Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
Annu Rev Cell Dev Biol. 2012;28:251-77. doi: 10.1146/annurev-cellbio-101011-155826.
The unfolded protein response (UPR) is a network of intracellular signaling pathways that maintain the protein-folding capacity of the endoplasmic reticulum (ER) in eukaryotic cells. Dedicated molecular sensors embedded in the ER membrane detect incompletely folded or unfolded proteins in the ER lumen and activate a transcriptional program that increases the abundance of the ER according to need. In metazoans the UPR additionally regulates translation and thus relieves unfolded protein load by globally reducing protein synthesis. If homeostasis in the ER cannot be reestablished, the metazoan UPR switches from the prosurvival to the apoptotic mode. The UPR involves a complex, coordinated action of many genes that is controlled by one ER-embedded sensor, Ire1, in yeasts, and three sensors, Ire1, PERK, and ATF6, in higher eukaryotes, including human. We discuss the emerging molecular understanding of the UPR and focus on the structural biology of Ire1 and PERK, the two recently crystallized UPR sensors.
未折叠蛋白反应（UPR）是一个细胞内信号通路网络，它维持真核细胞内质网（ER）的蛋白质折叠能力。内质网膜中嵌入的专用分子传感器检测内质网腔中未完全折叠或 unfolded 的蛋白质，并激活一个转录程序，根据需要增加 ER 的丰度。在后生动物中，UPR 还调节翻译，从而通过全局减少蛋白质合成来减轻 unfolded 蛋白的负荷。如果 ER 中的内稳态不能重建，后生动物的 UPR 会从存活模式切换到凋亡模式。UPR 涉及许多基因的复杂协调作用，这些基因受酵母中一个内质网嵌入传感器 Ire1 和高等真核生物（包括人类）中三个传感器 Ire1、PERK 和 ATF6 的控制。我们讨论了对 UPR 的分子理解的最新进展，并重点介绍了 Ire1 和 PERK 的结构生物学，这是最近结晶的两个 UPR 传感器。
