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A novel disulphide switch mechanism in Ero1 balances ER oxidation in human cells

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Christian Appenzeller-Herzog
  • Jan Riemer
  • Brian Christensen
  • Esben B. Sørensen
  • Ellgaard, Lars
Oxidative maturation of secretory and membrane proteins in the endoplasmic reticulum (ER) is powered by Ero1 oxidases. To prevent cellular hyperoxidation, Ero1 activity can be regulated by intramolecular disulphide switches. Here, we determine the redox-driven shutdown mechanism of Ero1alpha, the housekeeping Ero1 enzyme in human cells. We show that functional silencing of Ero1alpha in cells arises from the formation of a disulphide bond-identified by mass spectrometry-between the active-site Cys94 (connected to Cys99 in the active enzyme) and Cys131. Competition between substrate thiols and Cys131 creates a feedback loop where activation of Ero1alpha is linked to the availability of its substrate, reduced protein disulphide isomerase (PDI). Overexpression of Ero1alpha-Cys131Ala or the isoform Ero1beta, which does not have an equivalent disulphide switch, leads to augmented ER oxidation. These data reveal a novel regulatory feedback system where PDI emerges as a central regulator of ER redox homoeostasis.
OriginalsprogEngelsk
TidsskriftEMBO Journal
Vol/bind27
Sider (fra-til)2977–2987
ISSN0261-4189
DOI
StatusUdgivet - 2008

ID: 9700629