Targeting ABL-IRE1α Signaling Spares ER-Stressed Pancreatic β Cells to Reverse Autoimmune Diabetes

Publication date: 4 April 2017
Source:Cell Metabolism, Volume 25, Issue 4
Author(s): Shuhei Morita, S. Armando Villalta, Hannah C. Feldman, Ames C. Register, Wendy Rosenthal, Ingeborg T. Hoffmann-Petersen, Morvarid Mehdizadeh, Rajarshi Ghosh, Likun Wang, Kevin Colon-Negron, Rosa Meza-Acevedo, Bradley J. Backes, Dustin J. Maly, Jeffrey A. Bluestone, Feroz R. Papa
In cells experiencing unrelieved endoplasmic reticulum (ER) stress, the ER transmembrane kinase/endoribonuclease (RNase)—IRE1α—endonucleolytically degrades ER-localized mRNAs to promote apoptosis. Here we find that the ABL family of tyrosine kinases rheostatically enhances IRE1α'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 IRE1α's RNase. Imatinib—an anti-cancer tyrosine kinase inhibitor—antagonizes the ABL-IRE1α interaction, blunts IRE1α RNase hyperactivity, reduces pancreatic β cell apoptosis, and reverses type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse model. A mono-selective kinase inhibitor that allosterically attenuates IRE1α's RNase—KIRA8—also efficaciously reverses established diabetes in NOD mice by sparing β cells and preserving their physiological function. Our data support a model wherein ER-stressed β cells contribute to their own demise during T1D pathogenesis and implicate the ABL-IRE1α axis as a drug target for the treatment of an autoimmune disease.

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Teaser

Morita et al. show that the non-receptor ABL tyrosine kinases enhance the enzymatic activities of the ER transmembrane kinase/endoribonuclease, IRE1α, thereby potentiating ER stress-induced apoptosis. Targeting the ABL-IRE1α pathway with imatinib or selective IRE1α kinase inhibitors reverses autoimmune diabetes in mice.


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