Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
Cold Spring Harb Perspect Biol. 2022 Dec 1;14(12):a041247. doi: 10.1101/cshperspect.a041247.
Misfolded, potentially toxic proteins in the lumen and membrane of the endoplasmic reticulum (ER) are eliminated by proteasomes in the cytosol through ER-associated degradation (ERAD). The ERAD process involves the recognition of substrates in the lumen and membrane of the ER, their translocation into the cytosol, ubiquitination, and delivery to the proteasome for degradation. These ERAD steps are performed by membrane-embedded ubiquitin-ligase complexes of different specificity that together cover a wide range of substrates. Besides misfolded proteins, ERAD further contributes to quality control by targeting unassembled and mislocalized proteins. ERAD also targets a restricted set of folded proteins to influence critical ER functions such as sterol biosynthesis, calcium homeostasis, or ER contacts with other organelles. This review describes the ubiquitin-ligase complexes and the principles guiding protein degradation by ERAD.
内质网（ER）腔和膜中的错误折叠、潜在有毒的蛋白质通过细胞质中的蛋白酶体通过内质网相关降解（ERAD）来消除。ERAD 过程涉及到内质网腔和膜中底物的识别、它们向细胞质的易位、泛素化和递送到蛋白酶体进行降解。这些 ERAD 步骤由不同特异性的膜嵌入泛素连接酶复合物执行，这些复合物共同涵盖了广泛的底物。除了错误折叠的蛋白质外，ERAD 还通过靶向未组装和定位错误的蛋白质来促进质量控制。ERAD 还靶向一组受限的折叠蛋白质，以影响关键的 ER 功能，如固醇生物合成、钙稳态或 ER 与其他细胞器的接触。这篇综述描述了泛素连接酶复合物和指导 ERAD 中蛋白质降解的原则。
