The oxidative folding of nascent polypeptides provides electrons for reductive reactions in the ER

• Published in: Cell reports (Cambridge) 2023-07, Vol.42 (7), p.112742-112742, Article 112742
• Main Authors: Uegaki, Kaiku, Tokunaga, Yuji, Inoue, Michio, Takashima, Seiji, Inaba, Kenji, Takeuchi, Koh, Ushioda, Ryo, Nagata, Kazuhiro
• Format: Article
• Language: English
• Subjects: CP: Metabolism; Disulfides - metabolism; Electrons; endoplasmic reticulum; Endoplasmic Reticulum - metabolism; ER homeostasis; ER-associated degradation; ERAD; ERdj5; Ero1α; H2O2; hydrogen peroxide; Hydrogen Peroxide - metabolism; Membrane Glycoproteins - metabolism; nascent polypeptides; Oxidation-Reduction; oxidative folding; Oxidative Stress; Oxidoreductases - metabolism; Peptides - metabolism; Protein Disulfide-Isomerases - metabolism; Protein Folding; redox; ribosome
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112742

The endoplasmic reticulum (ER) maintains an oxidative redox environment that is advantageous for the oxidative folding of nascent polypeptides entering the ER. Reductive reactions within the ER are also crucial for maintaining ER homeostasis. However, the mechanism by which electrons are supplied for the reductase activity within the ER remains unknown. Here, we identify ER oxidoreductin-1α (Ero1α) as an electron donor for ERdj5, an ER-resident disulfide reductase. During oxidative folding, Ero1α catalyzes disulfide formation in nascent polypeptides through protein disulfide isomerase (PDI) and then transfers the electrons to molecular oxygen via flavin adenine dinucleotide (FAD), ultimately yielding hydrogen peroxide (H2O2). Besides this canonical electron pathway, we reveal that ERdj5 accepts electrons from specific cysteine pairs in Ero1α, demonstrating that the oxidative folding of nascent polypeptides provides electrons for reductive reactions in the ER. Moreover, this electron transfer pathway also contributes to maintaining ER homeostasis by reducing H2O2 production in the ER. [Display omitted] •Ero1α, a major ER-resident oxidase, acts as a reductase for ERdj5•The nascent polypeptide is the electron source for reductive reactions in the ER•ERdj5 suppresses Ero1α-dependent H2O2 production in the ER The reductase activity of ERdj5 maintains ER homeostasis. However, the mechanism of electron supply to ERdj5 for reductase activity was unclear. Uegaki et al. identify ER oxidoreductin-1α (Ero1α) as an electron donor for ERdj5 and reveal a specific electron transfer pathway in which ERdj5 salvages electrons from ER oxidative folding.