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

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 (Xb...

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Autores principales: Hassler, Justin R., Scheuner, Donalyn L., Wang, Shiyu, Han, Jaeseok, Kodali, Vamsi K., Li, Philip, Nguyen, Julie, George, Jenny S., Davis, Cory, Wu, Shengyang P., Bai, Yongsheng, Sartor, Maureen, Cavalcoli, James, Malhi, Harmeet, Baudouin, Gregory, Zhang, Yaoyang, Yates III, John R., Itkin-Ansari, Pamela, Volkmann, Niels, Kaufman, Randal J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607427/
https://www.ncbi.nlm.nih.gov/pubmed/26469762
http://dx.doi.org/10.1371/journal.pbio.1002277
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author Hassler, Justin R.
Scheuner, Donalyn L.
Wang, Shiyu
Han, Jaeseok
Kodali, Vamsi K.
Li, Philip
Nguyen, Julie
George, Jenny S.
Davis, Cory
Wu, Shengyang P.
Bai, Yongsheng
Sartor, Maureen
Cavalcoli, James
Malhi, Harmeet
Baudouin, Gregory
Zhang, Yaoyang
Yates III, John R.
Itkin-Ansari, Pamela
Volkmann, Niels
Kaufman, Randal J.
author_facet Hassler, Justin R.
Scheuner, Donalyn L.
Wang, Shiyu
Han, Jaeseok
Kodali, Vamsi K.
Li, Philip
Nguyen, Julie
George, Jenny S.
Davis, Cory
Wu, Shengyang P.
Bai, Yongsheng
Sartor, Maureen
Cavalcoli, James
Malhi, Harmeet
Baudouin, Gregory
Zhang, Yaoyang
Yates III, John R.
Itkin-Ansari, Pamela
Volkmann, Niels
Kaufman, Randal J.
author_sort Hassler, Justin R.
collection PubMed
description 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.
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spelling pubmed-46074272015-10-29 The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells Hassler, Justin R. Scheuner, Donalyn L. Wang, Shiyu Han, Jaeseok Kodali, Vamsi K. Li, Philip Nguyen, Julie George, Jenny S. Davis, Cory Wu, Shengyang P. Bai, Yongsheng Sartor, Maureen Cavalcoli, James Malhi, Harmeet Baudouin, Gregory Zhang, Yaoyang Yates III, John R. Itkin-Ansari, Pamela Volkmann, Niels Kaufman, Randal J. PLoS Biol Research Article 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. Public Library of Science 2015-10-15 /pmc/articles/PMC4607427/ /pubmed/26469762 http://dx.doi.org/10.1371/journal.pbio.1002277 Text en © 2015 Hassler et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Hassler, Justin R.
Scheuner, Donalyn L.
Wang, Shiyu
Han, Jaeseok
Kodali, Vamsi K.
Li, Philip
Nguyen, Julie
George, Jenny S.
Davis, Cory
Wu, Shengyang P.
Bai, Yongsheng
Sartor, Maureen
Cavalcoli, James
Malhi, Harmeet
Baudouin, Gregory
Zhang, Yaoyang
Yates III, John R.
Itkin-Ansari, Pamela
Volkmann, Niels
Kaufman, Randal J.
The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells
title The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells
title_full The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells
title_fullStr The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells
title_full_unstemmed The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells
title_short The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells
title_sort ire1α/xbp1s pathway is essential for the glucose response and protection of β cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607427/
https://www.ncbi.nlm.nih.gov/pubmed/26469762
http://dx.doi.org/10.1371/journal.pbio.1002277
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