Zhang K, Kaufman R J
Howard Hughes Medical Institute, Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor 48109, USA.
Handb Exp Pharmacol. 2006(172):69-91. doi: 10.1007/3-540-29717-0_3.
In all eukaryotic cells, the endoplasmic reticulum (ER) is an intracellular organelle where folding and assembly occurs for proteins destined to the extracellular space, plasma membrane, and the exo/endocytic compartments (Kaufman 1999). As a protein-folding compartment, 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 physiological 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. Elucidation of the molecular mechanisms by which accumulation of unfolded proteins in the ER transmits a signal to the cytoplasm and nucleus has led to major new insights into the diverse cellular and physiological processes that are regulated by the UPR. This chapter summarizes how cells respond to the accumulation of unfolded proteins in the cell and the relevance of these signaling pathways to human physiology and disease.
在所有真核细胞中，内质网（ER）是一种细胞内细胞器，负责折叠和组装 destined to the extracellular space、质膜以及胞吞/胞吐区室的蛋白质（考夫曼，1999年）。作为一个蛋白质折叠区室，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，进而导致内质网腔中未折叠或错误折叠的蛋白质积累。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。对未折叠蛋白在内质网中的积累如何向细胞质和细胞核传递信号的分子机制的阐明，为受UPR调控的各种细胞和生理过程带来了重大的新见解。本章总结了细胞如何应对细胞内未折叠蛋白的积累以及这些信号通路与人类生理和疾病的相关性。
