Protein kinase R-like ER kinase and its role in endoplasmic reticulum stress-decided cell fate.
Protein kinase R-like ER kinase and its role in endoplasmic reticulum stress-decided cell fate.
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DOI：
10.1038/cddis.2015.183
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发表时间：
2015-07-30
影响因子：
9
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Liu Z;Lv Y;Zhao N;Guan G;Wang J
在过去的几十年里，关于内质网应激在决定细胞命运中的作用的认识和证据一直在不断增长。通常，在内质网应激过程中，信号转导主要通过三种内质网信号转导途径进行：蛋白激酶R样内质网状激酶(PERK)、肌醇需求蛋白1(IRE1)和激活转录因子6(ATF6)。因此，来自内质网应激转导的有害刺激诱导细胞凋亡和自噬，这两个过程共有几个串扰，最终决定了细胞的命运。内质网应激诱导的细胞凋亡或自噬的优势取决于刺激的类型和程度。当内质网应激过强和持续时间过长时，诱导细胞凋亡以消除受损细胞；而当刺激较弱时，通过诱导自噬来促进细胞存活以维持正常的生理功能。虽然这三条途径都参与了内质网应激诱导的细胞凋亡和自噬，但PERK通过与一些特定的下游效应分子相互作用而显示出一些独特的特征。值得注意的是，有一些关于perk依赖的机制切换自噬和凋亡的初步发现。在这篇综述中，我们特别关注了PERK在内质网应激决定细胞命运中的新颖、有趣和复杂的作用，并讨论了PERK在恢复细胞内稳态中的更多作用。然而，未来对PERK的更深入的了解将有助于我们对许多人类疾病的了解，并有助于寻找新的分子治疗靶点。
Over the past few decades, understandings and evidences concerning the role of endoplasmic reticulum (ER) stress in deciding the cell fate have been constantly growing. Generally, during ER stress, the signal transductions are mainly conducted by three ER stress transducers: protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring kinase 1 (IRE1) and activating transcription factor 6 (ATF6). Consequently, the harmful stimuli from the ER stress transducers induce apoptosis and autophagy, which share several crosstalks and eventually decide the cell fate. The dominance of apoptosis or autophagy induced by ER stress depends on the type and degree of the stimuli. When ER stress is too severe and prolonged, apoptosis is induced to eliminate the damaged cells; however, when stimuli are mild, cell survival is promoted to maintain normal physiological functions by inducing autophagy. Although all the three pathways participate in ER stress-induced apoptosis and autophagy, PERK shows several unique characteristics by interacting with some specific downstream effectors. Notably, there are some preliminary findings on PERK-dependent mechanisms switching autophagy and apoptosis. In this review, we particularly focused on the novel, intriguing and complicated role of PERK in ER stress-decided cell fate, and also discussed more roles of PERK in restoring cellular homeostasis. However, more in-depth knowledge of PERK in the future would facilitate our understanding about many human diseases and benefit in searching for new molecular therapeutic targets.