Cell Metabolism
Volume 25, Issue 4, 4 April 2017, Pages 883-897.e8
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Article
Targeting ABL-IRE1α Signaling Spares ER-Stressed Pancreatic β Cells to Reverse Autoimmune Diabetes

https://doi.org/10.1016/j.cmet.2017.03.018Get rights and content
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Highlights

  • During endoplasmic reticulum (ER) stress, ABL kinases localize to the ER membrane

  • At the ER, ABL scaffolds IRE1α to hyperactivate the unfolded protein response (UPR)

  • Imatinib blunts the UPR and apoptosis by maintaining ABL in a 14-3-3 cytosolic pool

  • Direct targeting of IRE1α, using mono-selective KIRA8, reverses autoimmune diabetes

Summary

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

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

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These authors contributed equally

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