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.

中文翻译：

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ZDHHC18 通过棕榈酰化负向调节 cGAS 介导的先天免疫。

双链 DNA 被环磷酸鸟苷-磷酸腺苷合酶 (cGAS) 识别为危险信号，触发先天免疫反应。棕榈酰化是一种重要的翻译后修饰 (PTM)，由 DHHC-棕榈酰转移酶催化，参与多种生物过程的调节。然而，棕榈酰化是否调节 cGAS 功能尚未探索。在这里，我们发现 cGAS 在 C474 处的棕榈酰化在双链 DNA 存在的情况下限制了其酶活性。cGAS 棕榈酰化主要由棕榈酰转移酶 ZDHHC18 催化，双链 DNA 促进了这种修饰。从机制上讲，cGAS 的棕榈酰化降低了 cGAS 与双链 DNA 之间的相互作用，进一步抑制了 cGAS 二聚化。始终如一，ZDHHC18 负向调节人和小鼠细胞系中的 cGAS 激活。在更具生物学相关性的模型系统中，发现 Zdhhc18 缺陷小鼠对 DNA 病毒感染具有抵抗力，这与 ZDHHC18 负调节人和小鼠原代细胞中 cGAS 介导的先天免疫反应的观察结果一致。总之，ZDHHC18 介导的 cGAS 棕榈酰化的负面作用可能是先天免疫微调中的一种新型调节机制。