坏死性下垂
细胞生物学
生物
磷酸化
肿瘤坏死因子α
程序性细胞死亡
细胞凋亡
胞浆
生物化学
免疫学
酶
作者
Zhenyu Cai,Siriporn Jitkaew,Jie Zhao,Hsueh Cheng Chiang,Swati Choksi,Jie Liu,Yvona Ward,Ling Gang Wu,Zheng Gang Liu
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. Liu and colleagues find that MLKL translocates to the plasma membrane to induce TNF-induced necroptosis, possibly through an effect on calcium influx and the action of the cation channel TRPM7.
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