2. Academic Validation
  3. TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing

TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing

  • Nat Commun. 2018 Feb 9;9(1):613. doi: 10.1038/s41467-018-02936-3.
Gil Ju Seo 1,  Charlotte Kim 1,  Woo-Jin Shin 1,  Ella H Sklan 1 2,  Hyungjin Eoh 1,  Jae U Jung 3
Affiliations

Affiliations

  • 1 Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
  • 2 Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, 69978, Israel.
  • 3 Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA. jaeujung@med.usc.edu.
PMID: 29426904 DOI: 10.1038/s41467-018-02936-3
Abstract

Intracellular nucleic acid sensors often undergo sophisticated modifications that are critical for the regulation of antimicrobial responses. Upon recognition of DNA, the cytosolic sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) produces the second messenger cGAMP, which subsequently initiates downstream signaling to induce interferon-αβ (IFNαβ) production. Here we report that TRIM56 E3 ligase-induced monoubiquitination of cGAS is important for cytosolic DNA sensing and IFNαβ production to induce anti-DNA viral immunity. TRIM56 induces the Lys335 monoubiquitination of cGAS, resulting in a marked increase of its dimerization, DNA-binding activity, and cGAMP production. Consequently, TRIM56-deficient cells are defective in cGAS-mediated IFNαβ production upon herpes simplex virus-1 (HSV-1) Infection. Furthermore, TRIM56-deficient mice show impaired IFNαβ production and high susceptibility to lethal HSV-1 Infection but not to influenza A virus Infection. This adds TRIM56 as a crucial component of the cytosolic DNA sensing pathway that induces anti-DNA viral innate immunity.

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