title: The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells.
abstract: Although glucose uniquely stimulates proinsulin biosynthesis in β cells, surprisingly little is known of the underlying mechanism(s). Here, we demonstrate that glucose activates the unfolded protein response transducer inositol-requiring enzyme 1 alpha (IRE1α) to initiate X-box-binding protein 1 (Xbp1) mRNA splicing in adult primary β cells. Using mRNA sequencing (mRNA-Seq), we show that unconventional Xbp1 mRNA splicing is required to increase and decrease the expression of several hundred mRNAs encoding functions that expand the protein secretory capacity for increased insulin production and protect from oxidative damage, respectively. At 2 wk after tamoxifen-mediated Ire1α deletion, mice develop hyperglycemia and hypoinsulinemia, due to defective β cell function that was exacerbated upon feeding and glucose stimulation. Although previous reports suggest IRE1α degrades insulin mRNAs, Ire1α deletion did not alter insulin mRNA expression either in the presence or absence of glucose stimulation. Instead, β cell failure upon Ire1α deletion was primarily due to reduced proinsulin mRNA translation primarily because of defective glucose-stimulated induction of a dozen genes required for the signal recognition particle (SRP), SRP receptors, the translocon, the signal peptidase complex, and over 100 other genes with many other intracellular functions. In contrast, Ire1α deletion in β cells increased the expression of over 300 mRNAs encoding functions that cause inflammation and oxidative stress, yet only a few of these accumulated during high glucose. Antioxidant treatment significantly reduced glucose intolerance and markers of inflammation and oxidative stress in mice with β cell-specific Ire1α deletion. The results demonstrate that glucose activates IRE1α-mediated Xbp1 splicing to expand the secretory capacity of the β cell for increased proinsulin synthesis and to limit oxidative stress that leads to β cell failure.
authors.affiliation: Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America; Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Hassler
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America; Lilly Research Laboratories, Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana, United States of America.
authors.forename: Donalyn L
authors.initials: DL
authors.lastname: Scheuner
authors.affiliation: Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America.
authors.forename: Jaeseok
authors.initials: J
authors.lastname: Han
authors.affiliation: Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America.
authors.forename: Vamsi K
authors.initials: VK
authors.lastname: Kodali
authors.affiliation: Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America.
authors.forename: Philip
authors.initials: P
authors.lastname: Li
authors.affiliation: Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: Nguyen
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: Jenny S
authors.initials: JS
authors.lastname: George
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: Cory
authors.initials: C
authors.lastname: Davis
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: Shengyang P
authors.initials: SP
authors.lastname: Wu
authors.affiliation: NCIBI Department of Bioinformatics, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America; Department of Biology, Indiana State University, Terre Haute, Indiana, United States of America.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Bai
authors.affiliation: NCIBI Department of Bioinformatics, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: Maureen
authors.initials: M
authors.lastname: Sartor
authors.affiliation: NCIBI Department of Bioinformatics, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Cavalcoli
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: Harmeet
authors.initials: H
authors.lastname: Malhi
authors.affiliation: Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America.
authors.forename: Gregory
authors.initials: G
authors.lastname: Baudouin
authors.affiliation: Department of Chemical Physiology and Cell Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Yaoyang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Chemical Physiology and Cell Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America.
authors.forename: Pamela
authors.initials: P
authors.lastname: Itkin-Ansari
authors.affiliation: Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America.
authors.forename: Niels
authors.initials: N
authors.lastname: Volkmann
authors.affiliation: Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States of America; Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America; Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America.
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
mesh_terms: D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing; D000818:Animals; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D014019:Tissue Donors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071717:X-Box Binding Protein 1; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D007328:Insulin; D011994:Recombinant Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases