The three branches of UPR In the presence of unfolded and/or misfolded proteins, the IRE1α’s kinase domain trans-autophosphorylates. IRE1α phosphorylation leads to allosteric activation of the adjacent RNase. In response to low level of ER stress, IRE1α’s RNase excises a 26-nucleotide intron from the mRNA encoding the XBP1 transcription factor to produce transcription factor XBP1s. XBP1s then translocates to the nucleus and induces transcription of many genes that attempt to restore ER homeostasis. In the presence of unfolded/misfolded proteins, PERK dimerizes and phosphorylates eIF2α. Phosphorylation inhibits eIF2α activity and hence slows down global protein translation. In contrast, translation of the transcription factor ATF4 is selectively upregulated when the amount of active eIF2α is limited. ATF4 expression transcriptionally upregulates CHOP, which tips the ER toward homeostasis through the induction of a number of corrective genes. When activated, ATF6 translocates to the Golgi where it is cleaved by S1P and S2P protease to generate active transcription factor ATF6. The active ATF6 induces transcription of genes that restore ER homeostasis. XBP1u mRNA, unspliced XBP1 mRNA. XBP1s mRNA, spliced XBP1 mRNA.