Laboratory of Emerging Infectious Disease, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.
College of Basic Medical Science, Jilin University, Changchun, China.
Front Immunol. 2021 May 18;12:662989. doi: 10.3389/fimmu.2021.662989. eCollection 2021.
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative pathogen of current COVID-19 pandemic, and insufficient production of type I interferon (IFN-I) is associated with the severe forms of the disease. Membrane (M) protein of SARS-CoV-2 has been reported to suppress host IFN-I production, but the underlying mechanism is not completely understood. In this study, SARS-CoV-2 M protein was confirmed to suppress the expression of IFNβ and interferon-stimulated genes induced by RIG-I, MDA5, IKKϵ, and TBK1, and to inhibit IRF3 phosphorylation and dimerization caused by TBK1. SARS-CoV-2 M could interact with MDA5, TRAF3, IKKϵ, and TBK1, and induce TBK1 degradation K48-linked ubiquitination. The reduced TBK1 further impaired the formation of TRAF3-TANK-TBK1-IKKε complex that leads to inhibition of IFN-I production. Our study revealed a novel mechanism of SARS-CoV-2 M for negative regulation of IFN-I production, which would provide deeper insight into the innate immunosuppression and pathogenicity of SARS-CoV-2.
严重急性呼吸综合征冠状病毒 2 型（SARS-CoV-2）是当前 COVID-19 大流行的病原体，I 型干扰素（IFN-I）产生不足与疾病的严重程度有关。据报道，SARS-CoV-2 的膜（M）蛋白抑制宿主 IFN-I 的产生，但具体机制尚不完全清楚。在这项研究中，证实了 SARS-CoV-2 M 蛋白可抑制 RIG-I、MDA5、IKKε 和 TBK1 诱导的 IFNβ和干扰素刺激基因的表达，并抑制 TBK1 引起的 IRF3 磷酸化和二聚化。SARS-CoV-2 M 可以与 MDA5、TRAF3、IKKε 和 TBK1 相互作用，并诱导 TBK1 的 K48 连接泛素化降解。减少的 TBK1 进一步损害了 TRAF3-TANK-TBK1-IKKε 复合物的形成，从而抑制 IFN-I 的产生。我们的研究揭示了 SARS-CoV-2 M 负调控 IFN-I 产生的新机制，这将深入了解 SARS-CoV-2 的先天免疫抑制和致病性。
