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The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells.
- Source :
-
PLoS biology [PLoS Biol] 2015 Oct 15; Vol. 13 (10), pp. e1002277. Date of Electronic Publication: 2015 Oct 15 (Print Publication: 2015). - Publication Year :
- 2015
-
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.
- Subjects :
- Adolescent
Adult
Animals
Cells, Cultured
Crosses, Genetic
DNA-Binding Proteins genetics
Endoribonucleases genetics
Female
Humans
Hyperglycemia blood
Hyperglycemia pathology
Insulin Secretion
Insulin-Secreting Cells pathology
Insulin-Secreting Cells ultrastructure
Male
Mice, Knockout
Mice, Transgenic
Middle Aged
Protein Serine-Threonine Kinases genetics
Recombinant Proteins metabolism
Regulatory Factor X Transcription Factors
Signal Transduction
Tissue Donors
Transcription Factors genetics
X-Box Binding Protein 1
Young Adult
Alternative Splicing
DNA-Binding Proteins metabolism
Endoribonucleases metabolism
Hyperglycemia metabolism
Insulin metabolism
Insulin-Secreting Cells metabolism
Oxidative Stress
Protein Serine-Threonine Kinases metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1545-7885
- Volume :
- 13
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- PLoS biology
- Publication Type :
- Academic Journal
- Accession number :
- 26469762
- Full Text :
- https://doi.org/10.1371/journal.pbio.1002277