Dynamic regulation of Ero1α and peroxiredoxin 4 localization in the secretory pathway

Abstract

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 H2O2 as a byproduct. Peroxiredoxin 4 (Prx4) can utilize luminalH2O 2 to oxidize PDI, thus favoring oxidative folding while limiting oxidative stress. Interestingly, neitherERoxidase contains knownERretention 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. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.