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，对于宿主防御病原体感染非常重要。激活后，半胱天冬酶介导的 GSDMD 裂解释放氨基末端片段 (GSDMD-NT)，该片段寡聚化并在质膜中形成孔，导致细胞死亡并释放促炎细胞因子。细胞中这一过程的空间和时间调节仍不清楚。在这里，我们将 GSDMD 确定为焦亡过程中 C192 上可逆S-棕榈酰化的底物。棕榈酰酰基转移酶 DHHC7 使 GSDMD 棕榈酰化，以指导其被半胱天冬酶裂解。随后，GSDMD-NT 的棕榈酰化促进其易位至质膜，其中 APT2 使 GSDMD-NT 去棕榈酰化以暴露 C192 残基并促进 GSDMD-NT 寡聚化。棕榈酰化或去棕榈酰化的干扰可抑制细胞焦亡，从而提高脂多糖诱导的致命性败血性休克小鼠的存活率，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，棕榈酰化-去棕榈酰化中继在焦亡期间时空控制 GSDMD 激活。