Succination inactivates gasdermin D and blocks pyroptosis

doi:10.1126/science.abb9818

GSTDTAP > 气候变化

DOI	10.1126/science.abb9818
	Succination inactivates gasdermin D and blocks pyroptosis
	Fiachra Humphries; Liraz Shmuel-Galia; Natalia 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
	2020-09-25
发表期刊	Science
出版年	2020
英文摘要	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][1]; see also p. [1564][2] 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. [1]: /lookup/doi/10.1126/science.abb9818 [2]: /lookup/doi/10.1126/science.abe0917
领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/296524
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Fiachra Humphries,Liraz Shmuel-Galia,Natalia Ketelut-Carneiro,et al. Succination inactivates gasdermin D and blocks pyroptosis[J]. Science,2020.
APA	Fiachra Humphries.,Liraz Shmuel-Galia.,Natalia Ketelut-Carneiro.,Sheng Li.,Bingwei Wang.,...&Katherine A. Fitzgerald.(2020).Succination inactivates gasdermin D and blocks pyroptosis.Science.
MLA	Fiachra Humphries,et al."Succination inactivates gasdermin D and blocks pyroptosis".Science (2020).