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Open Access Publications from the University of California

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

  • Author(s): Morita, Shuhei
  • Villalta, S Armando
  • Feldman, Hannah C
  • Register, Ames C
  • Rosenthal, Wendy
  • Hoffmann-Petersen, Ingeborg T
  • Mehdizadeh, Morvarid
  • Ghosh, Rajarshi
  • Wang, Likun
  • Colon-Negron, Kevin
  • Meza-Acevedo, Rosa
  • Backes, Bradley J
  • Maly, Dustin J
  • Bluestone, Jeffrey A
  • Papa, Feroz R
  • et al.

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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