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

Bibliographic Details
Title: 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
Authors: Kyle LeBlanc, Jessie Lynch, Christine Layne, Robert Vendramelli, Angela Sloan, Nikesh Tailor, Yvon Deschambault, Fushun Zhang, Darwyn Kobasa, David Safronetz, Yan Xiang, Jingxin Cao
Source: Microbiology Spectrum, Vol 11, Iss 3 (2023)
Publisher Information: American Society for Microbiology, 2023.
Publication Year: 2023
Collection: LCC:Microbiology
Subject Terms: G3BP1, PKR, RNase L, RaTG13, SARS-CoV-2 nucleocapsid, double-stranded RNA virus, Microbiology, QR1-502
More Details: ABSTRACT 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.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2165-0497
Relation: https://doaj.org/toc/2165-0497
DOI: 10.1128/spectrum.00994-23
Access URL: https://doaj.org/article/73fcb0d71715445dbe5f0a8ebe2b1962
Accession Number: edsdoj.73fcb0d71715445dbe5f0a8ebe2b1962
Database: Directory of Open Access Journals
More Details
ISSN:21650497
DOI:10.1128/spectrum.00994-23
Published in:Microbiology Spectrum
Language:English