Targeting ABL-IRE1α Signaling Spares ER-Stressed Pancreatic β Cells to Reverse Autoimmune Diabetes
| Autor: | Kevin Colon-Negron, Wendy Rosenthal, Dustin J. Maly, Morvarid Mehdizadeh, Shuhei Morita, Rosa Meza-Acevedo, Jeffrey A. Bluestone, Ingeborg T. Hoffmann-Petersen, S. Armando Villalta, Hannah C. Feldman, Ames C. Register, Rajarshi Ghosh, Likun Wang, Feroz R. Papa, Bradley J. Backes |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty ABL Physiology Kinase Endoplasmic reticulum Endoribonuclease Cell Biology Biology medicine.disease Cell biology 03 medical and health sciences 030104 developmental biology Endocrinology Internal medicine medicine Unfolded protein response Molecular Biology Insulitis Tyrosine kinase NOD mice |
| Zdroj: | Cell Metabolism. 25:1207 |
| ISSN: | 1550-4131 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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