ZDHHC18 negatively regulates cGAS‐mediated innate immunity through palmitoylation

Abstract

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.

Diagnostic Biomarkers Screened by Machine Learning Algorithms in Ankylosing Spondilytis

“…In addition, palmitoylation of LCK could promote the T cell receptor signaling to activate T cells, while this was not seen in our study, which meant that it's not important in the pathogenesis of AS. Furthermore, ZDHHC18 could negatively regulate CGAS-STING signaling mediated antiviral innate immunity by palmitoylation of cGAS, which meant that the antiviral immunity in AS patient's might be impaired by high expression of ZDHHC18 [43]. In our study, KEGG and GSEA also indicated dysregulation in some antiviral immune pathways.…”

“…Researches on ZDHHC18 were rare and insufficient. Currently, it's reported to be associated with innate immunity [43], glioma [44], ovarian cancer [45], schizophrenia [46]. The common palmitoylation substrates of ZDHHC18 was HRAS and LCK [47][48][49].…”

Novel peripheral blood diagnostic biomarkers screened by machine learning algorithms in ankylosing spondylitis

“…Studies on ZDHHC18 are rare and insufficient. Currently, it is reported to be associated with innate immunity ( Shi et al, 2022 ), glioma ( Chen et al, 2019 ), ovarian cancer ( Pei et al, 2022 ), and schizophrenia ( Zhao et al, 2018 ). The common palmitoylation substrates of ZDHHC18 are HRAS and LCK ( Baumgart et al, 2010 ; Akimzhanov and Boehning, 2015 ; Adachi et al, 2016 ).…”

“…In addition, the palmitoylation of LCK could promote T-cell receptor signaling to activate T cells, although this was not seen in our study, which meant that it is not important in the pathogenesis of AS. Furthermore, ZDHHC18 could negatively regulate CGAS-STING signaling–mediated antiviral innate immunity via the palmitoylation of cGAS, which means that the antiviral immunity in AS patients might be impaired by the high expression of ZDHHC18 ( Shi et al, 2022 ). In our study, KEGG and GSEA also indicated dysregulation in some antiviral immune pathways.…”

Regulation of cGAS/STING signaling and corresponding immune escape strategies of viruses

“…Then, cytosolic PARP1 directly interacts with and PARylates cGAS at Asp191, which impairs its DNA-binding ability and inhibits antiviral immunity ( Wang et al., 2022 ). The palmitoyltransferase ZDHHC18 catalyzes the palmitoylation of cGAS at C474 to restrict the interaction between cGAS and DNA ( Shi et al., 2022 ). The glutamylation and deglutamylation of cGAS are also intimately related to its activity.…”