美国哈佛医学院Hao Wu等研究人员合作发现，依赖于ROS的S-棕榈酰化可激活切割的和完整的gasdermin D。相关论文于2024年4月10日在线发表在《自然》杂志上。

研究人员表示，gasdermin D（GSDMD）是炎性细胞活化下游细胞因子分泌和焦亡的共同效应物，以前的研究表明它在被炎性Caspase酶切割生成GSDMD N端结构域（GSDMD-NT）时会形成大型跨膜孔。

研究人员报告了GSDMD Cys191的S-棕榈酰化，而棕榈酰化是孔形成所必需的。S-棕榈酰化不会影响GSDMD的切割，但线粒体产生的活性氧（ROS）会增强其作用。令人惊讶的是，切割缺陷的D275A GSDMD在炎性小体刺激或ROS激活剂处理后也会发生棕榈酰化，并导致焦亡，但其效率低于棕榈酰化的GSDMD-NT。棕榈酰化而非非棕榈酰化的全长GSDMD可诱导脂质体渗漏，并形成与冷冻电镜显示的GSDMD-NT孔结构相似的孔。其他人类gasdermin的N端也存在棕榈酰化。

这些数据对“切割是GSDMD激活的唯一触发因素”这一观点提出了质疑。它们表明，可逆棕榈酰化是GSDMD-NT和完整GSDMD形成孔的一个检查点，并且是激活这一孔形成家族的通用开关。

附：英文原文

Title: ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D

Author: Du, Gang, Healy, Liam B., David, Liron, Walker, Caitlin, El-Baba, Tarick J., Lutomski, Corinne A., Goh, Byoungsook, Gu, Bowen, Pi, Xiong, Devant, Pascal, Fontana, Pietro, Dong, Ying, Ma, Xiyu, Miao, Rui, Balasubramanian, Arumugam, Puthenveetil, Robbins, Banerjee, Anirban, Luo, Hongbo R., Kagan, Jonathan C., Oh, Sungwhan F., Robinson, Carol V., Lieberman, Judy, Wu, Hao

Issue&Volume: 2024-04-10

Abstract: 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 upon cleavage by inflammatory caspases to generate the GSDMD N-terminal domain (GSDMD-NT)1-10. Here we report that GSDMD Cys191 is S-palmitoylated and palmitoylation is required for pore formation. S-palmitoylation, which does not affect GSDMD cleavage, is augmented by mitochondria-generated reactive oxygen species (ROS). Surprisingly, cleavage-deficient D275A GSDMD 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 in 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 serves as a general switch for the activation of this pore-forming family.

DOI: 10.1038/s41586-024-07373-5

Source: https://www.nature.com/articles/s41586-024-07373-5