Middle East respiratory syndrome coronavirus M protein suppresses type I interferon expression through the inhibition of TBK1-dependent phosphorylation of IRF3

Abstract

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.

Emerging Microbes and Infections (2016) 5, e39; doi:10.1038/emi.2016.33; published online 20 April 2016

Keywords:

• innate antiviral response
• IRF3 activation
• MERS coronavirus
• RIG-I-like receptors
• type I interferons

We thank Ron Fouchier (Erasmus Medical Center, Rotterdam, The Netherlands) for providing MERS-CoV isolate hCoV-EMC/2012; Genhong Cheng (University of California, Los Angeles, CA, USA) and Takashi Fujita (Kyoto University, Kyoto, Japan) for sharing constructs; and Hinson Cheung, Kitty Fung and Edwin Kong (The University of Hong Kong, Pokfulam, Hong Kong, China) for reading the manuscript critically. This work was supported by Hong Kong Health and Medical Research Fund (13121032, 14130822 and HKM-15-M01) and Hong Kong Research Grants Council (HKU1/CRF/11G, C7011-15R and T11-707/15-R).