Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Trends Cell Biol. 2017 Oct;27(10):722-737. doi: 10.1016/j.tcb.2017.05.006. Epub 2017 Jun 21.
Imbalances in secretory proteostasis induced by genetic, environmental, or aging-related insults are pathologically associated with etiologically diverse protein misfolding diseases. To protect the secretory proteome from these insults, organisms evolved stress-responsive signaling pathways that regulate the composition and activity of biologic pathways involved in secretory proteostasis maintenance. The most prominent of these is the endoplasmic reticulum (ER) unfolded protein response (UPR), which functions to regulate ER proteostasis in response to ER stress. While the signaling mechanisms involved in UPR activation are well defined, the impact of UPR activation on secretory proteostasis is only now becoming clear. Here, we highlight recent reports defining how activation of select UPR signaling pathways influences proteostasis within the ER and downstream secretory environments. Furthermore, we describe recent evidence that highlights the therapeutic potential for targeting UPR signaling pathways to correct pathologic disruption in secretory proteostasis associated with diverse types of protein misfolding diseases.
遗传、环境或与衰老相关的损伤导致的分泌蛋白稳态失衡与病因多样的蛋白质错误折叠疾病在病理上有关联。为了保护分泌蛋白组免受这些损伤，生物进化出应激反应信号通路来调节参与维持分泌蛋白稳态的生物途径的组成和活性。其中最主要的是内质网（ER）未折叠蛋白反应（UPR），其作用是调节 ER 蛋白稳态以响应 ER 应激。虽然 UPR 激活涉及的信号机制已经明确，但 UPR 激活对分泌蛋白稳态的影响现在才变得清晰。在这里，我们重点介绍最近的报告，这些报告定义了选择的 UPR 信号通路的激活如何影响 ER 内和下游分泌环境中的蛋白稳态。此外，我们还描述了最近的证据，这些证据强调了靶向 UPR 信号通路以纠正与多种类型蛋白质错误折叠疾病相关的分泌蛋白稳态病理性破坏的治疗潜力。
