ABSTRACT Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic with astonishing mortality and morbidity. The high replication and transmission of SARS-CoV-2 are remarkably distinct from those of previous closely related coronaviruses, and the underlying molecular mechanisms remain unclear. The innate immune defense is a physical barrier that restricts viral replication. We report here that the SARS-CoV-2 Nsp5 main protease targets RIG-I and mitochondrial antiviral signaling (MAVS) protein via two distinct mechanisms for inhibition. Specifically, Nsp5 cleaves off the 10 most-N-terminal amino acids from RIG-I and deprives it of the ability to activate MAVS, whereas Nsp5 promotes the ubiquitination and proteosome-mediated degradation of MAVS. As such, Nsp5 potently inhibits interferon (IFN) induction by double-stranded RNA (dsRNA) in an enzyme-dependent manner. A synthetic small-molecule inhibitor blunts the Nsp5-mediated destruction of cellular RIG-I and MAVS and processing of SARS-CoV-2 nonstructural proteins, thus restoring the innate immune response and impeding SARS-CoV-2 replication. This work offers new insight into the immune evasion strategy of SARS-CoV-2 and provides a potential antiviral agent to treat CoV disease 2019 (COVID-19) patients.
【저자키워드】 SARS-CoV-2, protease, RIG-I, nsp5, MAVS, E3 ligase, small-molecule inhibitor, 【초록키워드】 COVID-19, Coronaviruses, coronavirus, Mortality, innate immune response, Antiviral, interferon, molecular mechanism, Replication, global pandemic, Protein, nonstructural proteins, immune evasion, viral replication, morbidity, CoV, IFN, target, Degradation, inhibitor, disease, patients, SARS-CoV-2 replication, mechanism, Amino acid, cellular, innate immune, dsRNA, double-stranded RNA, mitochondrial, acute respiratory syndrome, treat, antiviral signaling, Defense, offer, transmission of SARS-CoV-2, caused, inhibit, provide, promote, restrict, activate, cleave, blunt, physical barrier, the SARS-CoV-2, 【제목키워드】 response, Innate, targeting,