Figure 1.

Integrated stress response (ISR) and unfolded protein response (UPR): The ISR (left side of figure) is a cellular response to extracellular stress signals that leads to activation of distinct kinases (PERK, HRI, GCN2, PKR). All 4 kinases phosphorylate eIF2α, which inhibits global protein translation and rescues the cell from stress. The UPR (right side of figure) is triggered by the presence of unfolded proteins in the endoplasmic reticulum (ER) and leads to the activation of 3 separate arms (PERK, IRE1α, ATF6). The PERK arm is shared with the ISR. The collective effect of the UPR is to delimit protein synthesis and activate chaperones to aid in protein folding.