Dynamic Regulation of Ero1α and Peroxiredoxin 4 Localization in the Secretory Pathway

In the early secretory compartment (ESC), a network of chaperones and enzymes assists oxidative folding of nascent proteins. Ero1 flavoproteins oxidize protein disulfide isomerase (PDI), generating H 2 O 2 as a byproduct. Peroxiredoxin 4 (Prx4) can utilize luminal H 2 O 2 to oxidize PDI, thus favoring oxidative folding while limiting oxidative stress. Interestingly, neither ER oxidase contains known ER retention signal(s), raising the question of how cells prevent their secretion. Here we show that the two proteins share similar intracellular localization mechanisms. Their secretion is prevented by sequential interactions with PDI and ERp44, two resident proteins of the ESC-bearing KDEL-like motifs. PDI binds preferentially Ero1α, whereas ERp44 equally retains Ero1α and Prx4. The different binding properties of Ero1α and Prx4 increase the robustness of ER redox homeostasis. Background: Ero1α and peroxiredoxin 4 contribute to disulfide formation in the early secretory compartment (ESC), but lack known retention signals. Results: Retention and localization of Ero1α and peroxiredoxin 4 are maintained through multistep and pH-dependent interactions with PDI and ERp44 in ESC. Conclusion: PDI and ERp44 dynamically localize Ero1α and peroxiredoxin 4 in ESC. Significance: The levels and localization of four interactors allow differential ESC redox control.