SARS-CoV-2 NSP5 and N protein counteract the RIG-I signaling pathway by suppressing the formation of stress granules.
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.
Mesh Terms:
Animals, Chlorocebus aethiops, Coronavirus 3C Proteases, Coronavirus Nucleocapsid Proteins, DEAD Box Protein 58, DNA Helicases, Gene Expression Regulation, HEK293 Cells, HeLa Cells, Humans, Immune Evasion, Phosphoproteins, Poly I-C, Poly-ADP-Ribose Binding Proteins, Protein Binding, RNA Helicases, RNA Recognition Motif Proteins, RNA, Double-Stranded, RNA-Binding Proteins, Receptors, Immunologic, SARS-CoV-2, Sendai virus, Signal Transduction, Stress Granules, Vero Cells, Vesiculovirus
Animals, Chlorocebus aethiops, Coronavirus 3C Proteases, Coronavirus Nucleocapsid Proteins, DEAD Box Protein 58, DNA Helicases, Gene Expression Regulation, HEK293 Cells, HeLa Cells, Humans, Immune Evasion, Phosphoproteins, Poly I-C, Poly-ADP-Ribose Binding Proteins, Protein Binding, RNA Helicases, RNA Recognition Motif Proteins, RNA, Double-Stranded, RNA-Binding Proteins, Receptors, Immunologic, SARS-CoV-2, Sendai virus, Signal Transduction, Stress Granules, Vero Cells, Vesiculovirus
Signal Transduct Target Ther
Date: Jan. 24, 2022
PubMed ID: 35075101
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