Figure 1.

Schematic illustration of integrated stress response (ISR) and unfolded protein response (UPR) signalling cascades.

ISR is schematically illustrated in the light blue and UPR in the light yellow area, respectively. The different stresses that activate ISR and UPR are depicted in red. UPR is activated by interaction of the ER chaperone BiP with accumulating unfolded proteins, leading to autophosphorylation of IRE1 and PERK kinase and proteolytic cleavage in the Golgi of ATF6. BiP-released activated IRE1 and ATF6 lead to transcriptional activation of various stress response genes, as described in section 2.2 of the text. Activated PERK, as well as the other ISR sensors HRI, PKR and GCN2 trigger different signalling cascades that converge on phosphorylation of eIF2α, which leads to global attenuation of cap-dependent translation while concomitantly promoting translation of ISR-specific mRNAs, as described in section 2.1 of the text.