ZDHHC18 negatively regulates cGAS-mediated innate immunity through palmitoylation

Double-stranded DNA is recognized as a danger signal by cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS), triggering innate immune responses. Palmitoylation is an important post-translational modification (PTM) catalyzed by DHHC-palmitoyl transferases, which participate in the regulation of diverse biological processes. However, whether palmitoylation regulates cGAS function has not yet been explored. Here, we found that palmitoylation of cGAS at C474 restricted its enzymatic activity in the presence of double-stranded DNA. cGAS palmitoylation was catalyzed mainly by the palmitoyltransferase ZDHHC18 and double-stranded DNA promoted this modification. Mechanistically, palmitoylation of cGAS reduced the interaction between cGAS and double-stranded DNA, further inhibiting cGAS dimerization. Consistently, ZDHHC18 negatively regulated cGAS activation in human and mouse cell lines. In a more biologically relevant model system, Zdhhc18-deficient mice were found to be resistant to infection by DNA viruses, in agreement with the observation that ZDHHC18 negatively regulated cGAS mediated innate immune responses in human and mouse primary cells. In summary, the negative role of ZDHHC18-mediated cGAS palmitoylation may be a novel regulatory mechanism in the fine-tuning of innate immunity.