Quality Control in the Endoplasmic Reticulum: Crosstalk between ERAD and UPR pathways

The UPR sensor IRE1α and SEL1L-HRD1 ERAD are the two most conserved branches of ER quality-control mechanisms. IRE1α activation is controlled by different modulators, such as newly identified ERdj4, HSP47, and SEL1L-HRD1 ERAD. SEL1L-HRD1 ERAD targets IRE1α for proteasomal degradation to restrain IRE1α signaling under basal condition. Crosstalk between UPR and ERAD is critical for the maintenance of ER homeostasis under physiological and pathological conditions. 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. 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. an ER-resident HSP70 chaperone that regulates both protein folding and quality control of unfolded proteins. a functionally related group of proteins assisting protein folding in the cell under physiological and stress conditions. They recognize and bind non-native proteins, thus preventing aggregation, and couple ATP binding/hydrolysis to the folding process. Repeated cycles of client binding and release ensure proper client folding. Typical chaperone members include HSP70 and HSP90. assist chaperones in protein folding and other functions. Co-chaperones catalyze the hydrolysis of ATP to ADP on their respective chaperones, which then undergo a large conformational change to either bind to their substrates with higher affinity or aid in the release of the substrate following protein folding. an ER luminal chaperone involved in collagen maturation and trafficking as well as the activation of the UPR sensor IRE1α. defined by the presence of a J domain that can regulate the activity of the HSP70 family, including BiP; is known to be involved in the ERAD. ERdj4 may also be involved in the regulation of IRE1α activity. a member of the thioredoxin superfamily of redox proteins with three catalytic activities: thiol-disulfide oxidoreductase, disulfide isomerase, and a redox-dependent chaperone. The disulfide isomerase function of PDIA6 has been reported to be important for limiting UPR signaling.