A novel reaction of peroxiredoxin 4 towards substrates in oxidative protein folding.

Peroxiredoxin 4 (Prx4) is the only endoplasmic reticulum localized peroxiredoxin. It functions not only to eliminate peroxide but also to promote oxidative protein folding via oxidizing protein disulfide isomerase (PDI). In Prx4-mediated oxidative protein folding we discovered a new reaction that the sulfenic acid form of Prx4 can directly react with thiols in folding substrates, resulting in non-native disulfide cross-linking and aggregation. We also found that PDI can inhibit this reaction by exerting its reductase and chaperone activities. This discovery discloses an off-pathway reaction in the Prx4-mediated oxidative protein folding and the quality control role of PDI.