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

Shuhei Morita; S Armando Villalta; Hannah C Feldman; Ames C Register; Wendy Rosenthal; Ingeborg T Hoffmann-Petersen; Morvarid Mehdizadeh; Rajarshi Ghosh; Likun Wang; Kevin Colon-Negron; Rosa Meza-Acevedo; Bradley J Backes; Dustin J Maly; Jeffrey A Bluestone; Feroz R Papa

doi:10.1016/j.cmet.2017.03.018

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.

Authors

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.

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.

MeSH terms

Animals
Apoptosis / drug effects
Diabetes Mellitus, Type 1 / metabolism*
Diabetes Mellitus, Type 1 / pathology
Endoplasmic Reticulum Stress* / drug effects
Endoribonucleases / metabolism*
Female
Humans
Imatinib Mesylate / pharmacology
Insulin-Secreting Cells / metabolism*
Insulin-Secreting Cells / pathology*
Male
Mice, Inbred NOD
Models, Biological
Protein Binding / drug effects
Protein Serine-Threonine Kinases / metabolism*
Proto-Oncogene Proteins c-abl / metabolism*
Pyrimidines / pharmacology
Rats
Signal Transduction* / drug effects
Unfolded Protein Response / drug effects

Substances

GNF-2 compound
Pyrimidines
Imatinib Mesylate
Proto-Oncogene Proteins c-abl
ERN1 protein, human
Ern1 protein, mouse
Protein Serine-Threonine Kinases
Endoribonucleases

Abstract

MeSH terms

Substances

Grants and funding