Translational and posttranslational regulation of XIAP by eIF2α and ATF4 promotes ER stress–induced cell death during the unfolded protein response
Year: 2014
Type: article
Abstract: Endoplasmic reticulum (ER) protein misfolding activates the unfolded protein response (UPR) to help cells cope with ER stress. If ER homeostasis is not restored, UPR promotes cell death. The mechanisms of UPR-mediated cell death are poorly understood. The PKR-like endoplasmic reticulum kinase (PERK) arm of the UPR is implicated in ER stress-induced cell death, in part through up-regulation of proapoptotic CCAAT/enhancer binding protein homologous protein (CHOP). Chop((-)/(-)) cells are partially resistant to ER stress-induced cell death, and CHOP overexpression alone does not induce cell death. These findings suggest that additional mechanisms regulate cell death downstream of PERK. Here we find dramatic suppression of antiapoptosis XIAP proteins in response to chronic ER stress. We find that PERK down-regulates XIAP synthesis through eIF2α and promotes XIAP degradation through ATF4. Of interest, PERK's down-regulation of XIAP occurs independently of CHOP activity. Loss of XIAP leads to increased cell death, whereas XIAP overexpression significantly enhances resistance to ER stress-induced cell death, even in the absence of CHOP. Our findings define a novel signaling circuit between PERK and XIAP that operates in parallel with PERK to CHOP induction to influence cell survival during ER stress. We propose a "two-hit" model of ER stress-induced cell death involving concomitant CHOP up-regulation and XIAP down-regulation both induced by PERK.
Source: Molecular Biology of the Cell
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
Funders: Crohn's and Colitis Foundation of America, Foundation Fighting Blindness, Crohn's and Colitis Foundation, National Institutes of Health, Japan Society for the Promotion of Science, National Heart, Lung, and Blood Institute, National Eye Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Regulation of ER stress-induced cell death, G149357191, G1613908829, Unfolded Protein Response in Glucose Homeostasis, P30 - Core Grant for Vision Research, G3175271839, Regulation of Factor FVIII Secretion, G4107735943, Cellular Mechanisms of Inherited Retinal Degeneration, G617610254, G6509391055, Endoplasmic Reticulum Stress in Retinal Degeneration, NEUROPHYSIOLOGY OF INTERMEDIATE LEVEL VISION, Models of Retinal Degeneration, Role of the Unfolded Protein Response in Beta Cell, G8837296437, G9000011897, G9000057239, G9000130035, G9000246823
OpenAlex ID: W1968431957