The unfolded protein response (UPR) is mediated by three ER membrane-bound proteins: double-stranded RNA-dependent protein kinase (PKR)-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme-1 (IRE1) and activating transcription factor 6 (ATF6) []. ATF6 has two isoforms, alpha and beta; this entry represents the isoform beta. ATF6 is a transcription factor that transduce signals from the ER to the cytoplasm and nucleus when unfolded proteins are accumulated in the ER []. It contains a basic leucine zipper (bZIP) domain that has regulatory function and a transmembrane domain that associates with the ER. Under ER stress the protein is cleaved at the membrane, and its cleaved N-terminal cytoplasmic domain (contains the bZIP domain) translocates into the nucleus where it activates the transcription of target genes that are mediated by ER stress-responsive and cyclic AMP-responsive elements [, ]. ATF6-beta can be cleaved and generate a nuclear form that inhibits ATF6-alpha mediated ER stress response gene activation [, ]. N-glycosylation of ATF6-beta is essential for its transcriptional repressor function to ATF6-alpha [].
