SARS-CoV-2 N Protein Antagonizes Stress Granule Assembly and IFN Production by Interacting with G3BPs to Facilitate Viral Replication
Open Access
- 2 June 2022
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 96 (12), e0041222
- https://doi.org/10.1128/jvi.00412-22
Abstract
In this study, by in vitro assay and live SARS-CoV-2 virus infection, we provide solid evidence that the SARS-CoV-2 NP associates with G3BP1 and G3BP2 in vitro and in vivo. NPSARS-CoV-2 could efficiently suppress G3BP-mediated SG formation and potentiate viral infection by overcoming antiviral innate immunity mediated by G3BP1 in A549 cell lines and G3BP1 conditional knockout mice (g3bp1-cKO) mice, which provide in-depth evidence showing the mechanism underlying NP-related SARS-CoV-2 pathogenesis through G3BPs. SARS-CoV-2 is the causative agent of the ongoing pandemic of coronavirus disease 2019 (COVID-19) and poses a significant threat to global health. N protein (NP), which is a major pathogenic protein among betacoronaviruses, binds to the viral RNA genome to allow viral genome packaging and viral particle release. Recent studies showed that NP antagonizes interferon (IFN) induction and mediates phase separation. Using live SARS-CoV-2 viruses, this study provides solid evidence showing that SARS-CoV-2 NP associates with G3BP1 and G3BP2 in vitro and in vivo. NPSARS-CoV-2 could efficiently suppress G3BP-mediated SG formation and potentiate viral infection by overcoming G3BP1-mediated antiviral innate immunity. G3BP1 conditional knockout mice (g3bp1(fl/fL), Sftpc-Cre) exhibit significantly higher lung viral loads after SARS-CoV-2 infection than wild-type mice. Our findings contribute to the growing body of knowledge regarding the pathogenicity of NPSARS-CoV-2 and provide insight into new therapeutics targeting NPSARS-CoV-2. IMPORTANCE In this study, by in vitro assay and live SARS-CoV-2 virus infection, we provide solid evidence that the SARS-CoV-2 NP associates with G3BP1 and G3BP2 in vitro and in vivo. NPSARS-CoV-2 could efficiently suppress G3BP-mediated SG formation and potentiate viral infection by overcoming antiviral innate immunity mediated by G3BP1 in A549 cell lines and G3BP1 conditional knockout mice (g3bp1-cKO) mice, which provide in-depth evidence showing the mechanism underlying NP-related SARS-CoV-2 pathogenesis through G3BPs.Keywords
Funding Information
- National Natural Science Foundation of China (82101865)
This publication has 30 references indexed in Scilit:
- G3BP1 inhibits RNA virus replication by positively regulating RIG-I-mediated cellular antiviral responseCell Death & Disease, 2019
- G3BP1 promotes DNA binding and activation of cGASNature Immunology, 2018
- Zika Virus Hijacks Stress Granule Proteins and Modulates the Host Stress ResponseJournal of Virology, 2017
- Translation inhibition and stress granules in the antiviral immune responseNature Reviews Immunology, 2017
- The Severe Acute Respiratory Syndrome Coronavirus Nucleocapsid Inhibits Type I Interferon Production by Interfering with TRIM25-Mediated RIG-I UbiquitinationJournal of Virology, 2017
- Co-transfection and tandem transfection of HEK293A cells for overexpression and RNAi experimentsCell Biology International, 2011
- Structure of the SARS Coronavirus Nucleocapsid Protein RNA-binding Dimerization Domain Suggests a Mechanism for Helical Packaging of Viral RNAJournal of Molecular Biology, 2007
- IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptorsNature Reviews Immunology, 2006
- Control of Fetal Growth and Neonatal Survival by the RasGAP-Associated Endoribonuclease G3BPMolecular and Cellular Biology, 2005
- RETRACTED: The RasGAP-associated endoribonuclease G3BP assembles stress granulesThe Journal of cell biology, 2003