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Regulating Secretory Proteostasis through the Unfolded Protein Response: From Function to Therapy
Trends in Cell Biology ( IF 19.0 ) Pub Date : 2017-06-21 , DOI: 10.1016/j.tcb.2017.05.006
Lars Plate , R. Luke Wiseman

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.



中文翻译:

通过展开的蛋白质反应调节分泌性蛋白稳态:从功能到治疗。

由遗传,环境或与衰老相关的损伤引起的分泌性蛋白稳态失衡在病理上与病因多样化的蛋白质错误折叠疾病有关。为了保护分泌蛋白质组免受这些侵害,生物体进化出了应激反应性信号传导途径,该信号传导途径调节了参与分泌性蛋白质稳态维持的生物途径的组成和活性。这些中最突出的是内质网(ER)展开的蛋白质反应(UPR),其功能是响应ER应激来调节ER蛋白质稳态。虽然已明确定义了参与UPR激活的信号传导机制,但直到现在,UPR激活对分泌性蛋白稳态的影响才变得清晰。这里,我们重点介绍了最近的报道,这些报道定义了选定的UPR信号通路的激活如何影响内质网和下游分泌环境中的蛋白稳态。此外,我们描述了最近的证据,这些证据突出了针对UPR信号通路来纠正与各种类型的蛋白质错误折叠疾病相关的分泌性蛋白变性的病理性破坏的治疗潜力。

更新日期:2017-06-21
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