4.7 Article

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

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DOI: 10.1038/s41392-022-00878-3

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资金

  1. Key Research and Development Program of Shandong Province [2020CXGC011305]
  2. Natural Science Foundation of Shandong Province [ZR2020QC085]
  3. Natural Science Foundation of Jiangsu Province [BK20200225]
  4. Natural Science Foundation of China [82101856, 81930039, 31730026, 81525012, 81901604]
  5. National Key R&D Program of China [2021YFC2701203]
  6. Fundamental Research Funds of Shandong University [21510078614099]
  7. Fundamental Research Funds of Cheeloo College of Medicine [21510089393109]
  8. China Postdoctoral Science Foundation [2018M642662]
  9. Future Scholar Program of Shandong University
  10. Key Research and Development Project of Shandong Province [2020SFXGFY08]

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This study reveals the involvement of the stress response pathway and innate antiviral immunity in the pathogenic mechanism of SARS-CoV-2. NSP5 and N protein of SARS-CoV-2 were found to attenuate the formation of antiviral stress granules (avSG). NSP5 suppressed avSG formation and disrupted the RIG-I-MAVS complex to weaken the RIG-I-mediated antiviral response, while N protein specifically targeted cofactors upstream of RIG-I and affected the recognition of dsRNA by RIG-I.
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.

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