Role of the unfolded protein response in cell death

Abstract

Unfolded protein response (UPR) is an important genomic response to endoplasmic reticulum (ER) stress. The ER chaperones, GRP78 and Gadd153, play critical roles in cell survival or cell death as part of the UPR, which is regulated by three signaling pathways: PERK/ATF4, IRE1/XBP1 and ATF6. During the UPR, accumulated unfolded protein is either correctly refolded, or unsuccessfully refolded and degraded by the ubiquitin-proteasome pathway. When the unfolded protein exceeds a threshold, damaged cells are committed to cell death, which is mediated by ATF4 and ATF6, as well as activation of the JNK/AP-1/Gadd153-signaling pathway. Gadd153 suppresses activation of Bcl-2 and NF-kappaB. UPR-mediated cell survival or cell death is regulated by the balance of GRP78 and Gadd153 expression, which is coregulated by NF-kappaB in accordance with the magnitude of ER stress. Less susceptibility to cell death upon activation of the UPR may contribute to tumor progression and drug resistance of solid tumors.

Membrane-Bound Serine Protease Inhibitor HAI-1 Is Required for Maintenance of Intestinal Epithelial Integrity

“…The underlying mechanism for ER stress in these cells is currently unknown, but this ER stress may be responsible for the enhanced apoptosis that was observed. 27 In fact, nuclear immunoreactivities of GADD153 and phosphorylated JNK/SAPK, both of which are up-regulated in the ER stress-induced apoptosis pathway, 18 were enhanced in HAI-1/SPINT1-deficient crypt epithelium. In addition, secreted clusterin was decreased in the HAI-1/SPINT1-deficient mucosa.…”

“…On the other hand, nuclear localization of phosphorylated JNK/SAPK was notably increased in the cecum and proximal aspect of the colon but not in the distal aspect of the colon ( Figure 4D). Moreover, nuclear immunoreactivity of GADD153, a member of the C/EBP gene family of transcription factors that is up-regulated by ER stress, 18 was also enhanced in HAI-1/SPINT1-deficient cecum and proximal aspect of the colon along with increased cleaved caspase-3 ( Figure 4E). These observations may implicate the activation of ER stress-induced apoptotic pathway in the absence of HAI-1/SPINT1.…”

Proteomics analysis of chinese hamster ovary cells undergoing apoptosis during prolonged cultivation

“…Since their corresponding molecular weights and PI (53 kDa/pH5.06 and 50 kDa/pH4.96, respectively) are similar, we attribute this to overlapping between multiple protein spots. Many cellular or ER stresses, including oxidative stress, amino acid depletion, protein over-expression FKBP52 FK506-binding protein 52, GAPDH glyceraldehyde-3-phosphate dehydrogenase, GRP gluose-regulated protein, HSC70 heat shock cognate protein 70 kDa, HSP heat shock protein, LAMR1 laminin receptor 1, LDH L-lactate dehydrogenase chain, PDI protein disulfide isomerase, PGM phosphoglycerate mutase, PGK phosphoglycerate kinase 1, PK pyruvate kinase isozyme M1/M2, Prx6 peroxiredoxin-6, TPI triosephosphate isomerase and inhibition of glycosylation reactions, can lead to the accumulation of misfolded proteins within the ER lumen and the activation of the unfolded protein response (UPR) (Kim et al 2006). Hence, it is not surprising that ten ER chaperone proteins were identified from the comparative proteomic analyses.…”

mTORC1 serves ER stress-triggered apoptosis via selective activation of the IRE1–JNK pathway

“…1 The UPR alleviates ER stress by reducing immature proteins in the ER, whereas severe or prolonged ER stress leads to activation of the pro-apoptotic UPR and consequent cellular death. 2 The UPR comprises three major signaling pathways mediated by ER type I transmembrane kinases, including inositol-requiring enzyme 1 (IRE1) and RNA-dependent protein kinase-like ER kinase (PERK), and a type II transmembrane protein, that is, activating transcription factor 6 (ATF6). 1,3 IRE1 has an endoribonuclease domain and a serine/threonine kinase domain.…”