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

(Cell Metabolism 25, 883–897; April 4, 2017) In the originally published version of this article, the immunoblot image of the HDAC1 nuclear extract protein control in Figure 3I was incorrectly cropped such that it included one extraneous lane. The corrected and original versions of Figure 3I are shown here. Furthermore, in the Discussion, after the sentence “Such compensatory, dysregulated UPR effects may be general as Perk deletion, likewise, hyperactivates IRE1α in β cells, which suffer early apoptosis, leading to postnatal diabetes,” we incorrectly cited Harding, H.P., and Ron, D. (2002). Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes 51, S455–S461. The correct citation is: Harding, H.P., Zeng, H., Zhang, Y., Jungries, R., Chung, P., Plesken, H., Sabatini, D.D., and Ron, D. (2001). Diabetes mellitus and exocrine pancreatic dysfunction in perk−/− mice reveals a role for translational control in secretory cell survival. Molecular Cell 7, 1153–1163. The authors apologize for any confusion these errors may have caused. [Figure presented

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

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