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

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

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: djmaly@uw.edu.
  • 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: jeff.bluestone@ucsf.edu.
  • 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: frpapa@medicine.ucsf.edu.
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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