ERK1/2 signalling protects against apoptosis following endoplasmic reticulum stress but cannot provide long-term protection against BAX/BAK-independent cell death.
ERK1/2 signalling protects against apoptosis following endoplasmic reticulum stress but cannot provide long-term protection against BAX/BAK-independent cell death.
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DOI：
10.1371/journal.pone.0184907
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Cook SJ
中科院分区：
文献类型：
--
作者：
Darling NJ;Balmanno K;Cook SJ
内质网（ER）中蛋白质折叠的破坏导致ER应激。未折叠蛋白反应（UPR）的激活用于恢复蛋白质稳态，或者如果ER应激严重或持续，则驱动细胞凋亡，这被认为是通过细胞内在的线粒体途径进行的。事实上，缺乏关键执行蛋白BAX和巴克的细胞受到保护，免受ER应激诱导的细胞凋亡。在这里，我们表明，慢性内质网应激导致细胞外信号调节激酶（ERK 1/2）信号通路的进行性抑制。这与ER应激有因果关系，因为ERK 1/2的再活化可以保护细胞免受ER应激诱导的凋亡，而ERK 1/2途径抑制使细胞对ER应激敏感。此外，具有组成型活性BRAFV 600 E的癌细胞系依赖于ERK 1/2信号传导以保护免受ER应激诱导的细胞死亡。ERK 1/2信号传导通常抑制促死亡蛋白BIM、BMF和CD 4A，并且已经提出ER应激诱导BIM依赖性细胞死亡。我们没有发现ER应激增加这些蛋白表达的证据;此外，BIM不是ER应激诱导死亡所必需的。相反，ER应激导致帽依赖性mRNA翻译的PERK依赖性抑制和促存活蛋白（包括BCL 2、BCL XL和MCL 1）的进行性丧失。尽管有这些观察结果，ERK 1/2激活或BAX/巴克的丢失都不能使暴露于ER应激的细胞获得长期的克隆存活。因此，ER应激通过至少两种生物化学和遗传学上不同的途径诱导细胞死亡：经典的BAX/BAK依赖性凋亡反应，可被ERK 1/2信号传导抑制，以及替代性ERK 1/2和BAX/BAK独立的细胞死亡途径。
Disruption of protein folding in the endoplasmic reticulum (ER) causes ER stress. Activation of the unfolded protein response (UPR) acts to restore protein homeostasis or, if ER stress is severe or persistent, drive apoptosis, which is thought to proceed through the cell intrinsic, mitochondrial pathway. Indeed, cells that lack the key executioner proteins BAX and BAK are protected from ER stress-induced apoptosis. Here we show that chronic ER stress causes the progressive inhibition of the extracellular signal-regulated kinase (ERK1/2) signalling pathway. This is causally related to ER stress since reactivation of ERK1/2 can protect cells from ER stress-induced apoptosis whilst ERK1/2 pathway inhibition sensitises cells to ER stress. Furthermore, cancer cell lines harbouring constitutively active BRAFV600E are addicted to ERK1/2 signalling for protection against ER stress-induced cell death. ERK1/2 signalling normally represses the pro-death proteins BIM, BMF and PUMA and it has been proposed that ER stress induces BIM-dependent cell death. We found no evidence that ER stress increased the expression of these proteins; furthermore, BIM was not required for ER stress-induced death. Rather, ER stress caused the PERK-dependent inhibition of cap-dependent mRNA translation and the progressive loss of pro-survival proteins including BCL2, BCLXL and MCL1. Despite these observations, neither ERK1/2 activation nor loss of BAX/BAK could confer long-term clonogenic survival to cells exposed to ER stress. Thus, ER stress induces cell death by at least two biochemically and genetically distinct pathways: a classical BAX/BAK-dependent apoptotic response that can be inhibited by ERK1/2 signalling and an alternative ERK1/2- and BAX/BAK-independent cell death pathway.
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影响因子：
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