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

作者: Xin Chen Wenjuan Li Junming Ren Deli Huang Wan-ting He Yunlong Song Chao Yang Wanyun Li Xinru Zheng PengdaChen Jiahuai Han
DOI:10.1038/cr.2013.171

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页码: 105-121
被引频次: 286
出版者: INST BIOCHEMISTRY & CELL BIOLOGY,Nature Publishing Group
ISSN: 1001-0602
卷期: Volume:24    Issue:1
语言: English
摘要: Mixed lineage kinase domain-like protein (MLKL) was identified to function downstream of receptor interacting protein 3 (RIP3) in tumor necrosis factor-α (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*) 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-α-helix bundle of MLKL (1-130 amino acids) is sufficient to trigger necroptosis. Both the HBD*-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 plas- ma membrane location is located in the junction of the first and second a-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.
相关主题: 蛋白, 质膜, 结构域, 易位, 激酶, 谱系, 坏死性, 细胞死亡, MLKL, sodium influx, plasma membrane translocation, MECHANISM, DETERMINANTS, TRANSCRIPTION, PROGRAMMED NECROSIS, MEDIATED APOPTOSIS, PYROPTOSIS, SIGNALING COMPLEX, CELL BIOLOGY, CHANNEL, TNF-ALPHA, RIP3, necroptosis, Protein Kinases - metabolism, Tumor Necrosis Factor-alpha - metabolism, Protein Kinases - genetics, Cricetulus, Cell Survival, Membrane Microdomains - metabolism, Humans, Necrosis - metabolism, Protein Transport - physiology, Signal Transduction - genetics, Sodium - metabolism, Gene Knockout Techniques, Receptor-Interacting Protein Serine-Threonine Kinases - genetics, Animals, HEK293 Cells, Cell Line, Tumor, Cell Membrane - metabolism, Mice, Apoptosis - physiology, HeLa Cells, Osmotic Pressure - physiology, CHO Cells, Original,

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