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jcb Home » 2018 Archive » 2 April » 217 (4): 1287
Article

IRE1–XBP1 pathway regulates oxidative proinsulin folding in pancreatic β cells

View ORCID ProfileYuichi Tsuchiya, View ORCID ProfileMichiko Saito, View ORCID ProfileHiroshi Kadokura, View ORCID ProfileJun-ichi Miyazaki, Fumi Tashiro, View ORCID ProfileYusuke Imagawa, View ORCID ProfileTakao Iwawaki, View ORCID ProfileKenji Kohno  Correspondence email
Yuichi Tsuchiya
Graduate School of Biological Sciences and Institute for Research Initiatives, Nara Institute of Science and Technology, Ikoma, Japan
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  • ORCID record for Yuichi Tsuchiya
Michiko Saito
Graduate School of Biological Sciences and Institute for Research Initiatives, Nara Institute of Science and Technology, Ikoma, JapanBio-science Research Center, Kyoto Pharmaceutical University, Kyoto, Japan
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  • ORCID record for Michiko Saito
Hiroshi Kadokura
Graduate School of Biological Sciences and Institute for Research Initiatives, Nara Institute of Science and Technology, Ikoma, JapanInstitute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Japan
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  • ORCID record for Hiroshi Kadokura
Jun-ichi Miyazaki
Division of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Suita, Japan
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  • ORCID record for Jun-ichi Miyazaki
Fumi Tashiro
Division of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Suita, Japan
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Yusuke Imagawa
Graduate School of Biological Sciences and Institute for Research Initiatives, Nara Institute of Science and Technology, Ikoma, JapanDepartment of Molecular and Cellular Biology, Research Center, Osaka International Cancer Institute, Osaka, Japan
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  • ORCID record for Yusuke Imagawa
Takao Iwawaki
Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Uchinada, Japan
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  • ORCID record for Takao Iwawaki
Kenji Kohno
Graduate School of Biological Sciences and Institute for Research Initiatives, Nara Institute of Science and Technology, Ikoma, Japan
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  • ORCID record for Kenji Kohno
  • For correspondence: kkouno@bs.naist.jp
DOI: 10.1083/jcb.201707143 | Published March 5, 2018
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Abstract

In mammalian pancreatic β cells, the IRE1α–XBP1 pathway is constitutively and highly activated under physiological conditions. To elucidate the precise role of this pathway, we constructed β cell–specific Ire1α conditional knockout (CKO) mice and established insulinoma cell lines in which Ire1α was deleted using the Cre–loxP system. Ire1α CKO mice showed the typical diabetic phenotype including impaired glycemic control and defects in insulin biosynthesis postnatally at 4–20 weeks. Ire1α deletion in pancreatic β cells in mice and insulinoma cells resulted in decreased insulin secretion, decreased insulin and proinsulin contents in cells, and decreased oxidative folding of proinsulin along with decreased expression of five protein disulfide isomerases (PDIs): PDI, PDIR, P5, ERp44, and ERp46. Reconstitution of the IRE1α–XBP1 pathway restored the proinsulin and insulin contents, insulin secretion, and expression of the five PDIs, indicating that IRE1α functions as a key regulator of the induction of catalysts for the oxidative folding of proinsulin in pancreatic β cells.

  • Submitted: 26 July 2017
  • Revision received 6 December 2017
  • Accepted: 22 January 2018
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This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

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© 2018 Tsuchiya et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

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IRE1–XBP1 pathway regulates oxidative proinsulin folding in pancreatic β cells
Yuichi Tsuchiya, Michiko Saito, Hiroshi Kadokura, Jun-ichi Miyazaki, Fumi Tashiro, Yusuke Imagawa, Takao Iwawaki, Kenji Kohno
J Cell Biol Apr 2018, 217 (4) 1287-1301; DOI: 10.1083/jcb.201707143

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The Journal of Cell Biology: 217 (4)

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April 2, 2018
Volume 217, No. 4

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