The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells

Justin R. Hassler, Donalyn L. Scheuner, Shiyu Wang, Jaeseok Han, Vamsi K. Kodali, Philip Li, Julie Nguyen, Jenny S. George, Cory Davis, Shengyang P. Wu, Yongsheng Bai, Maureen Sartor, James Cavalcoli, Harmeet M Malhi, Gregory Baudouin, Yaoyang Zhang, John R. Yates, Pamela Itkin-Ansari, Niels Volkmann, Randal J. Kaufman

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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.

Original languageEnglish (US)
Pages (from-to)e1002277
JournalPLoS Biology
Volume13
Issue number10
DOIs
StatePublished - Oct 1 2015

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ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

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. M., Baudouin, G., Zhang, Y., Yates, J. R., Itkin-Ansari, P., Volkmann, N., & Kaufman, R. J. (2015). The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells. PLoS Biology, 13(10), e1002277. https://doi.org/10.1371/journal.pbio.1002277