Unfolded Protein Response (UPR)

One level at which the URP operates is transcriptional and translational regulation: mobilization of ATF6, ATF6B, CREB3 factors and IRE1 leads to increased transcription of genes encoding chaperones, while mobilization of PERK (pancreatic eIF2alpha kinase, EIF2AK3) leads to phosphorylation of the translation initiation factor eIF2alpha and global down-regulation of protein synthesis.

ATF6, ATF6B, and CREB3 factors (CREB3 (LUMAN), CREB3L1 (OASIS), CREB3L2 (BBF2H7, Tisp40), CREB3L3 (CREB-H), and CREB3L4 (CREB4)) are membrane-bound transcription activators that respond to ER stress by transiting from the ER membrane to the Golgi membrane where their transmembrane domains are cleaved, releasing their cytosolic domains to transit to the nucleus and activate transcription of target genes. IRE1, also a resident of the ER membrane, dimerizes and autophosphorylates in response to ER stress. The activated IRE1 then catalyzes unconventional splicing of XBP1 mRNA to yield an XBP1 isoform that is targeted to the nucleus and activates chaperone genes.