SARS-CoV-2 Membrane Protein Inhibits Type I Interferon Production Through Ubiquitin-Mediated Degradation of TBK1.
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.
['Sui|Liyan|L|', 'Zhao|Yinghua|Y|', 'Wang|Wenfang|W|', 'Wu|Ping|P|', 'Wang|Zedong|Z|', 'Yu|Yang|Y|', 'Hou|Zhijun|Z|', 'Tan|Guangyun|G|', 'Liu|Quan|Q|']
D000071457:DEAD Box Protein 58 D057809:HEK293 Cells D006801:Humans D051550:I-kappa B Kinase D050838:Interferon Regulatory Factor-3 D007370:Interferon Type I D000072640:Interferon-Induced Helicase, IFIH1 D017346:Protein Serine-Threonine Kinases D059748:Proteolysis D011971:Receptors, Immunologic D000086402:SARS-CoV-2 D015398:Signal Transduction D048008:TNF Receptor-Associated Factor 3 D025801:Ubiquitin D014763:Viral Matrix Proteins
SARS-CoV-2 membrane protein type I interferon TBK1 ubiquitination