Role of Protein Translation in Unfolded Protein Response

The unfolded protein response (UPR) is an adaptive mechanism to maintain protein homeostasis by decreasing the accumulation of unfolded proteins in the endoplasmic reticulum (EnR) of cells. EnR stress activates three distinct sensors, namely, inositol requiring protein 1 alpha (IRE1-α), activating transcription factor 6 (ATF6), and protein kinase RNA-like endoplasmic reticulum kinase (PERK), that collectively mitigate the damaging effects of EnR stress. The downstream signaling from the PERK sensor phosphorylates the eukaryotic translational initiation factor 2 alpha (eIF2α) complex that inhibits global protein translation to restore proteostasis and promote cell survival. However, chronic and unmitigated activation of the PERK pathway leads to apoptosis. Phosphorylation of eIF2α is tightly controlled by the two specific regulatory subunits of protein phosphatase 1 (PP1) complex, (1) growth arrest and DNA damage inducible-34 (GADD34) and (2) constitutive repressor of eIF2α phosphorylation (CReP), that are responsible for de-phosphorylation of eIF2α. Phospho-eIF2α also directs preferential translational of stress-related genes such as ATF4 and CHOP. This chapter describes the mechanism by which the PERK pathway regulates the protein translational machinery that plays a critical role in deciding cell fate following endoplasmic reticulum stress.