Figure 2.
The ER stress pathway. The ER membrane contains 3 stress transducers: IRE1, ATF6, and PERK. Their activation is controlled by the ER molecular chaperone immunoglobulin-binding protein of B cells (BiP/GRP78). Release from BiP binding activates the ER stress transducers. IRE1 contains a cytoplasmic kinase domain and an endoribonuclease domain. The latter cleaves XBP1 to spliced XBP1 (sXBP1), leading to transcriptional activation of adaptive molecules to overcome ER stress, such as ER chaperones, lipid synthesis, and increasing ER-associated degradation (ERAD). PERK activation leads to phosphorylation of eukaryotic translation initiation factor 2α, leading to global translation attenuation. ATF6 also transcriptionally activates UPR target genes. These processes collectively function to overcome and correct ER stress. In the face of sustained ER stress, apoptotic machinery becomes activated. PERK leads to selective translation of ATF4, transcription of CHOP, and activation of the apoptotic machinery. CHOP can affect Bim levels and death receptor 5 levels. IRE1 can also activate JNK. Active Bax/Bak can permeabilize the ER membrane, leading to calcium release, activation of calpains, and apoptosis. Growth arrest and DNA damage protein 34 (GADD34) associates with protein phosphatase 1 (PP1), leading to dephosphorylation of eukaryotic translation initiation factor 2α and attenuation of the UPR.