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 via 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.
【저자키워드】 SARS-CoV-2, type I interferon, membrane protein, ubiquitination, TBK1, 【초록키워드】 COVID-19 pandemic, Immunosuppression, M protein, Protein, MDA5, Phosphorylation, IFN-I, IRF3, RIG-I, Degradation, pathogenicity, mechanism, Coronavirus-2, acute respiratory syndrome, TRAF3, complex, IFNβ, causative pathogen, negative regulation, interferon-stimulated gene, Host, caused, reported, inhibit, the disease, form, reduced, induce, suppress, suppress the expression, 【제목키워드】 Production, Type,