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ERO1-independent production of H2O2 within the endoplasmic reticulum fuels Prdx4-mediated oxidative protein folding.

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Konno, Tasuku 
Pinho Melo, Eduardo 
Lopes, Carlos 
Mehmeti, Ilir 
Lenzen, Sigurd 


The endoplasmic reticulum (ER)-localized peroxiredoxin 4 (PRDX4) supports disulfide bond formation in eukaryotic cells lacking endoplasmic reticulum oxidase 1 (ERO1). The source of peroxide that fuels PRDX4-mediated disulfide bond formation has remained a mystery, because ERO1 is believed to be a major producer of hydrogen peroxide (H2O2) in the ER lumen. We report on a simple kinetic technique to track H2O2 equilibration between cellular compartments, suggesting that the ER is relatively isolated from cytosolic or mitochondrial H2O2 pools. Furthermore, expression of an ER-adapted catalase to degrade lumenal H2O2 attenuated PRDX4-mediated disulfide bond formation in cells lacking ERO1, whereas depletion of H2O2 in the cytosol or mitochondria had no similar effect. ER catalase did not effect the slow residual disulfide bond formation in cells lacking both ERO1 and PRDX4. These observations point to exploitation of a hitherto unrecognized lumenal source of H2O2 by PRDX4 and a parallel slow H2O2-independent pathway for disulfide formation.



Animals, Catalase, Cell Line, Disulfides, Endoplasmic Reticulum, Fibroblasts, Glycoproteins, Humans, Hydrogen Peroxide, Mice, Mitochondria, Oxidoreductases, Peroxiredoxins, Protein Folding

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J Cell Biol

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Rockefeller University Press
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (084812/Z/08/Z)
European Commission (277713)
Supported by grants from the Wellcome Trust (Wellcome 084812) the European Commission (EU FP7 Beta-Bat No: 277713) and Fundação para a Ciência e Tecnologia, Portugal (PTDC/QUI-BIQ/119677/2010) and, a Wellcome Trust Strategic Award for core facilities to the Cambridge Institute for Medical Research (Wellcome 100140). DR is a Wellcome Trust Principal Research Fellow. TK was supported by Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation, Japan Society for the Promotion of Science (JSPS)