The Nucleocapsid Proteins of SARS-CoV-2 and Its Close Relative Bat Coronavirus RaTG13 Are Capable of Inhibiting PKR- and RNase L-Mediated Antiviral Pathways.

Autor:	LeBlanc K; Poxviruses and Vaccine Design, Division of Viral Diseases, Directorate of Science Reference and Surveillance, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada., Lynch J; Poxviruses and Vaccine Design, Division of Viral Diseases, Directorate of Science Reference and Surveillance, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada., Layne C; Poxviruses and Vaccine Design, Division of Viral Diseases, Directorate of Science Reference and Surveillance, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada., Vendramelli R; Special Pathogens, Division of Health Security and Response, Directorate of Scientific Operations and Response, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada., Sloan A; Special Pathogens, Division of Health Security and Response, Directorate of Scientific Operations and Response, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada., Tailor N; Special Pathogens, Division of Health Security and Response, Directorate of Scientific Operations and Response, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada., Deschambault Y; Special Pathogens, Division of Health Security and Response, Directorate of Scientific Operations and Response, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada., Zhang F; Department of Microbiology and Immunology, The University of Texas Health Science Center, San Antonio, Texas, USA., Kobasa D; Special Pathogens, Division of Health Security and Response, Directorate of Scientific Operations and Response, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada., Safronetz D; Special Pathogens, Division of Health Security and Response, Directorate of Scientific Operations and Response, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada., Xiang Y; Department of Microbiology and Immunology, The University of Texas Health Science Center, San Antonio, Texas, USA., Cao J; Poxviruses and Vaccine Design, Division of Viral Diseases, Directorate of Science Reference and Surveillance, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
Jazyk:	angličtina
Zdroj:	Microbiology spectrum [Microbiol Spectr] 2023 Jun 15; Vol. 11 (3), pp. e0099423. Date of Electronic Publication: 2023 May 08.
DOI:	10.1128/spectrum.00994-23
Abstrakt:	Coronaviruses (CoVs), including severe acute respiratory syndrome CoV (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), and SARS-CoV-2, produce double-stranded RNA (dsRNA) that activates antiviral pathways such as PKR and OAS/RNase L. To successfully replicate in hosts, viruses must evade such antiviral pathways. Currently, the mechanism of how SARS-CoV-2 antagonizes dsRNA-activated antiviral pathways is unknown. In this study, we demonstrate that the SARS-CoV-2 nucleocapsid (N) protein, the most abundant viral structural protein, is capable of binding to dsRNA and phosphorylated PKR, inhibiting both the PKR and OAS/RNase L pathways. The N protein of the bat coronavirus (bat-CoV) RaTG13, the closest relative of SARS-CoV-2, has a similar ability to inhibit the human PKR and RNase L antiviral pathways. Via mutagenic analysis, we found that the C-terminal domain (CTD) of the N protein is sufficient for binding dsRNA and inhibiting RNase L activity. Interestingly, while the CTD is also sufficient for binding phosphorylated PKR, the inhibition of PKR antiviral activity requires not only the CTD but also the central linker region (LKR). Thus, our findings demonstrate that the SARS-CoV-2 N protein is capable of antagonizing the two critical antiviral pathways activated by viral dsRNA and that its inhibition of PKR activities requires more than dsRNA binding mediated by the CTD. IMPORTANCE The high transmissibility of SARS-CoV-2 is an important viral factor defining the coronavirus disease 2019 (COVID-19) pandemic. To transmit efficiently, SARS-CoV-2 must be capable of disarming the innate immune response of its host efficiently. Here, we describe that the nucleocapsid protein of SARS-CoV-2 is capable of inhibiting two critical innate antiviral pathways, PKR and OAS/RNase L. Moreover, the counterpart of the closest animal coronavirus relative of SARS-CoV-2, bat-CoV RaTG13, can also inhibit human PKR and OAS/RNase L antiviral activities. Thus, the importance of our discovery for understanding the COVID-19 pandemic is 2-fold. First, the ability of SARS-CoV-2 N to inhibit innate antiviral activity is likely a factor contributing to the transmissibility and pathogenicity of the virus. Second, the bat relative of SARS-CoV-2 has the capacity to inhibit human innate immunity, which thus likely contributed to the establishment of infection in humans. The findings described in this study are valuable for developing novel antivirals and vaccines. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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