Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) membrane (M) protein inhibits type I and III interferon production by targeting RIG-I/MDA-5 signaling

Signal Transduct Target Ther. 2020 Dec 28;5(1):299. doi: 10.1038/s41392-020-00438-7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COVID-19 / genetics
  • COVID-19 / metabolism*
  • Chlorocebus aethiops
  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Interferon Lambda
  • Interferon Type I / biosynthesis*
  • Interferon Type I / genetics
  • Interferon-Induced Helicase, IFIH1 / genetics
  • Interferon-Induced Helicase, IFIH1 / metabolism*
  • Interferons / biosynthesis*
  • Interferons / genetics
  • Receptors, Immunologic
  • SARS-CoV-2 / genetics
  • SARS-CoV-2 / metabolism*
  • Signal Transduction*
  • Vero Cells
  • Viral Matrix Proteins / genetics
  • Viral Matrix Proteins / metabolism*


  • Interferon Type I
  • Receptors, Immunologic
  • Viral Matrix Proteins
  • membrane protein, SARS-CoV-2
  • Interferons
  • RIGI protein, human
  • IFIH1 protein, human
  • DEAD Box Protein 58
  • Interferon-Induced Helicase, IFIH1
  • Interferon Lambda