Rutkowski D Thomas, Arnold Stacey M, Miller Corey N, Wu Jun, Li Jack, Gunnison Kathryn M, Mori Kazutoshi, Sadighi Akha Amir A, Raden David, Kaufman Randal J
Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
PLoS Biol. 2006 Nov;4(11):e374. doi: 10.1371/journal.pbio.0040374.
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.
内质网（ER）中未折叠蛋白的积累会激活一种称为未折叠蛋白反应（UPR）的信号级联反应。尽管对UPR的激活已有充分描述，但对于这种既能启动凋亡途径又能启动适应性途径的反应如何选择性地实现适应，人们了解甚少。在此，我们描述了在细胞培养系统中适应性内质网应激反应的重建。通过监测促进适应或凋亡的代表性UPR基因表达途径的激活和维持，我们证明轻度内质网应激会激活所有UPR传感器。然而，在轻度应激期间，与促进蛋白质折叠和适应的mRNA和蛋白质相比，促进凋亡的mRNA和蛋白质具有内在不稳定性，因此细胞更倾向于存活。结果，随着细胞适应应激，凋亡蛋白的表达是短暂的。我们提供的证据表明，内质网伴侣蛋白表达的选择性持续也适用于至少一种遗传性内质网应激情况。这项工作为应激反应途径如何构建以使细胞在适应过程中避免死亡提供了新的见解。它强调了转录后和翻译后机制在影响这一结果中的作用。
