Journal Article

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

Han, Lulu, Xu, Yanwen, Zhang, Jing, Zhan, Peng, Wang, Pei-Hui, Zheng, Yi, Nan, Mei-Ling, Deng, Jian, Liu, Xinyong, Zhuang, Meng-Wei, Xiao, Yang, Gao, Chengjiang

2022

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 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