Journal
EMBO JOURNAL
Volume 29, Issue 19, Pages 3318-3329Publisher
WILEY
DOI: 10.1038/emboj.2010.203
Keywords
disulphide-bond formation; endoplasmic reticulum; Ero1; glutathione; protein disulphide isomerase
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Funding
- Swiss National Science Foundation (SNSF)
- Bohringer Ingelheim Foundation
- Novartis Stiftung
- Carlsbergfondet
- Novo Nordisk Fonden
- European Molecular Biology Organization
- National Institutes of Health
- Medical Research Council [G0600717B] Funding Source: researchfish
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The molecular networks that control endoplasmic reticulum (ER) redox conditions in mammalian cells are incompletely understood. Here, we show that after reductive challenge the ER steady-state disulphide content is restored on a time scale of seconds. Both the oxidase Ero1 alpha and the oxidoreductase protein disulphide isomerase (PDI) strongly contribute to the rapid recovery kinetics, but experiments in ERO1-deficient cells indicate the existence of parallel pathways for disulphide generation. We find PDI to be the main substrate of Ero1 alpha, and mixed-disulphide complexes of Ero1 primarily form with PDI, to a lesser extent with the PDI-family members ERp57 and ERp72, but are not detectable with another homologue TMX3. We also show for the first time that the oxidation level of PDIs and glutathione is precisely regulated. Apparently, this is achieved neither through ER import of thiols nor by transport of disulphides to the Golgi apparatus. Instead, our data suggest that a dynamic equilibrium between Ero1- and glutathione disulphide-mediated oxidation of PDIs constitutes an important element of ER redox homeostasis. The EMBO Journal (2010) 29, 3318-3329. doi:10.1038/emboj.2010.203; Published online 27 August 2010
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