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Phase-separated nucleocapsid protein of SARS-CoV-2 suppresses cGAS-DNA recognition by disrupting cGAS-G3BP1 complex

Sihui Cai1,2, Chenqiu Zhang1,2, Zhen Zhuang3

  • 1Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, The First Affiliated Hospital of Sun Yat-sen University, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China.

Signal Transduction and Targeted Therapy
|April 26, 2023
PubMed

Insights

SARS-CoV-2 hinders the body's antiviral defenses by blocking the cGAS-STING pathway. The virus's nucleocapsid protein prevents DNA sensing, thus reducing type I interferon signaling crucial for fighting infection.

Area of Science:

  • Immunology
  • Virology
  • Molecular Biology

Background:

  • SARS-CoV-2 infection is associated with suppressed type I interferon (IFN-I) signaling, impairing antiviral responses.
  • While SARS-CoV-2 strategies against RNA sensing are known, its antagonism of DNA sensing pathways like cGAS remains unclear.

Purpose of the Study:

  • To investigate the antagonism of cGAS-mediated IFN-I responses by SARS-CoV-2 during infection.
  • To elucidate the molecular mechanisms by which SARS-CoV-2 interferes with DNA sensing pathways.

Main Methods:

  • Studied the impact of SARS-CoV-2 infection on mitochondrial DNA (mtDNA) release and cGAS activation.
  • Investigated the role of SARS-CoV-2 nucleocapsid (N) protein in inhibiting cGAS-DNA binding and IFN-I signaling.
  • Utilized liquid-liquid phase separation (LLPS) assays to analyze the interaction between N protein, cGAS, and dsDNA.

Main Results:

  • SARS-CoV-2 infection causes accumulation of released mtDNA, which normally activates cGAS and IFN-I signaling.
  • The SARS-CoV-2 N protein inhibits cGAS-mediated IFN-I signaling by disrupting cGAS-DNA recognition.
  • N protein interferes with cGAS-G3BP1 co-factor assembly via DNA-induced LLPS, impairing dsDNA detection.

Conclusions:

  • SARS-CoV-2 employs a novel antagonistic strategy to evade innate immunity by disrupting cGAS-DNA phase separation.
  • This mechanism effectively impairs the DNA-triggered IFN-I pathway, contributing to viral infectivity and pathogenesis.

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