Middle-East respiratory syndrome coronavirus M protein is a type I IFN antagonist that impedes TRAF3-TBK1 complex formation

Abstract

Middle-East respiratory syndrome coronavirus (MERS-CoV) is a novel human coronavirus first identified in 2012. Individuals infected by MERSCoV present symptoms of acute respiratory distress syndrome with a high mortality rate. MERS-CoV is the second coronavirus identified to cause severe respiratory disorders after the outbreak of severe acute respiratory syndrome (SARS) in 2003. Exactly why MERS-CoV and SARS-CoV are particularly virulent in human remains to be elucidated. The ability to perturb host innate antiviral response might be a major determinant of viral pathogenicity and disease severity. In this study we reported on the inhibition of poly (I:C)- and Sendai virus-induced production of type I interferons (IFNs) by MERS-CoV membrane (M) protein. Coimmunoprecipitation experiments showed that M protein inhibits host type I IFN production by binding specifically to TRAF3 and therefore impeding the formation of TRAF3-TBK1 complex, leading eventually to diminution of IRF3 phosphorylation and dimerization. Furthermore, chimeric and truncation M protein mutants indicated that the N-terminal transmembrane domains of M protein alone are sufficient for IFN antagonism. Comparative analysis revealed that M proteins from the highly pathogenic SARS-CoV and MERS-CoV are capable of suppressing type I IFN production, whereas the counterpart in human coronavirus HKU1, which causes common cold only, has no influence on IFN expression, implicating a role for IFN antagonism of M protein in viral pathogenesis. Taken together, our findings suggest that the M protein of MERSCoV is an IFN antagonist that suppresses innate antiviral response by impeding the formation of TRAF3-TBK1 complex. Supported by HMRF (13121032, 14130822 and HKM-15-M01) and RGC (HKU1/CRF/11G, N-HKU712/12, HKU171091/14M, C7011-15R and T11-707/15-R).