Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Curr Opin Chem Biol. 2013 Jun;17(3):346-52. doi: 10.1016/j.cbpa.2013.04.009. Epub 2013 May 4.
Protein homeostasis (or proteostasis) within the endoplasmic reticulum (ER) is regulated by the unfolded protein response (UPR). The UPR consists of three integrated signaling pathways activated by the accumulation of misfolded proteins within the ER lumen. Activation of the UPR alters ER proteostasis through translational attenuation of new protein synthesis and transcriptional remodeling of ER proteostasis pathways, providing a mechanism to adapt ER proteostasis in response to cellular stress. The capacity of the UPR to alter ER proteostasis suggests that exogenous manipulation of UPR signaling pathways offers therapeutic promise to alter the fate of pathologic proteins associated with human protein misfolding diseases. Here, we discuss the therapeutic potential of exogenous UPR activation to treat human disease and highlight specific small molecule approaches for regulating UPR signaling that could be beneficial to treat protein misfolding diseases.
内质网（ER）中的蛋白质稳态（或蛋白质体稳态）受未折叠蛋白反应（UPR）的调节。UPR 由三条整合的信号通路组成，这些信号通路被内质网腔中错误折叠蛋白的积累激活。UPR 的激活通过新蛋白质合成的翻译衰减和内质网蛋白质稳态途径的转录重构来改变 ER 蛋白质稳态，提供了一种适应 ER 蛋白质稳态以应对细胞应激的机制。UPR 改变 ER 蛋白质稳态的能力表明，对外源 UPR 信号通路的操纵提供了治疗的可能性，以改变与人类蛋白质错误折叠疾病相关的病理性蛋白质的命运。在这里，我们讨论了外源性 UPR 激活治疗人类疾病的治疗潜力，并强调了调节 UPR 信号的特定小分子方法，这可能对治疗蛋白质错误折叠疾病有益。
