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

• Published in: Signal transduction and targeted therapy Vol. 7; no. 1; pp. 22 - 12
• Main Authors: Zheng, Yi, Deng, Jian, Han, Lulu, Zhuang, Meng-Wei, Xu, Yanwen, Zhang, Jing, Nan, Mei-Ling, Xiao, Yang, Zhan, Peng, Liu, Xinyong, Gao, Chengjiang, Wang, Pei-Hui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.01.2022; Nature Publishing Group
• Subjects: 631/250/262; 692/699/255; Animals; Antiviral drugs; Cancer Research; Cell Biology; Chlorocebus aethiops; Cofactors; Coronavirus 3C Proteases - genetics; Coronavirus 3C Proteases - immunology; Coronavirus Nucleocapsid Proteins - genetics; Coronavirus Nucleocapsid Proteins - immunology; Coronaviruses; COVID-19; DEAD Box Protein 58 - genetics; DEAD Box Protein 58 - immunology; DNA Helicases - genetics; DNA Helicases - immunology; Double-stranded RNA; Ectopic expression; Gene Expression Regulation; HEK293 Cells; HeLa Cells; Humans; Immune Evasion; Infections; Innate immunity; Interferon; Interferon regulatory factor 3; Internal Medicine; Medicine; Medicine & Public Health; N protein; Oncology; Pathology; Phosphoproteins - genetics; Phosphoproteins - immunology; Phosphorylation; Poly I-C - pharmacology; Poly-ADP-Ribose Binding Proteins - genetics; Poly-ADP-Ribose Binding Proteins - immunology; Polyinosinic:polycytidylic acid; Protein Binding; Proteins; Receptors, Immunologic - genetics; Receptors, Immunologic - immunology; RNA Helicases - genetics; RNA Helicases - immunology; RNA Recognition Motif Proteins - genetics; RNA Recognition Motif Proteins - immunology; RNA, Double-Stranded - genetics; RNA, Double-Stranded - immunology; RNA-Binding Proteins - genetics; RNA-Binding Proteins - immunology; SARS-CoV-2 - genetics; SARS-CoV-2 - immunology; SARS-CoV-2 - pathogenicity; Sendai virus - genetics; Sendai virus - immunology; Severe acute respiratory syndrome coronavirus 2; Signal Transduction; Stomatitis; Stress Granules - drug effects; Stress Granules - genetics; Stress Granules - immunology; Stress Granules - virology; Transfection; Vero Cells; Vesiculovirus - genetics; Vesiculovirus - immunology
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-022-00878-3

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.