Dataset Information

Targeting ABL-IRE1? Signaling Spares ER-Stressed Pancreatic ? Cells to Reverse Autoimmune Diabetes.

ABSTRACT: In cells experiencing unrelieved endoplasmic reticulum (ER) stress, the ER transmembrane kinase/endoribonuclease (RNase)-IRE1?-endonucleolytically degrades ER-localized mRNAs to promote apoptosis. Here we find that the ABL family of tyrosine kinases rheostatically enhances IRE1?'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 IRE1?'s RNase. Imatinib-an anti-cancer tyrosine kinase inhibitor-antagonizes the ABL-IRE1? interaction, blunts IRE1? RNase hyperactivity, reduces pancreatic ? cell apoptosis, and reverses type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse model. A mono-selective kinase inhibitor that allosterically attenuates IRE1?'s RNase-KIRA8-also efficaciously reverses established diabetes in NOD mice by sparing ? cells and preserving their physiological function. Our data support a model wherein ER-stressed ? cells contribute to their own demise during T1D pathogenesis and implicate the ABL-IRE1? axis as a drug target for the treatment of an autoimmune disease.

SUBMITTER: Morita S

PROVIDER: S-EPMC5497784 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Morita Shuhei S Villalta S Armando SA Feldman Hannah C HC Register Ames C AC Rosenthal Wendy W Hoffmann-Petersen Ingeborg T IT Mehdizadeh Morvarid M Ghosh Rajarshi R Wang Likun L Colon-Negron Kevin K Meza-Acevedo Rosa R Backes Bradley J BJ Maly Dustin J DJ Bluestone Jeffrey A JA Papa Feroz R FR

Cell metabolism 20170401 4

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- ...[more]

PMID: 28380378

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Project description:β cell proliferation rates decline with age and adult β cells have limited self-duplicating activity for regeneration, which predisposes to diabetes. Here we show that, among MYC family members, Mycl was expressed preferentially in proliferating immature endocrine cells. Genetic ablation of Mycl caused a modest reduction in cell proliferation of pancreatic endocrine cells in neonatal mice. By contrast, systemic expression of Mycl in mice stimulated proliferation in pancreatic islet cells and resulted in expansion of pancreatic islets without forming tumors in other organs. Single-cell RNA sequencing and genetic tracing experiments revealed that the expression of Mycl provoked transcription signatures associated with immature proliferating endocrine cells and stimulated self-duplication in adult hormone-expressing cells. The expanded hormone-expressing cells ceased proliferation but persisted after withdrawal of Mycl expression. Remarkably, a subset of the expanded α cells gave rise to insulin-producing cells after the withdrawal. Moreover, transient Mycl expression in vivo was sufficient to normalize increased blood glucose levels in diabetic mice evoked by chemical ablation of β cells. In vitro expression of Mycl similarly provoked active replication without inducing apoptosis in adult hormone-expressing islet cells, even those from aged mice. Furthermore, the expanded islet cells functioned in diabetic mice after transplantation. Finally, we show that MYCL stimulated self-duplication of human adult cadaveric islet cells. Collectively, these results demonstrate that sole induction of Mycl expands adult β cells both in vivo and in vitro. Moreover, islet cell-specific reprogramming via transient Mycl transduction elicits endogenous expansion of insulin-producing cells in adult pancreas through both self-duplication of β cells and transdifferentiation ofα cells into insulin-producing cells, which may provide a regenerative strategy of β cells.

Dataset Information

Targeting ABL-IRE1? Signaling Spares ER-Stressed Pancreatic ? Cells to Reverse Autoimmune Diabetes.

Publications

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

Similar Datasets

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