Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260.
Cold Spring Harb Perspect Biol. 2019 Aug 1;11(8):a033928. doi: 10.1101/cshperspect.a033928.
Misfolded proteins compromise cellular homeostasis. This is especially problematic in the endoplasmic reticulum (ER), which is a high-capacity protein-folding compartment and whose function requires stringent protein quality-control systems. Multiprotein complexes in the ER are able to identify, remove, ubiquitinate, and deliver misfolded proteins to the 26S proteasome for degradation in the cytosol, and these events are collectively termed ER-associated degradation, or ERAD. Several steps in the ERAD pathway are facilitated by molecular chaperone networks, and the importance of ERAD is highlighted by the fact that this pathway is linked to numerous protein conformational diseases. In this review, we discuss the factors that constitute the ERAD machinery and detail how each step in the pathway occurs. We then highlight the underlying pathophysiology of protein conformational diseases associated with ERAD.
错误折叠的蛋白质会破坏细胞内的平衡。内质网（endoplasmic reticulum，ER）尤其容易出现这种问题，因为内质网是一个大容量的蛋白质折叠区，其功能需要严格的蛋白质质量控制系统。内质网中的多蛋白复合物能够识别、去除、泛素化和将错误折叠的蛋白质递送至胞质溶胶中的 26S 蛋白酶体进行降解，这些事件统称为内质网相关降解（ER-associated degradation，ERAD）。ERAD 途径中的几个步骤都受到分子伴侣网络的促进，而该途径与许多蛋白质构象疾病有关，这一事实凸显了 ERAD 的重要性。在这篇综述中，我们讨论了构成 ERAD 机制的因素，并详细介绍了该途径中每个步骤的发生方式。然后，我们强调了与 ERAD 相关的蛋白质构象疾病的潜在病理生理学。
