The hereditary hemochromatosis protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells

HFE is the protein product of the gene mutated in the autosomal recessive d isease hereditary hemochromatosis (Feder, J. N., Gnirke, A., Thomas, W., Ts uchihashi, Z., Ruddy, D. A., Basava, A., Dormishian, F., Domingo, R. J., El lis, M. C., Fullan, A., Hinton, L. M., Jones, N. L., Kimmel, B. E., Kronmal , G. S., Lauer, P., Lee, V. K., Loeb, D. B., Mapa, F. A., McClelland, E., M eyer, N. C., Mintier, G. A., Moeller, N., Moore, T., Morikang, E., Prasss, C. E., Quintana, L., Starnes, S. M., Schatzman, R. C., Brunke, K. J., Drayn a, D. T., Risch, N. J., Bacon, B. R., and Wolff, R. R, (1996) Nat. Genet. 1 3, 399-408). At the cell surface, HFE complexes with transferrin receptor ( TfR), increasing the dissociation constant of transferrin (Tf) for its rece ptor 10-fold (Gross, C. N., Irrinki, A., Feder, J. N., and Enns, C. A. (199 8) J. Biol. Chem. 273, 22068-22074; Feder, J. N., Penny, D. M., Irrinki, A. , Lee, V. K., Lebron, J. A., Watson, N., Tsuchihashi, Z., Sigal, E., Bjorkm an, P. J., and Schatzman, R. C. (1998) Proc. Natl. Acad. Sci. U S A 95, 147 2-1477). HFE does not remain at the cell surface, but traffics with TfR to Tf-positive internal compartments (Gross ct at, 1998). Using a HeLa cell li ne in which the expression of HFE is controlled by tetracycline, we show th at the expression of HFE reduces Fe-55 uptake from Tf by 33% but does not a ffect the endocytic or exocytic rates of TfR cycling. Therefore, HFE appear s to reduce cellular acquisition of iron from Tf within endocytic compartme nts. HFE specifically reduces iron uptake from Tf, as non-Tf-mediated iron uptake from Fe-nitrilotriacetic acid is not altered. These results explain the decreased ferritin levels seen in our HeLa cell system and demonstrate the specific control of HFE over the Tf-mediated pathway of iron uptake. Th ese results also have implications for the understanding of cellular iron h omeostasis in organs such as the liver, pancreas, heart, and spleen that ar e iron loaded in hereditary hemochromatotic individuals lacking functional HFE.