IRE1 XBP 1 has been shown to regulate a variety of genes in various cell types in response to ER stress, mostly related to ER function and the secretory pathway, although the target genes vary depending on the cell type and nature of the stress selleckchem Ixazomib stimuli. In the proinsulin C96Y GFP model of ER stress numerous genes related to ER function, the secretory pathway and ER associated deg radation are increased. Here we show that some genes such as GRP78 are completely IRE 1 independent, which is consistent with GRP78 not requiring XBP 1 for its in duction. However, most other genes induced require IRE1 Inhibitors,Modulators,Libraries at least for maximal induction in response to mutant proinsulin induced ER stress. Previously we showed that perturbation of the ERAD pathway either by Herp knock down or proteasome inhib ition significantly perturbs mutant proinsulin Inhibitors,Modulators,Libraries degradation and significantly enhances susceptibility to apoptosis.

Although the extent of the increase in gene expression was reduced for most genes in the presence of the inhibi tor, genes such as those coding for ERAD components are still increased. This may explain the lack of effect Inhibitors,Modulators,Libraries of the inhibitor on the degradation of the mutant proinsulin and indicates that IRE1 output is not essential for maintaining ERAD capacity. Perhaps not surprisingly then, the inhibitor did not in crease susceptibility to apoptosis caused by mutant pro insulin expression. Several possibilities could contribute to a lack of effect on cell apoptosis, including reduced Inhibitors,Modulators,Libraries RIDD activity in response to chronic stress caused by the misfolded proinsulin, in addition to less induction of some pro apoptotic genes such as Trb3 and TxNIP.

Combined with no compromise in ERAD or ability to induce the main ER chaperone BiP GRP78, cells are no worse off if the IRE1 pathway is inhibited in the con text of chronic ER stress caused by mutant proinsulin expression. Our results Inhibitors,Modulators,Libraries are consistent with the effect of the inhibitor in other secretory cells where inhibition of IRE1 reduced expansion of secretory capacity, but did not sensitize the cells to ER stress. IRE1 activation results in the production of the XBP1 transcription factor that in vivo is required for the devel opment of various secretory cells including pancreatic cells. Indeed, disruption of the XBP1 gene in pancreatic B cells in mice using the RIP Cre system re sulted in hyperglycemia and abnormal B cell function caused by decreased insulin secretion, decreased insulin granule content and impaired insulin processing.

In addition, depletion of XBP1 resulted in constitutive towards hy peractivation of IRE1 including its RIDD activity. Thus, although inhibition of IRE1 in the context of the Akita insulin mutation does not sensitize the cells to in creased apoptosis, it is possible that inhibition of IRE1 in vivo in a physiological context might be detrimental to pancreatic B cell survival.