Fumarate targets pyroptosis A form of inflammatory cell death called pyroptosis depends on the caspase-mediated cleavage of gasdermin D (GSDMD), the fragments of which assemble into permeability pores that then kill the cell. The mechanisms regulating this important cellular process are not yet fully understood. Humphries et al. now report that the tricarboxylic acid cycle intermediate fumarate can act as an inhibitor of pyroptosis (see the Perspective by Pickering and Bryant). Both endogenous fumarate and exogenously delivered dimethyl fumarate (DMF) convert the cysteines in GSDMD to S-(2-succinyl)-cysteines (a process called succination) to prevent its interaction with caspases and subsequent processing and activation. Administration of DMF to mice alleviated inflammation in models of multiple sclerosis and familial Mediterranean fever. These findings may explain the efficacy of DMF as a treatment for multiple sclerosis and other inflammatory diseases and offer insights into future anti-inflammatory drug design. Science, this issue p. 1633; see also p. 1564 The Krebs cycle intermediate fumarate prevents a type of cell death by modifying a pore-forming protein. Activated macrophages undergo a metabolic switch to aerobic glycolysis, accumulating Krebs’ cycle intermediates that alter transcription of immune response genes. We extended these observations by defining fumarate as an inhibitor of pyroptotic cell death. We found that dimethyl fumarate (DMF) delivered to cells or endogenous fumarate reacts with gasdermin D (GSDMD) at critical cysteine residues to form S-(2-succinyl)-cysteine. GSDMD succination prevents its interaction with caspases, limiting its processing, oligomerization, and capacity to induce cell death. In mice, the administration of DMF protects against lipopolysaccharide shock and alleviates familial Mediterranean fever and experimental autoimmune encephalitis by targeting GSDMD. Collectively, these findings identify GSDMD as a target of fumarate and reveal a mechanism of action for fumarate-based therapeutics that include DMF, for the treatment of multiple sclerosis.

中文翻译：

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琥珀酸使 gasdermin D 失活并阻止细胞焦亡

富马酸盐靶向细胞焦亡 一种称为细胞焦亡的炎症性细胞死亡取决于半胱天冬酶介导的 gasdermin D (GSDMD) 裂解，其碎片组装成渗透性孔，然后杀死细胞。调节这一重要细胞过程的机制尚未完全了解。汉弗莱斯等人。现在报告三羧酸循环中间体富马酸盐可以作为焦亡抑制剂（参见 Pickering 和 Bryant 的观点）。内源性富马酸和外源性富马酸二甲酯 (DMF) 将 GSDMD 中的半胱氨酸转化为 S-(2-琥珀酰)-半胱氨酸（称为琥珀化的过程），以防止其与半胱天冬酶相互作用以及随后的加工和活化。向小鼠施用 DMF 可减轻多发性硬化症和家族性地中海热模型中的炎症。这些发现可以解释 DMF 作为治疗多发性硬化症和其他炎症性疾病的疗效，并为未来的抗炎药物设计提供见解。科学，本期第 3 页。1633; 另见第 1564 克雷布斯循环中间体富马酸盐通过修饰成孔蛋白来防止一种细胞死亡。活化的巨噬细胞经历代谢转换为有氧糖酵解，积累改变免疫反应基因转录的克雷布斯循环中间体。我们通过将富马酸盐定义为细胞焦亡的抑制剂来扩展这些观察结果。我们发现富马酸二甲酯 (DMF) 递送到细胞或内源性富马酸与 gasdermin D (GSDMD) 在关键半胱氨酸残基处反应形成 S-(2-琥珀酰)-半胱氨酸。GSDMD 琥珀酸化阻止其与半胱天冬酶的相互作用，限制其加工，寡聚化和诱导细胞死亡的能力。在小鼠中，DMF 的施用通过靶向 GSDMD 来防止脂多糖休克并减轻家族性地中海热和实验性自身免疫性脑炎。总的来说，这些发现将 GSDMD 确定为延胡索酸盐的靶标，并揭示了基于延胡索酸盐的治疗剂（包括 DMF）治疗多发性硬化症的作用机制。