TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing

Gil Ju Seo, Charlotte Kim, Woo-Jin Shin, Ella H. Sklan, Hyungjin Eoh and Jae U. Jung ()
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Gil Ju Seo: University of Southern California
Charlotte Kim: University of Southern California
Woo-Jin Shin: University of Southern California
Ella H. Sklan: University of Southern California
Hyungjin Eoh: University of Southern California
Jae U. Jung: University of Southern California

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-02936-3

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