Nakatsukasa Kunio, Brodsky Jeffrey L
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Traffic. 2008 Jun;9(6):861-70. doi: 10.1111/j.1600-0854.2008.00729.x. Epub 2008 Feb 24.
Secretory and membrane proteins that fail to fold in the endoplasmic reticulum (ER) are retained and may be sorted for ER-associated degradation (ERAD). During ERAD, ER-associated components such as molecular chaperones and lectins recognize folding intermediates and specific oligosaccharyl modifications on ERAD substrates. Substrates selected for ERAD are then targeted for ubiquitin- and proteasome-mediated degradation. Because the catalytic steps of the ubiquitin-proteasome system reside in the cytoplasm, soluble ERAD substrates that reside in the ER lumen must be retrotranslocated back to the cytoplasm prior to degradation. In contrast, it has been less clear how polytopic, integral membrane substrates are delivered to enzymes required for ubiquitin conjugation and to the proteasome. In this review, we discuss recent studies addressing how ERAD substrates are recognized, ubiquitinated and delivered to the proteasome and then survey current views of how soluble and integral membrane substrates may be retrotranslocated.
在内质网（ER）中未能正确折叠的分泌蛋白和膜蛋白会被滞留，并可能被分选用于内质网相关降解（ERAD）。在ERAD过程中，诸如分子伴侣和凝集素等内质网相关成分会识别折叠中间体以及ERAD底物上特定的寡糖基修饰。被选中进行ERAD的底物随后会被靶向用于泛素和蛋白酶体介导的降解。由于泛素-蛋白酶体系统的催化步骤位于细胞质中，因此位于内质网腔中的可溶性ERAD底物在降解之前必须逆向转运回细胞质。相比之下，多跨膜整合膜底物如何被递送至泛素缀合所需的酶以及蛋白酶体则不太清楚。在这篇综述中，我们讨论了关于ERAD底物如何被识别、泛素化并递送至蛋白酶体的最新研究，然后概述了关于可溶性和整合膜底物可能如何逆向转运的当前观点。
