Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
University of Chinese Academy of Sciences, Beijing, China.
Nat Cell Biol. 2024 May;26(5):757-769. doi: 10.1038/s41556-024-01397-9. Epub 2024 Mar 27.
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.
Gasdermin D (GSDMD) 是细胞焦亡的执行者，在宿主抵御病原体感染的防御中发挥着重要作用。在激活后，半胱天冬酶介导的 GSDMD 的切割释放出一个氨基末端片段（GSDMD-NT），该片段寡聚化并在质膜上形成孔，导致细胞死亡和促炎细胞因子的释放。该过程在细胞中的时空调节仍不清楚。在这里，我们确定 GSDMD 是细胞焦亡过程中 C192 上可逆 S-棕榈酰化的底物。棕榈酰转移酶 DHHC7 棕榈酰化 GSDMD 以指导其被半胱天冬酶切割。随后，GSDMD-NT 的棕榈酰化促进其向质膜的易位，在质膜上，APT2 去棕榈酰化 GSDMD-NT 以暴露 C192 残基并促进 GSDMD-NT 寡聚化。棕榈酰化或去棕榈酰化的干扰抑制细胞焦亡，导致脂多糖诱导的致命性败血症休克小鼠的存活率增加，并增加对细菌感染的敏感性。我们的研究结果揭示了一个模型，通过该模型，一个棕榈酰化-去棕榈酰化接力在细胞焦亡过程中时空控制 GSDMD 的激活。
