title: IRS1 deficiency protects β-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation.
abstract: Endoplasmic reticulum (ER) stress is among several pathological features that underlie β-cell failure in the development of type 1 and type 2 diabetes. Adaptor proteins in the insulin/insulin-like-growth factor-1 signaling pathways, such as insulin receptor substrate-1 (IRS1) and IRS2, differentially impact β-cell survival but the underlying mechanisms remain unclear. Here we report that β-cells deficient in IRS1 (IRS1KO) are resistant, while IRS2 deficiency (IRS2KO) makes them susceptible to ER stress-mediated apoptosis. IRS1KOs exhibited low nuclear accumulation of spliced XBP-1 due to its poor stability, in contrast to elevated accumulation in IRS2KO. The reduced nuclear accumulation in IRS1KO was due to protein instability of Xbp1 secondary to proteasomal degradation. IRS1KO also demonstrated an attenuation in their general translation status in response to ER stress revealed by polyribosomal profiling. Phosphorylation of eEF2 was dramatically increased in IRS1KO enabling the β-cells to adapt to ER stress by blocking translation. Furthermore, significantly high ER calcium (Ca(2+)) was detected in IRS1KO β-cells even upon induction of ER stress. These observations suggest that IRS1 could be a therapeutic target for β-cell protection against ER stress-mediated cell death by modulating XBP-1 stability, protein synthesis, and Ca(2+) storage in the ER.
authors.affiliation: Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Tomozumi
authors.initials: T
authors.lastname: Takatani
authors.affiliation: Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Shirakawa
authors.affiliation: Department of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, NY, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Roe
authors.affiliation: Department of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, NY, USA.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Leech
authors.affiliation: Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Bernhard F
authors.initials: BF
authors.lastname: Maier
authors.affiliation: Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Cellular and Integrative Physiology, Department of Biochemistry and Molecular Biology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Raghavendra G
authors.initials: RG
authors.lastname: Mirmira
authors.affiliation: Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D055786:Gene Knockout Techniques; D055504:Insulin Receptor Substrate Proteins / Q000172:deficiency* / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D014176:Protein Biosynthesis; D055550:Protein Stability; D000071717:X-Box Binding Protein 1 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D002118:Calcium