Hetz Claudio, Glimcher Laurie H
The FONDAP Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
Mol Cell. 2009 Sep 11;35(5):551-61. doi: 10.1016/j.molcel.2009.08.021.
Endoplasmic reticulum (ER) stress is a hallmark feature of secretory cells and many diseases, including cancer, neurodegeneration, and diabetes. Adaptation to protein-folding stress is mediated by the activation of an integrated signal transduction pathway known as the unfolded protein response (UPR). The UPR signals through three distinct stress sensors located at the ER membrane-IRE1alpha, ATF6, and PERK. Although PERK and IRE1alpha share functionally similar ER-luminal sensing domains and both are simultaneously activated in cellular paradigms of ER stress in vitro, they are selectively engaged in vivo by the physiological stress of unfolded proteins. The differences in terms of tissue-specific regulation of the UPR may be explained by the formation of distinct regulatory protein complexes. This concept is supported by the recent identification of adaptor and modulator proteins that directly interact with IRE1alpha. In this Review, we discuss recent evidence supporting a model where IRE1alpha signaling emerges as a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble.
内质网（ER）应激是分泌细胞和许多疾病（包括癌症、神经退行性疾病和糖尿病）的一个标志性特征。对蛋白质折叠应激的适应是由一种称为未折叠蛋白反应（UPR）的整合信号转导途径的激活介导的。UPR通过位于内质网膜上的三种不同的应激传感器——IRE1α、ATF6和PERK发出信号。尽管PERK和IRE1α具有功能相似的内质网腔传感结构域，并且在体外内质网应激的细胞模型中两者同时被激活，但它们在体内通过未折叠蛋白的生理应激被选择性地激活。UPR在组织特异性调节方面的差异可能由不同调节蛋白复合物的形成来解释。最近鉴定出直接与IRE1α相互作用的衔接蛋白和调节蛋白，这一概念得到了支持。在本综述中，我们讨论了最近的证据，这些证据支持一种模型，即IRE1α信号传导是一个高度受调控的过程，由一个动态支架的形成控制，许多调节成分组装在这个支架上。
