2024年3月27日，中国科学院上海有机化学研究所许代超团队在《自然—细胞生物学》杂志发表论文，提出了棕榈酰化-去棕榈酰化循环在时空上控制GSDMD在焦亡中的激活。

研究组发现消皮素D (GSDMD)是在焦亡过程中C192的可逆S-棕榈酰化的底物。棕榈酰酰基转移酶DHHC7棕榈酰化GSDMD，通过半胱天冬酶指导其剪切。随后，GSDMD-NT的棕榈酰化促进其转运到细胞质膜，在质膜上，APT2去棕榈酰化GSDMD-NT以揭开C192残基并促进GSDMD-NT寡聚。

干扰棕榈酰化或去棕榈酰化均可抑制焦亡，导致脂多糖诱导的致死性感染性休克小鼠的存活率增加，并增加对细菌感染的敏感性。他们的发现揭示了一个模型，通过该模型，棕榈酰化-去棕榈酰化循环在时空上控制焦亡过程中GSDMD的激活。

据介绍，消皮素D (GSDMD)是细胞焦亡的执行者，在宿主防御病原体感染中起重要作用。激活后，caspase介导的GSDMD剪切释放一个氨基末端片段(GSDMD-NT)，该片段寡聚化并在细胞质膜上形成孔，导致细胞死亡和释放促炎细胞因子。这一过程在细胞中的时空调控尚不清楚。

附：英文原文

Title: A palmitoylation–depalmitoylation relay spatiotemporally controls GSDMD activation in pyroptosis

Author: Zhang, Na, Zhang, Jian, Yang, Yuanxin, Shan, Hengyue, Hou, Shouqiao, Fang, Hongwen, Ma, Min, Chen, Zhongwen, Tan, Li, Xu, Daichao

Issue&Volume: 2024-03-27

Abstract: Gasdermin D (GSDMD) is the executor of pyroptosis, which is important for host defence against pathogen infection. Following activation, caspase-mediated cleavage of GSDMD releases an amino-terminal fragment (GSDMD-NT), which oligomerizes and forms pores in the plasma membrane, leading to cell death and release of proinflammatory cytokines. The spatial and temporal regulation of this process in cells remains unclear. Here we identify GSDMD as a substrate for reversible S-palmitoylation on C192 during pyroptosis. The palmitoyl acyltransferase DHHC7 palmitoylates GSDMD to direct its cleavage by caspases. Subsequently, palmitoylation of GSDMD-NT promotes its translocation to the plasma membrane, where APT2 depalmitoylates GSDMD-NT to unmask the C192 residue and promote GSDMD-NT oligomerization. Perturbation of either palmitoylation or depalmitoylation suppresses pyroptosis, leading to increased survival of mice with lipopolysaccharide-induced lethal septic shock and increased sensitivity to bacterial infection. Our findings reveal a model through which a palmitoylation–depalmitoylation relay spatiotemporally controls GSDMD activation during pyroptosis.

DOI: 10.1038/s41556-024-01397-9

Source: https://www.nature.com/articles/s41556-024-01397-9