tetano
Editor, Senior Moderator
mBio
. 2021 Sep 21;e0233521.
doi: 10.1128/mBio.02335-21. Online ahead of print.
SARS-CoV-2 Nsp5 Demonstrates Two Distinct Mechanisms Targeting RIG-I and MAVS To Evade the Innate Immune Response
Yongzhen Liu[SUP] 1 [/SUP], Chao Qin[SUP] 1 [/SUP], Youliang Rao[SUP] 1 [/SUP], Chau Ngo[SUP] 2 [/SUP], Joshua J Feng[SUP] 2 [/SUP], Jun Zhao[SUP] 1 3 [/SUP], Shu Zhang[SUP] 1 [/SUP], Ting-Yu Wang[SUP] 1 [/SUP], Jessica Carriere[SUP] 1 [/SUP], Ali Can Savas[SUP] 1 [/SUP], Mehrnaz Zarinfar[SUP] 1 [/SUP], Stephanie Rice[SUP] 1 [/SUP], Hanging Yang[SUP] 4 [/SUP], Weiming Yuan[SUP] 5 [/SUP], Julio A Camarero[SUP] 6 [/SUP], Jianhua Yu[SUP] 7 [/SUP], Xiaojiang S Chen[SUP] 4 [/SUP], Chao Zhang[SUP] 2 [/SUP], Pinghui Feng[SUP] 1 [/SUP]
Affiliations
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. 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.
. 2021 Sep 21;e0233521.
doi: 10.1128/mBio.02335-21. Online ahead of print.
SARS-CoV-2 Nsp5 Demonstrates Two Distinct Mechanisms Targeting RIG-I and MAVS To Evade the Innate Immune Response
Yongzhen Liu[SUP] 1 [/SUP], Chao Qin[SUP] 1 [/SUP], Youliang Rao[SUP] 1 [/SUP], Chau Ngo[SUP] 2 [/SUP], Joshua J Feng[SUP] 2 [/SUP], Jun Zhao[SUP] 1 3 [/SUP], Shu Zhang[SUP] 1 [/SUP], Ting-Yu Wang[SUP] 1 [/SUP], Jessica Carriere[SUP] 1 [/SUP], Ali Can Savas[SUP] 1 [/SUP], Mehrnaz Zarinfar[SUP] 1 [/SUP], Stephanie Rice[SUP] 1 [/SUP], Hanging Yang[SUP] 4 [/SUP], Weiming Yuan[SUP] 5 [/SUP], Julio A Camarero[SUP] 6 [/SUP], Jianhua Yu[SUP] 7 [/SUP], Xiaojiang S Chen[SUP] 4 [/SUP], Chao Zhang[SUP] 2 [/SUP], Pinghui Feng[SUP] 1 [/SUP]
Affiliations
- PMID: 34544279
- DOI: 10.1128/mBio.02335-21
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. 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.