[HTML][HTML] TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing

GJ Seo, C Kim, WJ Shin, EH Sklan, H Eoh… - Nature …, 2018 - nature.com
Nature communications, 2018nature.com
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 …
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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