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Updated: Jul 24, 2025

Analysis of Protein Folding, Transport, and Degradation in Living Cells by Radioactive Pulse Chase
Published on: February 12, 2019
The oxidative folding of nascent polypeptides provides electrons for reductive reactions in the ER
Kaiku Uegaki1, Yuji Tokunaga2, Michio Inoue3
1Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan.
Abstract:
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.
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