上睑下垂
富马酸二甲酯
半胱氨酸
程序性细胞死亡
化学
免疫系统
细胞生物学
生物化学
细胞凋亡
生物
酶
免疫学
多发性硬化
作者
Fiachra Humphries,Liraz Shmuel-Galia,Natália Ketelut-Carneiro,Sheng Li,Bingwei Wang,Venkatesh V. Nemmara,Ruth Wilson,Zhaozhao Jiang,Farnaz Khalighinejad,Khaja Muneeruddin,Scott A. Shaffer,Ranjan Dutta,Carolina Ionete,Scott Pesiridis,Shuo Yang,Paul R. Thompson,Katherine A. Fitzgerald
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2020-08-20
卷期号:369 (6511): 1633-1637
被引量:408
标识
DOI:10.1126/science.abb9818
摘要
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.
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