Glycosylation-independent ERAD pathway serves as a backup system under ER stress.
Glycosylation-independent ERAD pathway serves as a backup system under ER stress.
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DOI：
10.1091/mbc.e13-03-0138
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发表时间：
2013-10
影响因子：
3.3
通讯作者：
Nagata K
中科院分区：
文献类型：
--
作者：
Ushioda R;Hoseki J;Nagata K
内质网中错误折叠的糖基化和非糖基化蛋白通过ERAD系统中离散但可互换的途径被降解。二硫还原酶ERdj5通过与EDEM和/或BiP形成复合物在这两种途径中发挥核心作用。非糖蛋白ERAD通路在内质网应激条件下作为备用系统。在内质网（ER）相关降解（ERAD）过程中，最终错误折叠的蛋白质从内质网逆转录到细胞质，并被泛素-蛋白酶体系统降解。错误折叠的糖蛋白被钙连蛋白识别并转移到EDEM1，随后是ER二硫还原酶ERdj5和BiP复合物。然而，参与非糖蛋白ERAD的机制尚不清楚。在这里，我们发现非糖蛋白底物被BiP捕获，然后转移到ERdj5，而不经过calnexin/EDEM1途径；在ERdj5裂解二硫键后，非糖蛋白在BiP的帮助下转移到ERAD支架蛋白SEL1L上，并错位进入细胞质中。当底物的n -聚糖基团的葡萄糖修饰被抑制时，糖蛋白也靶向非糖蛋白ERAD途径。这些结果表明，哺乳动物细胞中存在两种不同的糖蛋白和非糖蛋白的ERAD途径，并且这些途径在内质网应激条件下是可互换的。
Glycosylated and nonglycosylated proteins misfolded in the ER are degraded by discrete but interchangeable pathways in the ERAD system. Disulfide reductase ERdj5 plays a central role in both pathways through the complex formation with EDEM and/or BiP. The nonglycoprotein ERAD pathway serves as a backup system under ER stress conditions. During endoplasmic reticulum (ER)–associated degradation (ERAD), terminally misfolded proteins are retrotranslocated from the ER to the cytosol and degraded by the ubiquitin-proteasome system. Misfolded glycoproteins are recognized by calnexin and transferred to EDEM1, followed by the ER disulfide reductase ERdj5 and the BiP complex. The mechanisms involved in ERAD of nonglycoproteins, however, are poorly understood. Here we show that nonglycoprotein substrates are captured by BiP and then transferred to ERdj5 without going through the calnexin/EDEM1 pathway; after cleavage of disulfide bonds by ERdj5, the nonglycoproteins are transferred to the ERAD scaffold protein SEL1L by the aid of BiP for dislocation into the cytosol. When glucose trimming of the N-glycan groups of the substrates is inhibited, glycoproteins are also targeted to the nonglycoprotein ERAD pathway. These results indicate that two distinct pathways for ERAD of glycoproteins and nonglycoproteins exist in mammalian cells, and these pathways are interchangeable under ER stress conditions.