The IRE1α-XBP1 pathway regulates metabolic stress-induced compensatory proliferation of pancreatic β-cells FREE

摘要

In eukaryotes, increased protein folding demand at the endoplasmic reticulum (ER) activates the unfolded protein response (UPR)1, which plays a pivotal role in control of cellular functions and survival under ER stress2. Chronic ER stress is thought to contribute to the pathogenic progression of diabetes3,4. Inositol-requiring enzyme 1 (IRE1), an ER-resident transmembrane Ser/Thr protein kinase and endoribonuclease, is the most conserved ER stress sensor that mediates a key branch of the UPR1. In mammals, activation of IRE1α results in non-conventional splicing of the mRNA encoding the transcription factor X-box binding protein 1 (XBP1), generating a spliced active form of XBP1 (XBP1s) to initiate a major UPR program1. The IRE1-XBP1 pathway has been implicated in the homeostatic regulation of pancreatic islet β-cells. Whereas glucose-stimulated IRE1α activation is coupled to insulin production5,6,7, IRE1α also degrades insulin mRNAs under severe ER stress conditions8. Interestingly, genetic deletion of XBP1 in β-cells of mice was reported to result in a feedback hyperactivation of IRE1α, causing defective proinsulin processing and insulin secretion9. However, the precise role in vivo of IRE1α in integrating metabolic ER stress signals to regulate β-cell functions remains largely elusive.