Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, 70569 Stuttgart, Germany; email:
Annu Rev Biochem. 2018 Jun 20;87:751-782. doi: 10.1146/annurev-biochem-062917-012749. Epub 2018 Feb 2.
Cells must constantly monitor the integrity of their macromolecular constituents. Proteins are the most versatile class of macromolecules but are sensitive to structural alterations. Misfolded or otherwise aberrant protein structures lead to dysfunction and finally aggregation. Their presence is linked to aging and a plethora of severe human diseases. Thus, misfolded proteins have to be rapidly eliminated. Secretory proteins constitute more than one-third of the eukaryotic proteome. They are imported into the endoplasmic reticulum (ER), where they are folded and modified. A highly elaborated machinery controls their folding, recognizes aberrant folding states, and retrotranslocates permanently misfolded proteins from the ER back to the cytosol. In the cytosol, they are degraded by the highly selective ubiquitin-proteasome system. This process of protein quality control followed by proteasomal elimination of the misfolded protein is termed ER-associated degradation (ERAD), and it depends on an intricate interplay between the ER and the cytosol.
细胞必须不断监测其大分子成分的完整性。蛋白质是最具多功能性的一类大分子，但对结构改变敏感。错误折叠或其他异常的蛋白质结构会导致功能障碍，最终导致聚集。它们的存在与衰老和多种严重的人类疾病有关。因此，错误折叠的蛋白质必须被迅速清除。分泌蛋白构成了真核生物蛋白质组的三分之一以上。它们被输入内质网（ER），在那里进行折叠和修饰。一个高度复杂的机制控制着它们的折叠，识别异常折叠状态，并将永久性错误折叠的蛋白质从 ER 反向转运回细胞质。在细胞质中，它们被高度选择性的泛素-蛋白酶体系统降解。这种蛋白质质量控制过程，随后是错误折叠蛋白质的蛋白酶体消除，称为内质网相关降解（ERAD），它依赖于 ER 和细胞质之间的复杂相互作用。
