TRIM35 Negatively Regulates the cGAS-STING-Mediated Signaling Pathway by Attenuating K63-Linked Ubiquitination of

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Jikai Zhang1,2, Yuhao Wu1, Yiwen Wang1

  • 1Xuzhou Medical University, Xuzhou, China.

Inflammation
|August 1, 2024
PubMed

Insights

Tripartite motif protein 35 (TRIM35) negatively regulates the cGAS-STING antiviral pathway. TRIM35 deubiquitinates STING, inhibiting type I interferon production and viral defense.

Area of Science:

  • Immunology
  • Virology
  • Molecular Biology

Background:

  • The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is crucial for antiviral immunity against DNA viruses.
  • Tripartite motif protein 35 (TRIM35) is known to positively regulate retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling.
  • The role of TRIM35 in the cGAS-STING pathway remained unclear.

Purpose of the Study:

  • To investigate the function of TRIM35 in the cGAS-STING signaling pathway.
  • To elucidate the mechanism by which TRIM35 affects cGAS-STING-mediated antiviral responses.

Main Methods:

  • Co-immunoprecipitation assays to confirm TRIM35 and STING interaction.
  • Western blotting to detect phosphorylation of TBK1 and IRF3.
  • Interferon-beta (IFN-β) reporter assays.
  • Site-directed mutagenesis of TRIM35's RING domain.

Main Results:

  • TRIM35 negatively regulates the cGAS-STING pathway by directly interacting with STING.
  • TRIM35 overexpression inhibited cGAMP-induced phosphorylation of TBK1 and IRF3, reducing IFN-β production.
  • TRIM35 deubiquitinates STING at K63-linked ubiquitin chains, impairing STING's interaction with TBK1/IKKε.
  • The RING domain of TRIM35 is essential for its antiviral activity.

Conclusions:

  • TRIM35 acts as a negative regulator of the cGAS-STING pathway.
  • TRIM35 inhibits type I interferon (IFN-I) production by deubiquitinating STING.
  • TRIM35 represents a potential therapeutic target for managing viral infections.
Keywords:
Antiviral responseSTINGTRIM35UbiquitinationcGAS-STING signaling

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