SARS-CoV-2 NSP5 and N protein counteract the RIG-I signaling pathway by suppressing the formation of stress granules.

Abstract

As a highly pathogenic human coronavirus, SARS-CoV-2 has to counteract an intricate network of antiviral host responses to establish infection and spread. The nucleic acid-induced stress response is an essential component of antiviral defense and is closely related to antiviral innate immunity. However, whether SARS-CoV-2 regulates the stress response pathway to achieve immune evasion remains elusive. In this study, SARS-CoV-2 NSP5 and N protein were found to attenuate antiviral stress granule (avSG) formation. Moreover, NSP5 and N suppressed IFN expression induced by infection of Sendai virus or transfection of a synthetic mimic of dsRNA, poly (I:C), inhibiting TBK1 and IRF3 phosphorylation, and restraining the nuclear translocalization of IRF3. Furthermore, HEK293T cells with ectopic expression of NSP5 or N protein were less resistant to vesicular stomatitis virus infection. Mechanistically, NSP5 suppressed avSG formation and disrupted RIG-I-MAVS complex to attenuate the RIG-I-mediated antiviral immunity. In contrast to the multiple targets of NSP5, the N protein specifically targeted cofactors upstream of RIG-I. The N protein interacted with G3BP1 to prevent avSG formation and to keep the cofactors G3BP1 and PACT from activating RIG-I. Additionally, the N protein also affected the recognition of dsRNA by RIG-I. This study revealed the intimate correlation between SARS-CoV-2, the stress response, and innate antiviral immunity, shedding light on the pathogenic mechanism of COVID-19.

• Authors: Yi Zheng, Jian Deng, Lulu Han, Meng-Wei Zhuang, Yanwen Xu, Jing Zhang, Mei-Ling Nan, Yang Xiao, Peng Zhan, Xinyong Liu, Chengjiang Gao, Pei-Hui Wang
• Journal: Signal transduction and targeted therapy (Signal Transduct Target Ther) Vol. 7 Issue 1 Pg. 22 (01 24 2022) ISSN: 2059-3635 [Electronic] England
• PMID: 35075101 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Coronavirus Nucleocapsid Proteins
• PRKRA protein, human
• Phosphoproteins
• Poly-ADP-Ribose Binding Proteins
• RNA Recognition Motif Proteins
• RNA, Double-Stranded
• RNA-Binding Proteins
• Receptors, Immunologic
• nucleocapsid phosphoprotein, SARS-CoV-2
• 3C-like proteinase, SARS-CoV-2
• Coronavirus 3C Proteases
• RIGI protein, human
• DNA Helicases
• G3BP1 protein, human
• DEAD Box Protein 58
• RNA Helicases
• Poly I-C

Topics

• Animals
• Chlorocebus aethiops
• Coronavirus 3C Proteases (genetics, immunology)
• Coronavirus Nucleocapsid Proteins (genetics, immunology)
• DEAD Box Protein 58 (genetics, immunology)
• DNA Helicases (genetics, immunology)
• Gene Expression Regulation
• HEK293 Cells
• HeLa Cells
• Humans
• Immune Evasion
• Phosphoproteins (genetics, immunology)
• Poly I-C (pharmacology)
• Poly-ADP-Ribose Binding Proteins (genetics, immunology)
• Protein Binding
• RNA Helicases (genetics, immunology)
• RNA Recognition Motif Proteins (genetics, immunology)
• RNA, Double-Stranded (genetics, immunology)
• RNA-Binding Proteins (genetics, immunology)
• Receptors, Immunologic (genetics, immunology)
• SARS-CoV-2 (genetics, immunology, pathogenicity)
• Sendai virus (genetics, immunology)
• Signal Transduction
• Stress Granules (drug effects, genetics, immunology, virology)
• Vero Cells
• Vesiculovirus (genetics, immunology)