Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death

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	Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death
	Chen, Xin ; Li, Wenjuan ; Ren, Junming ; Huang, Deli ; He, Wan-ting ; Song, Yunlong ; Yang, Chao ; Li, Wanyun ; Zheng, Xinru ; Chen, Pengda ; Han, Jiahuai ; Chen X(陈鑫) ; Han JH(韩家淮)
刊名	http://dx.doi.org/10.1038/cr.2013.171
	2014
关键词	MEDIATED APOPTOSIS PROGRAMMED NECROSIS SIGNALING COMPLEX TNF-ALPHA DETERMINANTS PYROPTOSIS MECHANISM CHANNEL RIP3 TRANSCRIPTION
英文摘要	National Basic Research Program of China (973 Program) [2013CB944903, 2014CB541804]; National Natural Science Foundation of China [31330047, 91029304, 31221065]; Hi-Tech Research and Development Program of China (863 program) [2012AA02A201]; 111 Project [B12001]; Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University [SKLCSB2012KF003]; Mixed lineage kinase domain-like protein (MLKL) was identified to function downstream of receptor interacting protein 3 (RIP3) in tumor necrosis factor-alpha (TNF)-induced necrosis (also called necroptosis). However, how MLKL functions to mediate necroptosis is unknown. By reconstitution of MLKL function in MLKL-knockout cells, we showed that the N-terminus of MLKL is required for its function in necroptosis. The oligomerization of MLKL in TNF-treated cells is essential for necroptosis, as artificially forcing MLKL together by using the hormone-binding domain (HBD star) triggers necroptosis. Notably, forcing together the N-terminal domain (ND) but not the C-terminal kinase domain of MLKL causes necroptosis. Further deletion analysis showed that the four-alpha-helix bundle of MLKL (1-130 amino acids) is sufficient to trigger necroptosis. Both the HBD star-mediated and TNF-induced complexes of MLKL(ND) or MLKL are tetramers, and translocation of these complexes to lipid rafts of the plasma membrane precedes cell death. The homo-oligomerization is required for MLKL translocation and the signal sequence for plasma membrane location is located in the junction of the first and second alpha-helices of MLKL. The plasma membrane translocation of MLKL or MLKL(ND) leads to sodium influx, and depletion of sodium from the cell culture medium inhibits necroptosis. All of the above phenomena were not seen in apoptosis. Thus, the MLKL oligomerization leads to translocation of MLKL to lipid rafts of plasma membrane, and the plasma membrane MLKL complex acts either by itself or via other proteins to increase the sodium influx, which increases osmotic pressure, eventually leading to membrane rupture.
语种	英语
出版者	INST BIOCHEMISTRY & CELL BIOLOGY
内容类型	期刊论文
源URL	[http://dspace.xmu.edu.cn/handle/2288/90860]
专题	生命科学－已发表论文
推荐引用方式 GB/T 7714	Chen, Xin,Li, Wenjuan,Ren, Junming,et al. Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death[J]. http://dx.doi.org/10.1038/cr.2013.171,2014.
APA	Chen, Xin.,Li, Wenjuan.,Ren, Junming.,Huang, Deli.,He, Wan-ting.,...&韩家淮.(2014).Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death.http://dx.doi.org/10.1038/cr.2013.171.
MLA	Chen, Xin,et al."Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death".http://dx.doi.org/10.1038/cr.2013.171 (2014).