identity with N protein of SARS-CoV (Supplementary information, Fig. S1a). The regions located between the N-terminus and NTD, between NTD and CTD, and between CTD and the C-terminus of the N protein of SARS-CoV-2 (thereafter referred to as N protein) are predicted to be intrinsically disordered (Supplementary information, Fig. S1b, c). At neutral pH, the N protein is positively charged (+24 e), consistent with its strong binding affinity with negatively charged