SARS-CoV-2 Nsp8 suppresses MDA5 antiviral immune responses by impairing TRIM4-mediated K63-linked polyubiquitination

Melanoma differentiation-associated gene-5 (MDA5) acts as a cytoplasmic RNA sensor to detect viral dsRNA and mediates antiviral innate immune responses to infection by RNA viruses. Upon recognition of viral dsRNA, MDA5 is activated with K63-linked polyubiquitination and then triggers the recruitment of MAVS and activation of TBK1 and IKK alpha/beta, subsequently leading to IRF3 and NF-kappa B phosphorylation. However, the specific E3 ubiquitin ligase for MDA5 K63-polyubiquitination has not been well characterized. Great numbers of symptomatic and severe infections of SARS-CoV-2 are spreading worldwide, and the poor efficacy of treatment with type I interferon and antiviral immune agents indicates that SARS-CoV-2 escapes from antiviral immune responses via several unknown mechanisms. Here, we report that SARS-CoV-2 nonstructural protein 8 (nsp8) acts as a suppressor of antiviral innate immune and inflammatory responses to promote infection of SARS-CoV-2. It downregulates the expression of type I interferon, IFN-stimulated genes and proinflammatory cytokines by binding to MDA5 and TRIM4 and impairing TRIM4-mediated MDA5 K63-linked polyubiquitination. Our findings reveal that nsp8 mediates innate immune evasion during SARS-CoV-2 infection and may serve as a potential target for future therapeutics for SARS-CoV-2 infectious diseases. The spread of SARS-CoV-2 infection and COVID-19 has caused mass casualties worldwide, and the failure of antiviral interferon treatment suggests the existence of important mechanisms of SARS-CoV-2 innate immune evasion. It has been reported that several viral proteins of severe coronaviruses suppress antiviral immune responses; however, the knowledge of immune suppression by SARS-CoV-2 remains limited. Here, we revealed that nsp8 protein of SARS-CoV-2 directly blocks the activation of viral dsRNA sensor MDA5 by impairing TRIM4-mediated K63-linked polyubiquitination and significantly downregulates antiviral immune responses. Our findings contribute to the comprehensive understanding of the direct immune evasion of SARS-CoV-2 that nsp8 suppresses the recognition of viral dsRNA and activation of MDA5 signalosome.