Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

The IRE1 α/XBP1s pathway is essential for the glucose response and protection of β cells

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • Hassler, J. R.
  • Scheuner, D. L.
  • Wang, S.
  • Han, J.
  • Kodali, V. K.
  • Li, P.
  • Nguyen, J.
  • George, J. S.
  • Davis, C.
  • Wu, S. P.
  • Bai, Y.
  • Sartor, M.
  • Cavalcoli, J.
  • Malhi, H.
  • Baudouin, G.
  • Zhang, Y.
  • Yates III, John
  • Itkin-Ansari, P.
  • Volkmann, N.
  • Kaufman, R. J.

publication date

  • 2015

journal

  • PLoS Biology  Journal

abstract

  • Although glucose uniquely stimulates proinsulin biosynthesis in ? 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 (IRE1?) to initiate X-box-binding protein 1 (Xbp1) mRNA splicing in adult primary ? 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 Ire1? deletion, mice develop hyperglycemia and hypoinsulinemia, due to defective ? cell function that was exacerbated upon feeding and glucose stimulation. Although previous reports suggest IRE1? degrades insulin mRNAs, Ire1? deletion did not alter insulin mRNA expression either in the presence or absence of glucose stimulation. Instead, ? cell failure upon Ire1? 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, Ire1? deletion in ? 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 ? cell-specific Ire1? deletion. The results demonstrate that glucose activates IRE1?-mediated Xbp1 splicing to expand the secretory capacity of the ? cell for increased proinsulin synthesis and to limit oxidative stress that leads to ? cell failure.
  • 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.

subject areas

  • Adolescent
  • Adult
  • Alternative Splicing
  • Animals
  • Cells, Cultured
  • Crosses, Genetic
  • DNA-Binding Proteins
  • Endoribonucleases
  • Female
  • Humans
  • Hyperglycemia
  • Insulin
  • Insulin-Secreting Cells
  • Male
  • Mice, Knockout
  • Mice, Transgenic
  • Middle Aged
  • Oxidative Stress
  • Protein-Serine-Threonine Kinases
  • Recombinant Proteins
  • Signal Transduction
  • Tissue Donors
  • Transcription Factors
  • Young Adult
scroll to property group menus

Identity

PubMed Central ID

  • PMC4607427

International Standard Serial Number (ISSN)

  • 1545-7885

Digital Object Identifier (DOI)

  • 10.1371/journal.pbio.1002277

PubMed ID

  • 26469762
scroll to property group menus

Additional Document Info

start page

  • e1002277

volume

  • 13

issue

  • 10

©2021 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support