Abstract
Endoplasmic reticulum (ER) is an important organelle that stores the intracellular calcium and manufactures secretory and membrane proteins. When the ER calcium homeostasis or the protein biosynthesis is disturbed, accumulation of misfolded proteins obstructs the ER homeostasis, which could activate the intracellular signaling pathways termed the unfolded protein response (UPR). Current knowledge distinguishes UPR as three signaling pathways, IRE1α (inositol-requiring protein-1α), PERK (protein kinase RNA (PKR)-like ER kinase), and ATF6 (activating transcription factor 6). These three pathways regulate the fate of those cells under the ER stress to either strive for adaptation or commit for apoptosis. In mammal, Derlin-1 (Der1-like domain family, member 1) is an integral ER membrane protein that functions as a retro-translocation channel to help misfolded ER proteins crossing the membrane for proteasome degradation, a process known as endoplasmic reticulum-associated protein degradation (ERAD). In a Drosophila model, we found that overexpression of fly Derlin-1 causes eye degeneration, a phenotype also coincide with the UPR activation. As Derlin-1 expression level is increased upon ER stressor tunicamycin treatment or cold shock condition, this data suggest that Derlin-1 may involve in UPR pathway to promote cell apoptosis. To further investigate the relationship of Derlin-1 and UPR, I performed Western blotting and the data suggests that PERK and ATF6 might contribute to Derlin-1 increasing upon ER stress. I used genetic approach aiming to delineate Derlin-1 regulation in the UPR pathway and apoptosis, and identified Derlin-1-mediated cell death is closely associated with GADD34, a gene downstream of the PERK-eIF2α pathway. Our data indicate that ER stress-induced signaling may exploit Derlin-1 and PERK pathway to control the cell fate determination. This study could advance our understanding on ER stress regulation, and potentially benefit the development of new clinical strategies for ER-stress related diseases.