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 M protein suppresses type I interferon expression through the inhibition of TBK1-dependent phosphorylation of IRF3.
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DOI：
10.1038/emi.2016.33
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发表时间：
2016-04-20
影响因子：
13.2
通讯作者：
Jin DY
中科院分区：
文献类型：
--
作者：
Lui PY;Wong LY;Fung CL;Siu KL;Yeung ML;Yuen KS;Chan CP;Woo PC;Yuen KY;Jin DY
中东呼吸综合征冠状病毒（MERS-CoV）感染自2012年在沙特阿拉伯出现以来，已造成数百人死亡，并已成为全球威胁。MERS-CoV逃避宿主先天性抗病毒反应的能力可能有助于其严重的发病机制。许多MERS-CoV编码的蛋白质被鉴定为具有干扰素（IFN）拮抗特性，这与在感染患者和离体模型中观察到的IFN水平降低密切相关。在这项研究中，我们充分表征了MERS-CoV M蛋白的IFN拮抗特性。MERS-CoV M蛋白的表达抑制了I型IFN对仙台病毒感染或poly（I：C）诱导的反应。这种抑制作用被发现是特异性的IFN调节因子3（IRF 3）的激活，而不是核因子-κB。MERS-CoV M蛋白与TRAF 3相互作用并破坏TRAF 3-TBK 1结合，导致IRF 3活化降低。MERS-CoV和SARS-CoV的M蛋白具有三个高度相似的保守的N-末端跨膜结构域和一个C-末端区域。使用嵌合和截短突变体，MERS-CoV M蛋白的N-末端跨膜结构域被发现足以抑制IFN表达，而C-末端结构域不能诱导这种抑制。总的来说，我们的研究结果表明一个共同的和保守的机制，通过该机制，高致病性MERS冠状病毒和SARS冠状病毒利用其M蛋白抑制I型IFN的表达在TBK 1依赖性磷酸化和激活的IRF 3的水平，导致逃避宿主先天性抗病毒反应。
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.