Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 41, Pages 29586-29594Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.467845
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Funding
- Human Frontier Science Program (HFSP)
- Telethon [GGP11077]
- Associazione Italiana Ricerca Cancro (AIRC)
- Japan Society for the Promotion of Science (JSPS) [08J03849, 12J02049, 12J04142]
- Grants-in-Aid for Scientific Research [08J03849] Funding Source: KAKEN
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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 luminal H2O2 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 Ero1 alpha, whereas ERp44 equally retains Ero1 alpha and Prx4. The different binding properties of Ero1 alpha and Prx4 increase the robustness of ER redox homeostasis.
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