Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins.
Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins.
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DOI：
10.1371/journal.pbio.0040374
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发表时间：
2006-11
期刊：
影响因子：
9.8
通讯作者：
Kaufman RJ
中科院分区：
文献类型：
--
作者：
Rutkowski DT;Arnold SM;Miller CN;Wu J;Li J;Gunnison KM;Mori K;Sadighi Akha AA;Raden D;Kaufman RJ
未折叠蛋白在内质网（ER）中的积累激活了称为未折叠蛋白反应（UPR）的信号级联反应。虽然UPR的激活被很好地描述，但启动凋亡和适应性途径的反应如何选择性地允许适应的意义不大。在这里，我们描述了在细胞培养系统中的适应性ER应激反应的重建。监测代表性的UPR基因表达途径，促进适应或凋亡的激活和维护，我们证明，温和的ER应激激活所有UPR传感器。然而，由于促进细胞凋亡的mRNA和蛋白质的内在不稳定性，与促进蛋白质折叠和适应的mRNA和蛋白质相比，在轻度应激期间存活是有利的。因此，凋亡蛋白的表达是短暂的，因为细胞适应压力。我们提供的证据表明，ER伴侣蛋白表达的选择性持久性也适用于至少一个遗传ER应激的情况。这项工作为如何构建压力反应途径以使细胞在适应时避免死亡提供了新的见解。它强调了影响这一结果的转录后和翻译后机制的贡献。细胞可以适应慢性、轻度的ER应激而不发生凋亡。这部分是因为促凋亡途径组分的表达是短暂的，这使得适应性途径占主导地位。
The accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates a signaling cascade known as the unfolded protein response (UPR). Although activation of the UPR is well described, there is little sense of how the response, which initiates both apoptotic and adaptive pathways, can selectively allow for adaptation. Here we describe the reconstitution of an adaptive ER stress response in a cell culture system. Monitoring the activation and maintenance of representative UPR gene expression pathways that facilitate either adaptation or apoptosis, we demonstrate that mild ER stress activates all UPR sensors. However, survival is favored during mild stress as a consequence of the intrinsic instabilities of mRNAs and proteins that promote apoptosis compared to those that facilitate protein folding and adaptation. As a consequence, the expression of apoptotic proteins is short-lived as cells adapt to stress. We provide evidence that the selective persistence of ER chaperone expression is also applicable to at least one instance of genetic ER stress. This work provides new insight into how a stress response pathway can be structured to allow cells to avert death as they adapt. It underscores the contribution of posttranscriptional and posttranslational mechanisms in influencing this outcome. Cells can adapt to chronic, mild ER stress without undergoing apoptosis. This is in part because the expression of pro-apoptotic pathway components is short-lived, which allows adaptive pathways to predominate.
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影响因子：
4.8
作者：
Li, JZ;Lee, B;Lee, AS
通讯作者：
Lee, AS
影响因子：
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