GPx8 peroxidase prevents leakage of H2O2 from the endoplasmic reticulum

Free Radic Biol Med. 2014 May;70:106-16. doi: 10.1016/j.freeradbiomed.2014.01.018. Epub 2014 Feb 22.


Unbalanced endoplasmic reticulum (ER) homeostasis (ER stress) leads to increased generation of reactive oxygen species (ROS). Disulfide-bond formation in the ER by Ero1 family oxidases produces hydrogen peroxide (H2O2) and thereby constitutes one potential source of ER-stress-induced ROS. However, we demonstrate that Ero1α-derived H2O2 is rapidly cleared by glutathione peroxidase (GPx) 8. In 293 cells, GPx8 and reduced/activated forms of Ero1α co-reside in the rough ER subdomain. Loss of GPx8 causes ER stress, leakage of Ero1α-derived H2O2 to the cytosol, and cell death. In contrast, peroxiredoxin (Prx) IV, another H2O2-detoxifying rough ER enzyme, does not protect from Ero1α-mediated toxicity, as is currently proposed. Only when Ero1α-catalyzed H2O2 production is artificially maximized can PrxIV participate in its reduction. We conclude that the peroxidase activity of the described Ero1α-GPx8 complex prevents diffusion of Ero1α-derived H2O2 within and out of the rough ER. Along with the induction of GPX8 in ER-stressed cells, these findings question a ubiquitous role of Ero1α as a producer of cytoplasmic ROS under ER stress.

Keywords: Apoptosis; Endoplasmic reticulum stress; Free radicals; Hydrogen peroxide; Peroxidases; Redox homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disulfides / pharmacology
  • Endoplasmic Reticulum Stress / genetics*
  • Glutathione Peroxidase / metabolism*
  • HEK293 Cells
  • Humans
  • Hydrogen Peroxide / metabolism*
  • Oxidation-Reduction
  • Peroxidases / genetics
  • Peroxidases / metabolism*
  • Protein Folding
  • Reactive Oxygen Species / metabolism


  • Disulfides
  • Reactive Oxygen Species
  • Hydrogen Peroxide
  • GPX8 protein, human
  • Peroxidases
  • Glutathione Peroxidase