Endoplasmic reticulum (ER)-associated degradation (ERAD) and the unfolded protein response (UPR) are two key quality-control machineries in the cell. ERAD is responsible for the clearance of misfolded proteins in the ER for cytosolic proteasomal degradation, while UPR is activated in response to the accumulation of misfolded proteins. It has long been thought that ERAD is an integral part of UPR because expression of many ERAD genes is controlled by UPR; however, recent studies have suggested that ERAD has a direct role in controlling the protein turnover and abundance of IRE1α, the most conserved UPR sensor. Here, we review recent advances in our understanding of IRE1α activation and propose that UPR and ERAD engage in an intimate crosstalk to define folding capacity and maintain homeostasis in the ER.

内质网 (ER) 相关降解 (ERAD) 和未折叠蛋白反应 (UPR) 是细胞中两个关键的质量控制机制。ERAD 负责清除 ER 中错误折叠的蛋白质以进行细胞溶质蛋白酶体降解，而 UPR 则响应错误折叠蛋白质的积累而被激活。长期以来，人们一直认为 ERAD 是 UPR 的组成部分，因为许多 ERAD 基因的表达受 UPR 控制；然而，最近的研究表明，ERAD 在控制 IRE1α（最保守的 UPR 传感器）的蛋白质周转和丰度方面具有直接作用。在这里，我们回顾了我们对 IRE1α 激活的理解的最新进展，并提出 UPR 和 ERAD 进行密切的串扰以定义折叠能力并维持 ER 中的稳态。