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.
【저자키워드】 type I interferons, MERS coronavirus, RIG-I-like receptors, innate antiviral response, IRF3 activation, 【초록키워드】 Pathogenesis, SARS-CoV, Infection, interferon, MERS-CoV, Saudi Arabia, M protein, Regulatory, Protein, Phosphorylation, IRF3, IFN, mutants, expression, mechanism, association, antiviral response, C-terminal domain, Middle East, Type I IFN, chimeric, Activation, TRAF3, inhibitory effect, respiratory syndrome coronavirus, transmembrane domain, N-terminal, nuclear, Sendai virus, highly pathogenic, Host, resulting, conserved, reduced, characterized, contribute, infected patient, induce, suppressed, evade, suppress, C-terminal, claimed, ex vivo models, 【제목키워드】 type I interferon, M protein, Phosphorylation, IRF3, expression, Middle East, respiratory syndrome coronavirus, suppresse,