Cellular Stress Responses: Cell Survival and Cell Death

Figure 2

ER stress and the unfolded protein response. Stress to the ER stimulates the activation of the three endoplasmic reticulum (ER) stress receptors, PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (Ire1) that are involved in the unfolded protein response (UPR). PERK phosphorylates eukaryotic initiation factor 2 (eIF2α) which inhibits general protein translation, allowing eIF2α-independent translation of ATF4, which activates transcription of chaperones such as GRP78. ATF6 undergoes specific proteolysis in the Golgi apparatus which leads to activation. One of the ATF6 target genes is XBP1. IRE1 catalyzes the alternative splicing of XBP1 mRNA leading to expression of the active XBP1 transcription factor. Together the three arms of the UPR block protein translation, increase chaperone expression and enhance ER-associated protein degradative pathways.