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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 Erol alpha-derived H2O2 is rapidly cleared by glutathiope peroxidase (GPx) 8. In 293 cells, GPx8 and reduced/activated forms of Erol alpha co-reside in the rough ER subdomain. Loss of GPx8 causes ER stress, leakage of Erol alpha-clerivet1 H2O2 to the cytosol, and cell death. In cqptrast, peroxiredoxin (Prx) IV, another H2O2-detoxifying rough ER enzyme, does not protect from Erol alpha-rnediated toxicity, as is currently proposed. Only when Ero1 alpha-catalyzed H2O2 production is artificially maximized can PrxIV participate in its reduction. We conclude that the peroxidase activity of the described Ero1 alpha-GPx8 complex prevents diffusion of Erol alpha or-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 Erol alpha cc as a producer of cytoplasmic ROS under ER stress. (c) 2014 Elsevier Inc. All rights reserved.