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首页> 美国卫生研究院文献>Cell Death and Differentiation >Imaging of single cell responses to ER stress indicates that the relative dynamics of IRE1/XBP1 and PERK/ATF4 signalling rather than a switch between signalling branches determine cell survival
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Imaging of single cell responses to ER stress indicates that the relative dynamics of IRE1/XBP1 and PERK/ATF4 signalling rather than a switch between signalling branches determine cell survival

机译：单个细胞对内质网应激反应的成像表明IRE1 / XBP1和PERK / ATF4信号的相对动态决定了细胞存活而不是信号分支之间的切换

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An accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR) mediated via the activation of three transmembrane proteins IRE1, PERK and ATF6. Signalling through these proteins is aimed at enhancing the ER folding capacity and reducing the folding load. If these processes fail to re-establish protein homeostasis within the ER, then cell death prevails via apoptosis. How the shift from pro-survival to pro-apoptotic signalling is regulated remains unclear with both IRE1 and PERK signalling associated with pro-survival as well as pro-apoptotic signalling. To investigate the temporal activation of IRE1 and PERK in live cells and their relationship to cellular fate, we devised single cell reporters for both ER stress signalling branches. SH-SY5Y neural cells stably expressing these fluorescent protein reporter constructs to monitor IRE1-splicing activity and PERK-mediated ATF4-translation were imaged using single cell and high content time lapse live cell microscopy. We could correlate an early onset and attenuation of XBP1 splicing in the IRE1-reporter cells as cytoprotective. Indeed, silencing of IRE1 expression using shRNA inhibited splicing of XBP1 resulting in an early onset of cell death. In contrast, in the PERK-reporter cells, we observed that a slow rate of ATF4-translation and late re-initiation of general translation coincided with cells which were resistant to ER stress-induced cell death. Interestingly, whereas silencing of PERK did not affect overall levels of cell death in response to ER stress, it did increase sensitivity to ER stressors at early time points following treatment. Our results suggest that apoptosis activation in response to ER stress is not caused by a preferential activation of a single UPR branch, or by a switch from one branch to the other. Rather, our data indicated that the relative timing of IRE1 and PERK signalling determines the shift from cell survival to apoptosis.
机译：内质网（ER）中错误折叠的蛋白的积累触发了通过三个跨膜蛋白IRE1，PERK和ATF6的激活介导的未折叠蛋白反应（UPR）。通过这些蛋白发出的信号旨在增强ER折叠能力并降低折叠负荷。如果这些过程未能在ER内重新建立蛋白质稳态，则细胞死亡将通过凋亡发生。对于与生存前以及凋亡前信号相关的IRE1和PERK信号，尚不清楚如何调节从生存前信号向凋亡前信号的转变。为了研究IRE1和PERK在活细胞中的暂时激活及其与细胞命运的关系，我们设计了两个ER应激信号分支的单细胞报道分子。稳定表达这些荧光蛋白报道基因构建体以监测IRE1剪接活性的SH-SY5Y神经细胞和PERK介导的ATF4转化使用单细胞和高含量延时活细胞显微镜成像。我们可以将IRE1报道细胞中XBP1剪接的早期发作和减弱与细胞保护相关联。实际上，使用shRNA抑制IRE1表达可抑制XBP1的剪接，从而导致细胞死亡的早期发作。相反，在PERK-reporter细胞中，我们观察到ATF4翻译的缓慢速率和一般翻译的后期重新启动与抵抗ER应激诱导的细胞死亡的细胞相吻合。有趣的是，虽然PERK沉默并不影响响应ER应激的细胞死亡的总体水平，但确实在治疗后的早期提高了对ER应激源的敏感性。我们的结果表明，响应内质网应激的凋亡激活不是由单个UPR分支的优先激活或从一个分支切换到另一个分支引起的。相反，我们的数据表明IRE1和PERK信号传导的相对时机决定了从细胞存活到凋亡的转变。

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