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

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-1a (Ero1a) as an electron donor for ERdj5, an ER-resident disulfide reductase. During oxidative folding, Ero1a 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 ca-nonical electron pathway, we reveal that ERdj5 accepts electrons from specific cysteine pairs in Ero1a, 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.

Automated summary

The ER maintains an oxidative redox environment for the folding of nascent polypeptides, while reductive reactions are crucial for ER homeostasis. The mechanism of electrons supply for ER reductase activity is still unknown. This study identifies Ero1a as an electron donor for ERdj5, indicating the contribution of oxidative folding to reductive reactions in the ER and the maintenance of ER homeostasis.