Fig. 2.

An array of cellular stressors can perturb the folding environment in the endoplasmic reticulum (ER) leading to unfolded or misfolded protein. In response to the folding imbalance, cells initiate the cytoprotective unfolded protein response (UPR). A: The problem of unfolded or misfolded proteins in the ER is addressed by increasing the folding capacity through the up-regulation of the expression of chaperone proteins, attenuating translation by regulating eIF2α, and promoting the degradation of misfolded proteins through ER-associated degradation (ERAD). If UPR is unable to restore the folding balance, ER stress will eventually lead to apoptotic cell-death. B: The three signal transduction pathways mediating the unfolded protein response in higher eukaryotes. First, the PRKR-like ER kinase (PERK) pathway is initiated after BiP dissociation from PERK. While PERK transduces both pro-and anti-apoptotic signals, its main function is translation attenuation through the phosphorylation of eIF2α. Next, the activating transcription factor 6 (ATF6) pathway is activated following BiP dissociation. ATF6 induces the expression of chaperones e.g., BiP as well as apoptosis effectors such as CHOP. Lastly, the inositol-requiring kinase 1 (IRE1) pathway is activated following BiP dissociation from IRE1. Activated IRE1 has both an endoribonuclease and a serine-threonine kinase activity that drive can pro-apoptotic signals.