首页|Natural evidence of coronaviral 2'-O-methyltransferase activity affecting viral pathogenesis via improved substrate RNA binding
Natural evidence of coronaviral 2'-O-methyltransferase activity affecting viral pathogenesis via improved substrate RNA binding
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Previous studies through targeted mutagenesis of K-D-K-E motif have demonstrated that 2'-O-MTase activity is essential for efficient viral replication and immune evasion.However,the K-D-K-E catalytic motif of 2'-O-MTase is highly conserved across numerous viruses,including flaviviruses,vaccinia viruses,coronaviruses,and extends even to mammals.Here,we observed a stronger 2'-O-MTase activity in SARS-CoV-2 compared to SARS-CoV,despite the presence of a consistently active catalytic center.We further identified critical residues(Leu-36,Asn-138 and lle-153)which served as determinants of discrepancy in 2'-O-MTase activity between SARS-CoV-2 and SARS-CoV.These residues significantly enhanced the RNA binding affinity of 2'-O-MTase and boosted its versatility toward RNA substrates.Of interest,a triple substitution(Leu36 → Ile36,Asn138 → His138,Ile153 → Leu153,from SARS-CoV-2 to SARS-CoV)within nsp16 resulted in a proportional reduction in viral 2'-O-methylation and impaired viral replication.Furthermore,it led to a significant upregulation of type Ⅰ interferon(IFN-Ⅰ)and proinflammatory cytokines both in vitro and vivo,relying on the cooperative sensing of melanoma differentiation-associated protein 5(MDA5)and laboratory of genetics and physiology 2(LGP2).In conclusion,our findings demonstrated that alterations in residues other than K-D-K-E of 2'-O-MTase may affect viral replication and subsequently influence pathogenesis.Monitoring changes in nsp16 residues is crucial as it may aid in identifying and assessing future alteration in viral pathogenicity resulting from natural mutations occurring in nsp16.
State Key Laboratory of Virology,RNA Institute,College of Life Sciences and Frontier Science Center for Immunology and Metabolism,Wuhan University,Wuhan,China
School of Medicine,Tsinghua University,Beijing,China
School of Basic Medical Sciences,Wuhan University,Wuhan,China
Animal Bio-Safety Level Ⅲ Laboratory/Institute for Vaccine Research,Wuhan University School of Medicine,Wuhan,China
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National Key R&D Program of ChinaChina NSFC projectsChina NSFC projectsChina NSFC projectsFundamental Research Funds for Central UniversitiesFundamental Research Funds for Central Universities
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