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

• Published in: Signal transduction and targeted therapy Vol. 5; no. 1; pp. 299 - 13
• Main Authors: Zheng, Yi, Zhuang, Meng-Wei, Han, Lulu, Zhang, Jing, Nan, Mei-Ling, Zhan, Peng, Kang, Dongwei, Liu, Xinyong, Gao, Chengjiang, Wang, Pei-Hui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.12.2020; Nature Publishing Group
• Subjects: 631/250/255; 631/250/262; Animals; Cancer Research; Cell Biology; Chlorocebus aethiops; Coronaviruses; COVID-19; COVID-19 - genetics; COVID-19 - metabolism; 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; Internal Medicine; Medicine; Medicine & Public Health; Oncology; Pathology; Proteins; Receptors, Immunologic; SARS-CoV-2 - genetics; SARS-CoV-2 - metabolism; Severe acute respiratory syndrome coronavirus 2; Signal Transduction; Vero Cells; Viral Matrix Proteins - genetics; Viral Matrix Proteins - metabolism
• ISSN: 2059-3635; 2095-9907; 2059-3635
• 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.