Within the ER, misfolded proteins are detected by Bip (GPR78). In the presence of misfolded proteins, GPR78 disscociates from PERK, allowing it to homodimerize and autophosphoyate. In its dimerized phosphorylated form, PERK phosphorylates eIF2. The phosphorylation of eIF2 blocks the majority of translation to prevent the continued accumulation of protein in the ER. GRP78 also binds to IRE1 and ATF6 under normal ER conditions, but dissociates upon accumulation of misfolded proteins. Unbound ATF6 is translocated to the gogli where it is converted into a cleaved, active form. The cleaved form of ATF6 is then able to up regulate transcription of UPR genes including XBP1. Activated IRE1 acts as an endoribonuclease to an intron from XBP1 transcripts. The XBP1 splice variant codes for an active transcription factor which activates transcription of P58IPK. P58IPK is a HSP40 protein which binds to and inhibits PERK. Thus, if the accumulated misfolded proteins have been removed, P58IPK acts to shut down the UPR by removing the block to translation.