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

Cell metabolism | Apr 4, 2017

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.

Pubmed ID: 28380378 RIS Download

Mesh terms: Animals | Apoptosis | Diabetes Mellitus, Type 1 | Endoplasmic Reticulum Stress | Endoribonucleases | Female | Humans | Imatinib Mesylate | Insulin-Secreting Cells | Male | Mice, Inbred NOD | Models, Biological | Protein Binding | Protein-Serine-Threonine Kinases | Proto-Oncogene Proteins c-abl | Pyrimidines | Rats | Signal Transduction | Unfolded Protein Response

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Associated grants

  • Agency: NIDDK NIH HHS, Id: P30 DK063720
  • Agency: NIGMS NIH HHS, Id: R01 GM086858
  • Agency: NIAID NIH HHS, Id: R01 AI046643
  • Agency: NIDDK NIH HHS, Id: R01 DK080955
  • Agency: NIDDK NIH HHS, Id: R01 DK100623
  • Agency: NIGMS NIH HHS, Id: T32 GM008268

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