ZDHHC18 negatively regulates cGAS-mediated innate immunity through palmitoylation
ZDHHC18 negatively regulates cGAS-mediated innate immunity through palmitoylation
复制标题
ZDHHC18 通过棕榈酰化负向调节 cGAS 介导的先天免疫
DOI：
10.15252/embj.2021109272
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发表时间：
2022-04-19
期刊：
影响因子：
11.4
通讯作者：
Yin, Hang
中科院分区：
文献类型：
--
作者：
Shi, Chengrui;Yang, Xikang;Yin, Hang
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DHHC-棕榈酰转移酶催化的一种重要的翻译后修饰（PTM），参与多种生物过程的调节。然而，棕榈酰化是否调节 cGAS 功能尚未被探索。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 的棕榈酰化减少了 cGAS 与双链 DNA 之间的相互作用，进一步抑制 cGAS 二聚化。一致地，ZDHHC18 在人和小鼠细胞系中负向调节 cGAS 激活。在一个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 负向调节人类和小鼠原代细胞中 cGAS 介导的先天免疫反应的观察结果一致。综上所述，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的调节机制。
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.