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jcb Home » 2013 Archive » 25 November » 203 (4): 615
Article

Two phases of disulfide bond formation have differing requirements for oxygen

Marianne Koritzinsky, Fiana Levitin, Twan van den Beucken, Ryan A. Rumantir, Nicholas J. Harding, Kenneth C. Chu, Paul C. Boutros, Ineke Braakman, Bradly G. Wouters
Marianne Koritzinsky
Ontario Cancer Institute and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario M5G 2M9, CanadaDepartments of Radiation Oncology, Medical Biophysics, and Institute of Medical Science, University of Toronto, Ontario M5S 1A1, CanadaDepartments of Radiation Oncology, Medical Biophysics, and Institute of Medical Science, University of Toronto, Ontario M5S 1A1, CanadaDepartment of Radiation Oncology (Maastro Lab), GROW School for Oncology & Developmental Biology, Maastricht University, 6200 MD Maastricht, Netherlands
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Fiana Levitin
Ontario Cancer Institute and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario M5G 2M9, Canada
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Twan van den Beucken
Department of Radiation Oncology (Maastro Lab), GROW School for Oncology & Developmental Biology, Maastricht University, 6200 MD Maastricht, Netherlands
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Ryan A. Rumantir
Ontario Cancer Institute and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario M5G 2M9, CanadaDepartments of Radiation Oncology, Medical Biophysics, and Institute of Medical Science, University of Toronto, Ontario M5S 1A1, Canada
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Nicholas J. Harding
Informatics and Biocomputing Platform and Selective Therapies Program, Ontario Institute for Cancer Research, Ontario M5G 0A3, Canada
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Kenneth C. Chu
Ontario Cancer Institute and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario M5G 2M9, CanadaInformatics and Biocomputing Platform and Selective Therapies Program, Ontario Institute for Cancer Research, Ontario M5G 0A3, Canada
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Paul C. Boutros
Departments of Radiation Oncology, Medical Biophysics, and Institute of Medical Science, University of Toronto, Ontario M5S 1A1, CanadaInformatics and Biocomputing Platform and Selective Therapies Program, Ontario Institute for Cancer Research, Ontario M5G 0A3, Canada
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Ineke Braakman
Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, 3584 CH Utrecht, Netherlands
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Bradly G. Wouters
Ontario Cancer Institute and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario M5G 2M9, CanadaDepartments of Radiation Oncology, Medical Biophysics, and Institute of Medical Science, University of Toronto, Ontario M5S 1A1, CanadaDepartments of Radiation Oncology, Medical Biophysics, and Institute of Medical Science, University of Toronto, Ontario M5S 1A1, CanadaDepartment of Radiation Oncology (Maastro Lab), GROW School for Oncology & Developmental Biology, Maastricht University, 6200 MD Maastricht, NetherlandsInformatics and Biocomputing Platform and Selective Therapies Program, Ontario Institute for Cancer Research, Ontario M5G 0A3, Canada
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DOI: 10.1083/jcb.201307185 | Published November 18, 2013
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Abstract

Most proteins destined for the extracellular space require disulfide bonds for folding and stability. Disulfide bonds are introduced co- and post-translationally in endoplasmic reticulum (ER) cargo in a redox relay that requires a terminal electron acceptor. Oxygen can serve as the electron acceptor in vitro, but its role in vivo remains unknown. Hypoxia causes ER stress, suggesting a role for oxygen in protein folding. Here we demonstrate the existence of two phases of disulfide bond formation in living mammalian cells, with differential requirements for oxygen. Disulfide bonds introduced rapidly during protein synthesis can occur without oxygen, whereas those introduced during post-translational folding or isomerization are oxygen dependent. Other protein maturation processes in the secretory pathway, including ER-localized N-linked glycosylation, glycan trimming, Golgi-localized complex glycosylation, and protein transport, occur independently of oxygen availability. These results suggest that an alternative electron acceptor is available transiently during an initial phase of disulfide bond formation and that post-translational oxygen-dependent disulfide bond formation causes hypoxia-induced ER stress.

  • Submitted: 29 July 2013
  • Accepted: 16 October 2013

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 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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© 2013 Koritzinsky et al. 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 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
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Two phases of disulfide bond formation have differing requirements for oxygen
Marianne Koritzinsky, Fiana Levitin, Twan van den Beucken, Ryan A. Rumantir, Nicholas J. Harding, Kenneth C. Chu, Paul C. Boutros, Ineke Braakman, Bradly G. Wouters
J Cell Biol Nov 2013, 203 (4) 615-627; DOI: 10.1083/jcb.201307185

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The Journal of Cell Biology: 218 (2)

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February 4, 2019
Volume 218, No. 2

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