The Hemochromatosis Protein HFE Inhibits Iron Export from Macrophages

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 99; no. 24; pp. 15602 - 15607
• Main Authors: Drakesmith, Hal, Sweetland, Emma, Schimanski, Lisa, Edwards, Jon, Cowley, Diana, Ashraf, Mubeen, Bastin, Judy, Alain R. M. Townsend
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26-11-2002; National Acad Sciences
• Subjects: Amino Acid Substitution; Antibodies; Binding, Competitive; Biological Sciences; Biological Transport - drug effects; Cell lines; Crypts; Cultured cells; Dietary iron; Ferritins; Ferritins - metabolism; HeLa Cells; Hemochromatosis - genetics; Hemochromatosis - metabolism; Hemochromatosis - pathology; Hemochromatosis Protein; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - pharmacology; Histocompatibility Antigens Class I - physiology; Histograms; Humans; Iron; Iron - metabolism; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Medical research; Membrane Proteins - genetics; Membrane Proteins - pharmacology; Membrane Proteins - physiology; Models, Molecular; Monocytes - drug effects; Monocytes - metabolism; Mutation; Protein Conformation; Proteins; Recombinant Fusion Proteins - pharmacology; Transferrin - metabolism; Transferrin - pharmacology; Transferrins; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - metabolism; U937 Cells - drug effects; U937 Cells - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.242614699

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 monocyte/macrophage 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.