ATF6β regulates the Wfs1 gene and has a cell survival role in the ER stress response in pancreatic β-cells

Endoplasmic reticulum (ER) stress is implicated in pancreatic beta-cell dysfunction and death resulting in type 2 diabetes. Activating transcription factor 6 (ATF6) is an essential component of the Unfolded Protein Response (UPR) and consists of two isoforms, ATF6 alpha and ATF6 beta. Here we investigated the role of ATF6 beta. ATF6 beta mRNA was detected in pancreatic beta-cell lines and rodent and human islets. We also detected ATF6 beta protein and production of the active form (ATF6 beta p60) in response to ER stress. Knock-down of ATF6 beta in INS-1 832/13 insulinoma cells did not affect mRNA induction of several major UPR genes in response to ER stress, suggesting ATF6 beta is not essential for the basic UPR. Expressing active ATF6 beta p60 or ATF6 alpha p50 followed by microarray analysis showed that they regulate similar UPR genes, although some genes such as Wfs1 are ATF6 beta-specific. ATF6 beta, but not ATF6 alpha, is able to bind the Wfs1 promoter and induce Wfs1 gene and protein expression. Knock-down of ATF6 beta increased the susceptibility of beta-cells to ER stress-induced apoptosis, while overexpression of active ATF6 beta p60 reduced apoptosis. Thus, ATF6 beta is not essential for induction of most UPR genes, but is required to maintain cell survival in beta-cells undergoing chronic ER stress, which in part relates to its ability to induce Wfs1, a pro-survival gene. (C) 2014 Elsevier Inc. All rights reserved.