MLKL mediates apoptosis via a mutual regulation with PERK/eIF2α pathway in response to reactive oxygen species generation
MLKL mediates apoptosis via a mutual regulation with PERK/eIF2α pathway in response to reactive oxygen species generation
复制标题
DOI：
10.1007/s10495-018-1475-6
复制
发表时间：
2018-10-01
期刊：
影响因子：
7.2
通讯作者：
Lu, Jin-Jian
中科院分区：
文献类型：
--
作者：
Cao, Wen-Xiang;Li, Ting;Lu, Jin-Jian
伪激酶混合谱系激酶结构域样蛋白（MLKL）是坏死性上睑下垂的核心效应蛋白，其在坏死性上睑下垂中的作用被广泛研究。然而，MLKL在细胞凋亡中的作用尚不清楚。在本研究中，我们研究了MLKL在chelerythrine (CHE)-促进细胞凋亡中的作用。经CHE治疗后，观察到一个特殊的MLKL带（即*MLKL）。经CHE处理后，MLKL和*MLKL在细胞核中积累，MLKL沉默逆转了CHE诱导的细胞凋亡。阻断che触发的活性氧（ROS）生成或抑制che激活的蛋白激酶样内质网激酶(PERK)-真核起始因子2 α亚基（eIF2 α）途径可逆转细胞凋亡。ROS水平降低抑制了che介导的MLKL和*MLKL的核易位以及eIF2 α的激活，而MLKL或eIF2 α沉默不影响che触发的ROS生成。此外，MLKL沉默抑制了che激活的eIF2 α信号，eIF2 α沉默阻断了che诱导的MLKL和*MLKL的核易位。我们的研究表明，CHE可能通过MLKL和*MLKL的核易位诱导细胞凋亡，而MLKL和PERK-eIF2 α通路在响应ROS形成的过程中相互调控，促进了MLKL的核易位。本研究阐明了MLKL在细胞凋亡中的新功能。
The pseudokinase mixed lineage kinase domain-like protein (MLKL) is a core effector of necroptosis, and its function in necroptosis is widely studied. However, the function of MLKL in apoptosis remains unclear. In the present study, the role of MLKL in chelerythrine (CHE)-promoted apoptosis was studied. A special band of MLKL (i.e., *MLKL) was observed after treatment with CHE. MLKL and *MLKL were accumulated in the nucleus upon treatment with CHE and MLKL silencing reversed the CHE-induced apoptosis. Blockade of CHE-triggered reactive oxygen species (ROS) generation or inhibition of CHE-activated protein kinase-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2 alpha subunit (eIF2 alpha) pathway reversed the apoptosis. A decreased ROS level inhibited CHE-mediated nuclear translocation of MLKL and *MLKL and the activation of eIF2 alpha, whereas MLKL or eIF2 alpha silencing did not affect the CHE-triggered ROS generation. Furthermore, MLKL silencing prevented the CHE-activated eIF2 alpha signal, and eIF2 alpha silencing blocked the CHE-induced nuclear translocation of MLKL and *MLKL. Our studies suggested that CHE possibly induces apoptosis through the nuclear translocation of MLKL and *MLKL, which is promoted by a mutual regulation between MLKL and PERK-eIF2 alpha pathway in response to ROS formation. The present study clarified the new function of MLKL in apoptosis.