Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis

被引：1048

作者：

Cai, Zhenyu ^{[1
]}

Jitkaew, Siriporn ^{[1
]}

Zhao, Jie ^{[1
]}

Chiang, Hsueh-Cheng ^{[2
]}

Choksi, Swati ^{[1
]}

Liu, Jie ^{[3
]}

Ward, Yvona ^{[1
]}

Wu, Ling-gang ^{[2
]}

Liu, Zheng-Gang ^{[1
]}

机构：

[1] NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[2] NINDS, Synapt Transmiss Sect, NIH, Bethesda, MD 20892 USA

[3] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA

来源：

NATURE CELL BIOLOGY | 2014年 / 16卷 / 01期

基金：

美国国家卫生研究院;

关键词：

NONAPOPTOTIC CELL-DEATH; MIXED LINEAGE KINASE; PROGRAMMED NECROSIS; NECROTIC DEATH; DOMAIN-LIKE; INFLAMMATION; APOPTOSIS; TRPM7; RIP3; DOWNSTREAM;

D O I：

10.1038/ncb2883

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The mixed lineage kinase domain-like protein (MLKL) has recently been identified as a key RIP3 (receptor interacting protein 3) downstream component of tumour necrosis factor (TNF)-induced necroptosis. MLKL is phosphorylated by RIP3 and is recruited to the necrosome through its interaction with RIP3. However, it is still unknown how MLKL mediates TNF-induced necroptosis. Here, we report that MLKL forms a homotrimer through its amino-terminal coiled-coil domain and locates to the cell plasma membrane during TNF-induced necroptosis. By generating different MLKL mutants, we demonstrated that the plasma membrane localization of trimerized MLKL is critical for mediating necroptosis. Importantly, we found that the membrane localization of MLKL is essential for Ca2+ influx, which is an early event of TNF-induced necroptosis. Furthermore, we identified that TRPM7 (transient receptor potential melastatin related 7) is a MLKL downstream target for the mediation of Ca2+ influx and TNF-induced necroptosis. Hence, our study reveals a crucial mechanism of MLKL-mediated TNF-induced necroptosis.

引用

页码：55 / +

页数：26

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