AI Article Synopsis
- * ABL family tyrosine kinases enhance the activity of IRE1α, increasing the likelihood of apoptosis in stressed cells, while the anti-cancer drug imatinib can inhibit this interaction, potentially reducing cell death.
- * Research shows that targeting the ABL-IRE1α relationship with drugs like imatinib or other inhibitors could help reverse type 1 diabetes in mice by protecting β cells and improving their function.
Article Abstract
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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Source |
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497784 | PMC |
| http://dx.doi.org/10.1016/j.cmet.2017.03.018 | DOI Listing |
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