title: Oxidative protein folding by an endoplasmic reticulum-localized peroxiredoxin.
abstract: Endoplasmic reticulum (ER) oxidation 1 (ERO1) transfers disulfides to protein disulfide isomerase (PDI) and is essential for oxidative protein folding in simple eukaryotes such as yeast and worms. Surprisingly, ERO1-deficient mammalian cells exhibit only a modest delay in disulfide bond formation. To identify ERO1-independent pathways to disulfide bond formation, we purified PDI oxidants with a trapping mutant of PDI. Peroxiredoxin IV (PRDX4) stood out in this list, as the related cytosolic peroxiredoxins are known to form disulfides in the presence of hydroperoxides. Mouse embryo fibroblasts lacking ERO1 were intolerant of PRDX4 knockdown. Introduction of wild-type mammalian PRDX4 into the ER rescued the temperature-sensitive phenotype of an ero1 yeast mutation. In the presence of an H(2)O(2)-generating system, purified PRDX4 oxidized PDI and reconstituted oxidative folding of RNase A. These observations implicate ER-localized PRDX4 in a previously unanticipated, parallel, ERO1-independent pathway that couples hydroperoxide production to oxidative protein folding in mammalian cells.
authors.affiliation: Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Ester
authors.initials: E
authors.lastname: Zito
authors.forename: Eduardo Pinho
authors.initials: EP
authors.lastname: Melo
authors.forename: Yun
authors.initials: Y
authors.lastname: Yang
authors.forename: Åsa
authors.initials: Å
authors.lastname: Wahlander
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Neubert
authors.forename: David
authors.initials: D
authors.lastname: Ron
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D010084:Oxidation-Reduction; D054464:Peroxiredoxins / Q000737:chemistry* / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000737:chemistry / Q000378:metabolism; D017510:Protein Folding
chemical_list: D006861:Hydrogen Peroxide; D054464:Peroxiredoxins; C515981:Prdx4 protein, mouse; D019704:Protein Disulfide-Isomerases