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

Yi Zheng,Meng-Wei Zhuang,Chengjiang Gao,Dongwei Kang,Xinyong Liu,Pei-Hui Wang,Peng Zhan,Mei-Ling Nan,Jing Zhang,Lulu Han

doi:10.1038/s41392-020-00438-7

Abstract

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.

Highlights

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a vast number of infections and fatalities worldwide, constituting an acute and rapidly developing global health crisis
We reported that the SARS-CoV-2 M protein acts as an antagonist of both type I and III IFNs by affecting the formation of the retinoic acid-inducible gene I (RIG-I)/ melanoma differentiation-associated gene 5 (MDA-5)–MAVS–TRAF3–TANK-binding kinase 1 (TBK1) signalosome, a multiprotein complex
Our previous studies have shown that innate antiviral immunity may play an important role in the SARS-CoV-2 clearance observed in COVID-19.36 SARS-CoV-2–mediated dysregulation of innate antiviral immunity and inflammatory responses is largely responsible for human deaths caused by COVID-19.6,18 Type I and III IFNs are typically suppressed in COVID-19 patients; the molecular mechanism of this phenomenon induced by SARS-CoV2 needs to be elucidated.[6,27]

Summary

Introduction

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a vast number of infections and fatalities worldwide, constituting an acute and rapidly developing global health crisis. The sequence of SARS-CoV-2 has 79.5% identity with that of SARS-CoV-1 and ∼50% identity with that of Middle East respiratory syndrome coronavirus (MERS-CoV) at the whole-genome level.[1,2,3] SARS-CoV-2, like SARSCoV-1 and MERS-CoV, belongs to the betacoronavirus genus in the Coronaviridae family. The gRNA is packaged into structures comprising the structural proteins, namely, the spike, membrane (M), and envelope proteins, to assemble progeny virions.[5] Like SARS and MERS, COVID-19 may be life-threatening and typically begins with pneumonia.[3] During the period 2002–2003, SARS-CoV-1 infected ∼8000 people, with an ∼11% fatality rate worldwide; since 2012, MERS-CoV has infected ∼2500 people with an ∼36% fatality rate.[6] As of June 27, 2020, SARS-CoV-2 has infected 9,827,925 individuals and caused 494,841 deaths since its initial outbreak in December

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