ER stress triggers PERK dimerization and auto-phosphorylation. Activated PERK attenuates protein biosynthesis by phosphorylating eIF2α. Phosphorylated eIF2α also activates transcription factor ATF4, which enhances the stress-induced expression of numerous cytoprotective genes. Additionally, ATF4 increases the expression of CHOP, which induces GADD34 expression. GAAD34 binds to PP1 and forms the GADD34-PP1 complex that specifically dephosphorylates eIF2α. ER stress also triggers IRE1dimerization and auto-phosphorylation. Activation of IRE1 initiates the splicing of XBP1 mRNA, producing an active transcription factor sXBP-1. Additionally, ATF6 becomes an active transcription factor by transiting to the Golgi complex, where it is cleaved by the proteases S1P and S2P. The activation of IRE1 signaling and the cleavage of ATF6 promote ER expansion and the expression of ER-localized chaperones. In multicellular organisms, if these adaptive responses are not sufficient to resolve the folding problems in the ER, the UPR will trigger an apoptotic program, such as activation of caspase 12 or CHOP, to eliminate the cells.
