Figure 1.

Overview of UPR stress response pathways. In unstressed conditions, the three UPR master regulators IRE1, PERK, and ATF6 are held in inactive monomeric form by the GRP78 chaperone. When ER stress increases, GRP78 complexes with misfolded proteins, allowing IRE1 and PERK to dimerize, autophosphorylate, and activate and releasing ATF6 to transit to Golgi to activate. Active IRE1 has both kinase and RNase activities, leading to a phosphorylation cascade culminating in phosphorylation of JNK, and Xbp1 splicing to generate the sXBP1 transcription factor, respectively. Active PERK phosphorylates eIF2α leading to suppression of global translation but a selective increase in translation of transcripts such as Atf4, to generate the ATF4 transcription factor. ATF6 is cleaved in the Golgi in SREBP-like fashion by proteases S1P and S2P, releasing its cytoplasmic domain as the nATF6 transcription factor. Much of the adaptive response to ER stress is implemented by transcriptional upregulation of genes that increase capacity for protein folding and clearance of misfolded proteins. A few commonly examined transcriptional targets are included. Green arrows indicate transcriptional regulation. ASK1, apoptosis signal regulating kinase 1; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; CHOP, C/EBP homologous protein; eIF2α, eukaryotic translation initiation factor 2 subunit 1; GRP78, glucose regulated protein 78; IRE1, inositol-requiring enzyme 1; JNK, c-Jun N-terminal kinase; nATF6, nuclear ATF6; P, phosphorylation; PERK, protein kinase R-like ER kinase; S1P, site 1 protease; S2P, site 2 protease; sXbp1, spliced Xbp1; TRAF2, TNF receptor–associated factor 2; uXbp1, unspliced Xbp1; XBP1, X-box binding protein 1.