Targeting ABL-IRE1? Signaling Spares ER-Stressed Pancreatic ? Cells to Reverse Autoimmune Diabetes.

ABSTRACT: In cells experiencing unrelieved endoplasmic reticulum (ER) stress, the ER transmembrane kinase/endoribonuclease (RNase)-IRE1?-endonucleolytically degrades ER-localized mRNAs to promote apoptosis. Here we find that the ABL family of tyrosine kinases rheostatically enhances IRE1?'s enzymatic activities, thereby potentiating ER stress-induced apoptosis. During ER stress, cytosolic ABL kinases localize to the ER membrane, where they bind, scaffold, and hyperactivate IRE1?'s RNase. Imatinib-an anti-cancer tyrosine kinase inhibitor-antagonizes the ABL-IRE1? interaction, blunts IRE1? RNase hyperactivity, reduces pancreatic ? cell apoptosis, and reverses type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse model. A mono-selective kinase inhibitor that allosterically attenuates IRE1?'s RNase-KIRA8-also efficaciously reverses established diabetes in NOD mice by sparing ? cells and preserving their physiological function. Our data support a model wherein ER-stressed ? cells contribute to their own demise during T1D pathogenesis and implicate the ABL-IRE1? axis as a drug target for the treatment of an autoimmune disease.

SUBMITTER: Morita S 

PROVIDER: S-EPMC5497784 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature