| First Author | Morita S | Year | 2017 |
| Journal | Cell Metab | Volume | 25 |
| Issue | 4 | Pages | 883-897.e8 |
| PubMed ID | 28380378 | Mgi Jnum | J:251836 |
| Mgi Id | MGI:6106702 | Doi | 10.1016/j.cmet.2017.03.018 |
| Citation | Morita S, et al. (2017) Targeting ABL-IRE1alpha Signaling Spares ER-Stressed Pancreatic beta Cells to Reverse Autoimmune Diabetes. Cell Metab 25(4):883-897.e8 |
| abstractText | In cells experiencing unrelieved endoplasmic reticulum (ER) stress, the ER transmembrane kinase/endoribonuclease (RNase)-IRE1alpha-endonucleolytically degrades ER-localized mRNAs to promote apoptosis. Here we find that the ABL family of tyrosine kinases rheostatically enhances IRE1alpha'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 IRE1alpha's RNase. Imatinib-an anti-cancer tyrosine kinase inhibitor-antagonizes the ABL-IRE1alpha interaction, blunts IRE1alpha RNase hyperactivity, reduces pancreatic beta cell apoptosis, and reverses type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse model. A mono-selective kinase inhibitor that allosterically attenuates IRE1alpha's RNase-KIRA8-also efficaciously reverses established diabetes in NOD mice by sparing beta cells and preserving their physiological function. Our data support a model wherein ER-stressed beta cells contribute to their own demise during T1D pathogenesis and implicate the ABL-IRE1alpha axis as a drug target for the treatment of an autoimmune disease. |
