SARS-CoV-2 Nsp5 Demonstrates Two Distinct Mechanisms Targeting RIG-I and MAVS To Evade the Innate Immune Response

• Published in: mBio Vol. 12; no. 5; p. e0233521
• Main Authors: Liu, Yongzhen, Qin, Chao, Rao, Youliang, Ngo, Chau, Feng, Joshua J., Zhao, Jun, Zhang, Shu, Wang, Ting-Yu, Carriere, Jessica, Savas, Ali Can, Zarinfar, Mehrnaz, Rice, Stephanie, Yang, Hanging, Yuan, Weiming, Camarero, Julio A., Yu, Jianhua, Chen, Xiaojiang S., Zhang, Chao, Feng, Pinghui
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 26.10.2021
• Subjects: A549 Cells; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Caco-2 Cells; Coronavirus 3C Proteases - genetics; Coronavirus 3C Proteases - metabolism; DEAD Box Protein 58 - genetics; DEAD Box Protein 58 - metabolism; Enzyme-Linked Immunosorbent Assay; HCT116 Cells; HEK293 Cells; Humans; Immunity, Innate - genetics; Immunity, Innate - physiology; Immunoblotting; Interferon Type I - metabolism; Mice; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Research Article; Reverse Transcriptase Polymerase Chain Reaction; SARS-CoV-2 - immunology; SARS-CoV-2 - pathogenicity; Signal Transduction - genetics; Signal Transduction - physiology; Ubiquitination; Virology; Virus Replication - genetics; Virus Replication - physiology; protease; MAVS; SARS-CoV-2; E3 ligase; RIG-I; small-molecule inhibitor; Nsp5
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mBio.02335-21

The ongoing COVID-19 pandemic is caused by SARS-CoV-2, which is rapidly evolving with better transmissibility. Understanding the molecular basis of the SARS-CoV-2 interaction with host cells is of paramount significance, and development of antiviral agents provides new avenues to prevent and treat COVID-19 diseases. This study describes a molecular characterization of innate immune evasion mediated by the SARS-CoV-2 Nsp5 main protease and subsequent development of a small-molecule inhibitor. 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. IMPORTANCE The ongoing COVID-19 pandemic is caused by SARS-CoV-2, which is rapidly evolving with better transmissibility. Understanding the molecular basis of the SARS-CoV-2 interaction with host cells is of paramount significance, and development of antiviral agents provides new avenues to prevent and treat COVID-19 diseases. This study describes a molecular characterization of innate immune evasion mediated by the SARS-CoV-2 Nsp5 main protease and subsequent development of a small-molecule inhibitor.