The Role of IRE1α in the Degradation of Insulin mRNA in Pancreatic β-Cells

Background: The endoplasmic reticulum (ER) is a cellular compartment for the biosynthesis and folding of newly synthesized secretory proteins such as insulin. Perturbations to ER homeostasis cause ER stress and subsequently activate cell signaling pathways, collectively known as the Unfolded Protein Response (UPR). IRE1 alpha is a central component of the UPR. In pancreatic beta-cells, IRE1 alpha also functions in the regulation of insulin biosynthesis. Principal Findings: Here we report that hyperactivation of IRE1 alpha caused by chronic high glucose treatment or IRE1 alpha overexpression leads to insulin mRNA degradation in pancreatic beta-cells. Inhibition of IRE1 alpha signaling using its dominant negative form prevents insulin mRNA degradation. Islets from mice heterozygous for IRE1 alpha retain expression of more insulin mRNA after chronic high glucose treatment than do their wild-type littermates. Conclusions/Significance: These results reveal a role of IRE1 alpha in insulin mRNA expression under ER stress conditions caused by chronic high glucose. The rapid degradation of insulin mRNA could provide immediate relief for the ER and free up the translocation machinery. Thus, this mechanism would preserve ER homeostasis and help ensure that the insulin already inside the ER can be properly folded and secreted. This adaptation may be crucial for the maintenance of beta-cell homeostasis and may explain why the beta-cells of type 2 diabetic patients with chronic hyperglycemia stop producing insulin in the absence of apoptosis. This mechanism may also be involved in suppression of the autoimmune type 1 diabetes by reducing the amount of misfolded insulin, which could be a source of "neo-autoantigens.''