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

  • Cell Metab. 2017 Apr 4;25(4):883-897.e8. doi: 10.1016/j.cmet.2017.03.018.
Shuhei Morita  1 ,  S Armando Villalta  2 ,  Hannah C Feldman  3 ,  Ames C Register  3 ,  Wendy Rosenthal  4 ,  Ingeborg T Hoffmann-Petersen  1 ,  Morvarid Mehdizadeh  4 ,  Rajarshi Ghosh  1 ,  Likun Wang  1 ,  Kevin Colon-Negron  1 ,  Rosa Meza-Acevedo  1 ,  Bradley J Backes  5 ,  Dustin J Maly  6 ,  Jeffrey A Bluestone  7 ,  Feroz R Papa  8
Affiliations
  • 1. Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Lung Biology Center, University of California, San Francisco, San Francisco, CA 94143, USA; California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 2. Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, USA; Institute for Immunology, University of California, Irvine, Irvine, CA 92697, USA.
  • 3. Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
  • 4. Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 5. Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Lung Biology Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 6. Department of Chemistry, University of Washington, Seattle, WA 98195, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Electronic address: [email protected].
  • 7. Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: [email protected].
  • 8. Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Lung Biology Center, University of California, San Francisco, San Francisco, CA 94143, USA; California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: [email protected].
PMID: 28380378 DOI: 10.1016/j.cmet.2017.03.018
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.

Keywords
ER stress; IRE1; NOD; apoptosis; c-Abl; imatinib; inflammation; insulitis; type 1 diabetes; unfolded protein response; β cell dysfunction.
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