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SARS-COV-2 protein NSP9 promotes cytokine production by targeting TBK1

Yihua Zhang1, Bowen Xin1, Yinan Liu1

  • 1Department of Immunology, School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity & Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.

Frontiers in Immunology
|October 19, 2023
PubMed

Insights

SARS-CoV-2 protein NSP9 triggers cytokine storms by activating TBK1, leading to tissue damage and death. Inhibiting NSP9 degradation offers a potential COVID-19 treatment strategy.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Cytokine storms from SARS-CoV-2 infection can cause severe tissue damage and mortality.
  • The precise molecular mechanisms by which SARS-CoV-2 induces cytokine storms remain incompletely understood.

Purpose of the Study:

  • To elucidate the mechanism of SARS-CoV-2-induced cytokine storm.
  • To identify potential therapeutic targets for COVID-19.

Main Methods:

  • Investigated the interaction between SARS-CoV-2 protein NSP9 and TANK-binding kinase-1 (TBK1).
  • Utilized an rVSV-NSP9 virus infection model in mice.
  • Analyzed protein ubiquitination, phosphorylation, and translocation pathways.

Main Results:

  • SARS-CoV-2 NSP9 directly interacts with and activates TBK1, promoting cytokine production.
  • NSP9 induces K63-linked ubiquitination and phosphorylation of TBK1, leading to IRF3 activation and cytokine release.
  • The E3 ligase MID1 targets NSP9 for degradation, but SARS-CoV-2 infection disrupts this interaction, stabilizing NSP9.

Conclusions:

  • SARS-CoV-2 protein NSP9 is a key driver of cytokine storms via TBK1 activation.
  • Disrupting NSP9-TBK1 interaction or enhancing NSP9 degradation are potential therapeutic strategies for COVID-19.
Keywords:
SARS-CoV-2TBK1antiviral immunitycytokine stormtype I interferon

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