ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D.
ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D.
复制标题
ROS 依赖性 S-棕榈酰化可激活裂解且完整的gasdermin D。
DOI：
10.1038/s41586-024-07373-5
复制
发表时间：
2024
期刊：
影响因子：
64.8
通讯作者：
Bane
中科院分区：
文献类型：
--
作者：
Du,Gang;Healy,LiamB;David,Liron;Walker,Caitlin;El-Baba,TarickJ;Lutomski,CorinneA;Goh,Byoungsook;Gu,Bowen;Pi,Xiong;Devant,Pascal;Fontana,Pietro;Dong,Ying;Ma,Xiyu;Miao,Rui;Balasubramanian,Arumugam;Puthenveetil,Robbins;Bane
Gasdermin D(GSDMD)是炎性小体激活下游细胞因子分泌和下垂的共同效应因子，先前被炎性caspase切割后形成大的跨膜孔，产生GSDMD-NT，，，-。在这里，我们报告了GSDMD Cys191 ISS-棕榈酰化，并且棕榈酰化是孔道形成所必需的。S-棕榈酰化，不影响GSDMD的切割，被线粒体产生的活性氧(ROS)所增强。裂解缺陷的GSDMD基因(D275A)在炎症小体刺激或用ROS激活剂治疗后也被棕榈酰化，并导致下垂，尽管不如棕榈酰化的GSDMD-NT有效。棕榈酰化的，但不是非棕榈酰化的，全长的GSDMD会导致脂质体泄漏，并形成结构类似于低温电子显微镜所示的GSDMD-NT的孔。ZDHHC5和ZDHHC9是介导GSDMD棕榈酰化的主要棕榈酰基转移酶，它们的表达受炎症小体激活和ROS的上调。其他的人类瓦斯蛋白也在其N端被棕榈酰化。这些数据挑战了卵裂是GSDMD激活的唯一触发因素的概念。他们认为可逆的棕榈酰化是GSDMD-NT和完整的GSDMD形成孔的检查点，它起着激活这个孔形成家族的总开关的作用。
Gasdermin D (GSDMD) is the common effector for cytokine secretion and pyroptosis downstream of inflammasome activation and was previously shown to form large transmembrane pores after cleavage by inflammatory caspases to generate the GSDMD N-terminal domain (GSDMD-NT), , , , , , , , –. Here we report that GSDMD Cys191 isS-palmitoylated and that palmitoylation is required for pore formation.S-palmitoylation, which does not affect GSDMD cleavage, is augmented by mitochondria-generated reactive oxygen species (ROS). Cleavage-deficient GSDMD (D275A) is also palmitoylated after inflammasome stimulation or treatment with ROS activators and causes pyroptosis, although less efficiently than palmitoylated GSDMD-NT. Palmitoylated, but not unpalmitoylated, full-length GSDMD induces liposome leakage and forms a pore similar in structure to GSDMD-NT pores shown by cryogenic electron microscopy. ZDHHC5 and ZDHHC9 are the major palmitoyltransferases that mediate GSDMD palmitoylation, and their expression is upregulated by inflammasome activation and ROS. The other human gasdermins are also palmitoylated at their N termini. These data challenge the concept that cleavage is the only trigger for GSDMD activation. They suggest that reversible palmitoylation is a checkpoint for pore formation by both GSDMD-NT and intact GSDMD that functions as a general switch for the activation of this pore-forming family.