Intersection of the ATF6 and XBP1 ER stress pathways in mouse islet cells

Success or failure of pancreatic beta cell adaptation to ER stress is a determinant of diabetes susceptibility. The ATF6 and IRE1/XBP1 pathways are separate ER stress-response effectors important to beta cell health and function. ATF6 alpha. and XBP1 direct overlapping transcriptional responses in some cell types. However, the signaling dynamics and interdependence of ATF6 alpha and XBP1 in pancreatic beta cells have not been explored. To assess pathway-specific signal onset, we performed timed exposures of primary mouse islet cells to ER stressors and measured the early transcriptional response. Comparing the time course of induction of ATF6 and XBP1 targets suggested that the two pathways have similar response dynamics. The role of ATF6 alpha in target induction was assessed by acute knockdown using islet cells fromAtf6 alpha(flox/flox)mice transduced with adenovirus expressing Cre recombinase. Surprisingly, given the mild impact of chronic deletion in mice, acute ATF6 alpha knockdown markedly reduced ATF6-pathway target gene expression under both basal and stressed conditions. Intriguingly, although ATF6 alpha knockdown did not alterXbp1splicing dynamics or intensity, it did reduce induction of XBP1 targets. Inhibition ofXbp1splicing did not decrease induction of ATF6 alpha targets. Taken together, these data suggest that the XBP1 and ATF6 pathways are simultaneously activated in islet cells in response to acute stress and that ATF6 alpha is required for full activation of XBP1 targets, but XBP1 is not required for activation of ATF6 alpha targets. These observations improve understanding of the ER stress transcriptional response in pancreatic islets.