Plasma membrane perforation elicited by caspase cleavage of the gasdermin D (GSDMD) N-terminal domain (GSDMD-NT) triggers pyroptosis. The mechanisms underlying GSDMD membrane translocation and pore formation are not fully understood. Here, using a proteomic approach, we identified fatty acid synthase (FASN) as a GSDMD-binding partner. S-palmitoylation of GSDMD at Cys¹⁹¹/Cys¹⁹² (human/mouse), catalyzed by palmitoyl acyltransferases ZDHHC5 and ZDHHC9 and facilitated by reactive oxygen species (ROS), directly mediated membrane translocation of GSDMD-NT but not full-length GSDMD (GSDMD-FL). Palmitoylation of GSDMD-FL could be induced before inflammasome activation by stimuli such as lipopolysaccharide (LPS), consequently serving as an essential molecular event in macrophage priming. Inhibition of GSDMD palmitoylation suppressed macrophage pyroptosis and IL-1β release, mitigated organ damage, and enhanced the survival of septic mice. Thus, GSDMD-NT palmitoylation is a key regulatory mechanism controlling GSDMD membrane localization and activation, which may offer an additional target for modulating immune activity in infectious and inflammatory diseases.

中文翻译：

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Gasdermin D 的棕榈酰化在焦亡过程中指导其膜易位和孔形成

Caspase 裂解 Gasdermin D (GSDMD) N 末端结构域 (GSDMD-NT) 引起的质膜穿孔会引发细胞焦亡。 GSDMD 膜易位和孔形成的机制尚不完全清楚。在这里，我们使用蛋白质组学方法，确定了脂肪酸合酶 (FASN) 作为 GSDMD 结合伴侣。 GSDMD 在 Cys ¹⁹¹ /Cys ¹⁹²（人/小鼠）处的 S-棕榈酰化，由棕榈酰酰基转移酶 ZDHHC5 和 ZDHHC9 催化，并由活性氧 (ROS) 促进，直接介导 GSDMD-NT 的膜易位，但不是全长 GSDMD (GSDMD) -FL）。 GSDMD-FL 的棕榈酰化可以在脂多糖 (LPS) 等刺激激活炎症小体之前被诱导，因此成为巨噬细胞启动中的重要分子事件。抑制 GSDMD 棕榈酰化可抑制巨噬细胞焦亡和 IL-1β 释放，减轻器官损伤，并提高脓毒症小鼠的存活率。因此，GSDMD-NT 棕榈酰化是控制 GSDMD 膜定位和激活的关键调节机制，这可能为调节传染性和炎症性疾病中的免疫活性提供额外的靶点。