Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate

doi:10.1038/s41419-020-2476-2

	Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate
	Hu, Lei 1,2,3; Chen, Meng 1,2,3; Chen, Xueran 1,2; Zhao, Chenggang 1,2,3; Fang, Zhiyou 1,2; Wang, Hongzhi 1,2; Dai, Haiming 1,2
刊名	CELL DEATH & DISEASE
	2020-04-24
卷号	11
ISSN号	2041-4889
DOI	10.1038/s41419-020-2476-2
通讯作者	Dai, Haiming(daih@cmpt.ac.cn)
英文摘要	Many chemotherapy treatments induce apoptosis or pyroptosis through BAK/BAX-dependent mitochondrial pathway. BAK/BAX activation causes the mitochondrial outer membrane permeabilization (MOMP), which induces the activation of pro-apoptotic caspase cascade. GSDME cleavage by the pro-apoptotic caspases determines whether chemotherapy drug treatments induce apoptosis or pyroptosis, however, its regulation mechanisms are not clear. In this study, we showed that TNF alpha +CHX and navitoclax-induced cancer cell pyroptosis through a BAK/BAX-caspase-3-GSDME signaling pathway. GSDME knockdown inhibited the pyroptosis, suggesting the essential role of GSDME in this process. Interestingly, GSDME was found to be palmitoylated on its C-terminal (GSDME-C) during chemotherapy-induced pyroptosis, while 2-bromopalmitate (2-BP) could inhibit the GSDME-C palmitoylation and chemotherapy-induced pyroptosis. Mutation of palmitoylation sites on GSDME also diminished the pyroptosis induced by chemotherapy drugs. Moreover, 2-BP treatment increased the interaction between GSDME-C and GSDME-N, providing a potential mechanism of this function. Further studies indicated several ZDHHC proteins including ZDHHC-2,7,11,15 could interact with and palmitoylate GSDME. Our findings offered new targets to achieve the transformation between chemotherapy-induced pyroptosis and apoptosis.
资助项目	National Natural Science Foundation of China[21772201] ; National Natural Science Foundation of China[81572948] ; innovative program of Development Foundation of Hefei Center for Physical Science and Technology[2018CXFX007]
WOS关键词	CELL-DEATH ; GASDERMIN D ; INFLAMMATORY CASPASES ; MOLECULAR-MECHANISMS ; DFNA5 GENE ; PROTEIN ; PALMITOYLATION ; ACTIVATION ; GSDMD ; CLEAVAGE
WOS研究方向	Cell Biology
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000530255700012
资助机构	National Natural Science Foundation of China ; innovative program of Development Foundation of Hefei Center for Physical Science and Technology
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/103413]
专题	中国科学院合肥物质科学研究院
通讯作者	Dai, Haiming
作者单位	1.Chinese Acad Sci, Ctr Med Phys & Technol, Anhui Prov Key Lab Med Phys & Technol, Hefei Inst Phys Sci, Hefei 230031, Peoples R China 2.Chinese Acad Sci, Hefei Canc Hosp, Hefei 230031, Peoples R China 3.Univ Sci & Technol China, Hefei 230026, Peoples R China
推荐引用方式 GB/T 7714	Hu, Lei,Chen, Meng,Chen, Xueran,et al. Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate[J]. CELL DEATH & DISEASE,2020,11.
APA	Hu, Lei.,Chen, Meng.,Chen, Xueran.,Zhao, Chenggang.,Fang, Zhiyou.,...&Dai, Haiming.(2020).Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate.CELL DEATH & DISEASE,11.
MLA	Hu, Lei,et al."Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate".CELL DEATH & DISEASE 11(2020).