Signal integration in the endoplasmic reticulum unfolded protein response

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Abstract
The endoplasmic reticulum (ER)-localized transmembrane proteins IRE1, PERK and ATF6 detect the load of unfolded protein in the lumen of the organelle, serving as stress receptors. They transduce the ER stress signal to the nucleus to regulate transcription and to the translational apparatus to regulate protein synthesis. Collectively, they signal the unfolded protein response (UPR). Despite the unrelated mechanisms of downstream signalling, significant functional redundancy exists between the three known arms of the UPR. The transcriptional effects of the three arms also overlap significantly, which is achieved, in part, through mutual positive reinforcement. The UPR reprogrammes transcription to enhance the capacity of the ER to cope with misfolded proteins, but also affects the function of the translocon and the repertoire of mRNA translated in the cell. Lipid synthesis is also integrated into the UPR to result in an expansion of the ER, which is especially prominent in professional secretory cells. The UPR enhances the capacity of cells to degrade misfolded ER proteins by two parallel mechanisms: ER associated degradation, in which individual misfolded proteins are retro-translocated to the cytosol for proteasomal degradation, and autophagy — a less selective process in which segments of ER are engulfed by a limiting membrane and trafficked to the lysosome. The three arms of the UPR have powerful pro-survival effects on ER-stressed cells. However, there are examples of failed homeostasis in which specific facets of UPR signalling contribute actively to the death of ER-stressed cells. The pro-survival features of the UPR benefit cancer cells in the hypoxic cores of tumours, raising the possibility that inhibitors of IRE1, PERK or ATF6 might be useful as anti-cancer drugs.