The Unfolded Protein Response: An Overview

Abstract

The unfolded protein response is the mechanism by which cells control endoplasmic reticulum (ER) protein homeostasis. Under normal conditions, the UPR is not activated; however, under certain stresses, such as hypoxia or altered glycosylation, the UPR can be activated due to an accumulation of unfolded proteins. The activation of the UPR involves three signaling pathways, IRE1, PERK and ATF6, which all play vital roles in returning protein homeostasis to levels seen in non-stressed cells. IRE1 is the best studied of the three pathways, as it is the only pathway present in Saccharomyces cerevisiae. This pathway involves spliceosome independent splicing of HAC1 or XBP1 in yeast and mammalians cells, respectively. PERK limits protein synthesis, therefore reducing the number of new proteins requiring folding. ATF6 is translocated and proteolytically cleaved, releasing a NH2 domain fragment which is transported to the nucleus and which affects gene expression. If the UPR is unsuccessful at reducing the load of unfolded proteins in the ER and the UPR signals remain activated, this can lead to programmed cell death.

Candida albicans Sfp1 Is Involved in the Cell Wall and Endoplasmic Reticulum Stress Responses Induced by Human Antimicrobial Peptide LL-37

“…The UPR is a cellular response related to ER stress and is characterized by the splicing of HAC1 mRNA [ 25 ]. To link the UPR and Sfp1, reverse transcription PCR was performed to detect spliced HAC1 mRNA.…”

“…Upon disruption of ER homeostasis, accumulation of unfolded and misfolded proteins occurs in the ER lumen, generating a harmful condition known as ER stress [ 23 ]. To restore ER homeostasis, cells activate the unfolded protein response (UPR) signaling pathway, which is conserved among different yeast species [ 24 , 25 ]. In Saccharomyces cerevisiae , Ire1 functions as an ER stress sensor to trigger the UPR pathway [ 26 , 27 ].…”

Intertwined and Finely Balanced: Endoplasmic Reticulum Morphology, Dynamics, Function, and Diseases

“…Any proteins that fail to fold are recognised and removed from this cycle, to be retrotranslocated out of the ER and degraded by the proteosome in a process termed ER-associated degradation (ERAD) [ 51 ]. The load of misfolded proteins is closely monitored, and if too many build up, the unfolded protein response (UPR) is triggered, which leads to upregulation of the key ER-resident proteins required for protein folding combined with inhibition in protein synthesis [ 53 ]. While the proteins involved in folding and glycan addition are ubiquitously distributed throughout the ER, there is evidence that certain key proteins in the quality control and ERAD pathways may be concentrated in specialised structures called the ER-derived quality control compartment (ERQC) which is localised next to the nucleus [ 52 ].…”

Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Age Related Macular Degeneration, Role in Pathophysiology, and Possible New Therapeutic Strategies

“…The UPR is triggered by the combined action of three conserved ER transmembrane stress sensors: activating transcription factor 6α (ATF6), PKR-like ER kinase (PERK), and inositol-requiring enzyme 1α (IRE1α) [ 47 ] ( Figure 5 ). Under homeostatic conditions, these three proteins are inactive due to association with BiP.…”