Middle East respiratory syndrome coronavirus M protein suppresses type I interferon expression through the inhibition of TBK1-dependent phosphorylation of IRF3.
Middle East respiratory syndrome coronavirus (MERS-CoV) infection has claimed hundreds of lives and has become a global threat since its emergence in Saudi Arabia in 2012. The ability of MERS-CoV to evade the host innate antiviral response may contribute to its severe pathogenesis. Many MERS-CoV-encoded proteins were identified to have interferon (IFN)-antagonizing properties, which correlates well with the reduced IFN levels observed in infected patients and ex vivo models. In this study, we fully characterized the IFN-antagonizing property of the MERS-CoV M protein. Expression of MERS-CoV M protein suppressed type I IFN expression in response to Sendai virus infection or poly(I:C) induction. This suppressive effect was found to be specific for the activation of IFN regulatory factor 3 (IRF3) but not nuclear factor-κB. MERS-CoV M protein interacted with TRAF3 and disrupted TRAF3-TBK1 association leading to reduced IRF3 activation. M proteins from MERS-CoV and SARS-CoV have three highly similar conserved N-terminal transmembrane domains and a C-terminal region. Using chimeric and truncation mutants, the N-terminal transmembrane domains of the MERS-CoV M protein were found to be sufficient for its inhibitory effect on IFN expression, whereas the C-terminal domain was unable to induce this suppression. Collectively, our findings suggest a common and conserved mechanism through which highly pathogenic MERS-CoV and SARS-CoV harness their M proteins to suppress type I IFN expression at the level of TBK1-dependent phosphorylation and activation of IRF3 resulting in evasion of the host innate antiviral response.
School of Biomedical Sciences, The University of Hong Kong, Pokfulam Hong Kong, China.
Pak-Yin
PY
Lui
School of Biomedical Sciences, The University of Hong Kong, Pokfulam Hong Kong, China.
Lok-Yin Roy
LY
Wong
School of Biomedical Sciences, The University of Hong Kong, Pokfulam Hong Kong, China.
Cheuk-Lai
CL
Fung
School of Biomedical Sciences, The University of Hong Kong, Pokfulam Hong Kong, China.
Kam-Leung
KL
Siu
Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong, China.
Man-Lung
ML
Yeung
School of Biomedical Sciences, The University of Hong Kong, Pokfulam Hong Kong, China.
Kit-San
KS
Yuen
School of Biomedical Sciences, The University of Hong Kong, Pokfulam Hong Kong, China.
Chi-Ping
CP
Chan
Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong, China.
Patrick Chiu-Yat
PC
Woo
Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong, China.
Kwok-Yung
KY
Yuen
School of Biomedical Sciences, The University of Hong Kong, Pokfulam Hong Kong, China.
Dong-Yan
http://orcid.org/0000-0002-2778-3530
DY
Jin
D000086862:Coronavirus M Proteins; D000071457:DEAD Box Protein 58 / Q000235:genetics; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D065207:Middle East Respiratory Syndrome Coronavirus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D010766:Phosphorylation; D010770:Phosphotransferases; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D012529:Saudi Arabia; D029082:Sendai virus / Q000235:genetics / Q000276:immunology; D016415:Sequence Alignment; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000276:immunology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000502:physiology*
D000086862:Coronavirus M Proteins; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C000706237:M protein, SARS-CoV; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; D014763:Viral Matrix Proteins; D010770:Phosphotransferases; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D000071457:DEAD Box Protein 58