Zhang Kezhong, Kaufman Randal J
Department of Biological Chemistry, Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Neurology. 2006 Jan 24;66(2 Suppl 1):S102-9. doi: 10.1212/01.wnl.0000192306.98198.ec.
The endoplasmic reticulum (ER) is an intracellular organelle consisting of a membranous labyrinth network that extends throughout the cytoplasm of the cell and is contiguous with the nuclear envelope. In all eukaryotic cells, the ER is the site where folding and assembly occurs for proteins destined to the extracellular space, plasma membrane, and the exo/endocytic compartments. The ER is exquisitely sensitive to alterations in homeostasis, and provides stringent quality control systems to ensure that only correctly folded proteins transit to the Golgi and unfolded or misfolded proteins are retained and ultimately degraded. A number of biochemical and physiologic stimuli, such as perturbation in calcium homeostasis or redox status, elevated secretory protein synthesis, expression of misfolded proteins, sugar/glucose deprivation, altered glycosylation, and overloading of cholesterol can disrupt ER homeostasis, impose stress to the ER, and subsequently lead to accumulation of unfolded or misfolded proteins in the ER lumen. The ER has evolved highly specific signaling pathways called the unfolded protein response (UPR) to cope with the accumulation of unfolded or misfolded proteins. Recent discoveries of the mechanisms of ER stress signaling have led to major new insights into the diverse cellular and physiologic processes that are regulated by the UPR. This review summarizes the complex regulation of UPR signaling and its relevance to human physiology and disease.
内质网（ER）是一种细胞内细胞器，由一个延伸至整个细胞质并与核膜相连的膜性迷宫网络组成。在所有真核细胞中，内质网是注定要进入细胞外空间、质膜以及胞吞/胞吐区室的蛋白质进行折叠和组装的场所。内质网对稳态变化极为敏感，并提供严格的质量控制系统，以确保只有正确折叠的蛋白质才能转运至高尔基体，而未折叠或错误折叠的蛋白质则被保留并最终降解。许多生化和生理刺激，如钙稳态或氧化还原状态的扰动、分泌蛋白合成增加、错误折叠蛋白的表达、糖/葡萄糖剥夺、糖基化改变以及胆固醇超载，都可能破坏内质网稳态，给内质网带来压力，随后导致未折叠或错误折叠的蛋白质在内质网腔中积累。内质网进化出了高度特异性的信号通路，即未折叠蛋白反应（UPR），以应对未折叠或错误折叠蛋白质的积累。最近对内质网应激信号传导机制的发现，为受UPR调节的各种细胞和生理过程带来了重大的新见解。本综述总结了UPR信号传导的复杂调节及其与人类生理和疾病的相关性。
