The hemochromatosis protein HFE inhibits iron export from macrophages.
Hereditary hemochromatosis (HH) is a disorder of iron metabolism caused by common mutations in the gene HFE. The HFE protein binds to transferrin receptor-1 (TfR1) in competition with transferrin, and in vitro, reduces cellular iron by reducing iron uptake. However, in vivo, HFE is strongly expressed by liver macrophages and intestinal crypt cells, which behave as though they are relatively iron-deficient in HH. These latter observations suggest, paradoxically, that expression of wild-type HFE may lead to iron accumulation in these specialized cell types. Here we show that wild-type HFE protein raises cellular iron by inhibiting iron efflux from the monocytemacrophage cell line THP-1, and extend these results to macrophages derived from healthy individuals and HH patients. In addition, we find that the HH-associated mutant H41D has lost the ability to inhibit iron release despite binding to TfR1 as well as wild-type HFE. Finally, we show that the ability of HFE to block iron release is not competitively inhibited by transferrin. We conclude that HFE has two mutually exclusive functions, binding to TfR1 in competition with Tf, or inhibition of iron release.
Drakesmith
Hal
H
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, United Kingdom. hdrakes@molbiol.ox.ac.uk
Sweetland
Emma
E
Schimanski
Lisa
L
Edwards
Jon
J
Cowley
Diana
D
Ashraf
Mubeen
M
Bastin
Judy
J
Townsend
Alain R M
AR
D019943:Amino Acid Substitution; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D005293:Ferritins / Q000378:metabolism; D006367:HeLa Cells; D006432:Hemochromatosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008958:Models, Molecular; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014168:Transferrin / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D020298:U937 Cells / Q000187:drug effects / Q000378:metabolism
C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D014168:Transferrin; D005293:Ferritins; D007501:Iron