Temasek Life Sciences Laboratory, National University of Singapore, Singapore 117604.
Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20597-602. doi: 10.1073/pnas.1117184109. Epub 2011 Dec 5.
Stress pathways monitor intracellular systems and deploy a range of regulatory mechanisms in response to stress. One of the best-characterized pathways, the unfolded protein response (UPR), is responsible for maintaining endoplasmic reticulum (ER) homeostasis. The highly conserved Ire1 branch regulates hundreds of gene targets by activating a UPR-specific transcription factor. To understand how the UPR manages ER stress, a unique genetic approach was applied to reveal how the system corrects disequilibria. The data show that the UPR can address a wide range of dysfunctions that are otherwise lethal if not for its intervention. Transcriptional profiling of stress-alleviated cells shows that the program can be modulated, not just in signal amplitude, but also through differential target gene expression depending on the stress. The breadth of the functions mitigated by the UPR further supports its role as a major mechanism maintaining systems robustness.
应激途径监测细胞内系统，并针对应激部署一系列调节机制。其中研究最为透彻的途径之一是未折叠蛋白反应 (UPR)，其负责维持内质网 (ER) 稳态。高度保守的 Ire1 分支通过激活 UPR 特异性转录因子来调控数百个基因靶标。为了了解 UPR 如何应对 ER 应激，应用了一种独特的遗传方法来揭示系统如何纠正失衡。研究数据表明，UPR 可以解决广泛的功能障碍，如果没有它的干预，这些功能障碍是致命的。对减轻应激的细胞进行转录谱分析表明，该程序不仅可以在信号幅度上进行调节，而且还可以通过不同的靶基因表达进行调节，具体取决于应激的类型。UPR 缓解的功能范围之广进一步支持了其作为维持系统鲁棒性的主要机制的作用。
