未折叠蛋白反应及其在生理功能与疾病中的作用

The unfolded protein response: its roles in physiological function and disease

未折叠或错误折叠的蛋白质在内质网(endoplasmic reticulum,ER)中聚集促使细胞做出适应性反应,包括上调位于内质网的各种酶和分子伴侣,这被称为未折叠蛋白反应(unfolded protein response,UPR)。未折叠蛋白反应存在于所有的真核细胞中,是人们了解最多的细胞器间信号传导系统模型。未折叠蛋白反应信号传导的基本机制最先在酵母中被阐明,在哺乳动物中有类似机制但表现得更为复杂。目前已经知道哺乳动物中有三条途径涉及UPR信号传导,分别是IRE1-XBP1路径,ATF6路径和PERK-elF2α磷酸化-ATF4路径。UPR在细胞生理病理中发挥重要作用。很多疾病如神经退行性疾病、糖尿病与高同型半胱氨酸血症等与蛋白折叠错误及由此引起的UPR有关。这些疾病也被称为错误折叠蛋白疾病。

Cells respond to the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum （ER） by up-regulating ER-resident enzymes at the transcription level. This is referred to the unfolded protein response （UPR）. The UPR takes place in all eukaryotes and is currently the best understood model of inter-organellar signal transduction system. The basic signaling mechanism of the UPR is first illustrated in yeast. A Similar mechanism is now found to be operating in mammalian cells, but it is more complex. Three signaling pathways are involved in the UPR in mammalian cells including Ire1-XBP1, ATF6 and PERK-elF2-phosphated ATF4 pathway. The UPR plays important roles in cellular pathophysiology. Many human diseases including neurodegenerative diseases, diabetes and hyperhomocysteinemia are related to the UPR caused by misfolding of disease proteins. These diseases are also called misfolded protein diseases.