Significance To establish infection, pathogenic viruses have to overcome the type I interferon (IFN-I) antiviral response. A previous study demonstrated that the SARS-CoV-2 NSP14 is able to inhibit IFN-I responses. In this study, we report that SARS-CoV-2 NSP14 is a virus-encoded translation inhibitory factor which shuts down host protein synthesis, including synthesis of antiviral proteins. Our finding reveals a mechanism by which SARS-CoV-2 evades host antiviral responses. A comprehensive understanding of the strategies employed by SARS-CoV-2 to subvert host immune responses is critical for the design of next-generation antivirals and to prepare for future emerging viral pathogens. The ongoing COVID-19 pandemic has caused an unprecedented global health crisis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19. Subversion of host protein synthesis is a common strategy that pathogenic viruses use to replicate and propagate in their host. In this study, we show that SARS-CoV-2 is able to shut down host protein synthesis and that SARS-CoV-2 nonstructural protein NSP14 exerts this activity. We show that the translation inhibition activity of NSP14 is conserved in human coronaviruses. NSP14 is required for virus replication through contribution of its exoribonuclease (ExoN) and N7-methyltransferase (N7-MTase) activities. Mutations in the ExoN or N7-MTase active sites of SARS-CoV-2 NSP14 abolish its translation inhibition activity. In addition, we show that the formation of NSP14−NSP10 complex enhances translation inhibition executed by NSP14. Consequently, the translational shutdown by NSP14 abolishes the type I interferon (IFN-I)-dependent induction of interferon-stimulated genes (ISGs). Together, we find that SARS-CoV-2 shuts down host innate immune responses via a translation inhibitor, providing insights into the pathogenesis of SARS-CoV-2.
【저자키워드】 coronavirus, Innate immunity, immune evasion, nsp14, translation inhibition, 【초록키워드】 COVID-19, severe acute respiratory syndrome coronavirus 2, viruses, SARS-CoV-2, coronavirus, Pathogenesis, innate immune response, Antiviral, translation, COVID-19 pandemic, Infection, interferon, Proteins, severe acute respiratory syndrome Coronavirus, type I interferon, Health crisis, Protein, Health, Viral, Host immune response, nsp14, immune responses, IFN-I, virus replication, Pathogens, respiratory, inhibitor, synthesis, Critical, mechanism, ISGs, human coronaviruses, antiviral response, interferon-stimulated genes, Exoribonuclease, causative agent, antiviral proteins, active sites, active site, acute respiratory syndrome, pathogenic viruses, acute respiratory syndrome coronavirus, complex, host protein, activities, host immune responses, ExoN, previous study, viral pathogens, interferon-stimulated gene, inhibitory, host antiviral responses, subversion, pathogenesis of SARS-CoV-2, inhibition activity, Host, ENhance, caused, conserved, addition, inhibit, required, replicate, overcome, demonstrated, evade, reveal, translational, pathogenic virus, IFN-I responses, Significance, the SARS-CoV-2, 【제목키워드】 SARS-CoV-2, innate immune response, Protein,