CO-TRAFFICKING OF HFE, A NONCLASSICAL MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I PROTEIN, WITH THE TRANSFERRIN RECEPTOR IMPLIES A ROLE IN INTRACELLULAR IRON REGULATION

The mechanism by which a novel major histocompatibility compiler class I protein, HFE, regulates iron uptake into the body is not known. HFE is the product of the gene that is mutated in >80% of hereditary hemo chromatosis patients. It was recently found to coprecipitate with the transferrin receptor (Feder, J. N., Penny, D. M., Irrinki, A., Lee, V. K., Lebron, J. A., Watson, N., Tsuchihashi, Z., Sigal, E., Bjorkman, P. J., and Schatzman, R. C. (1998) Proc. Natl. Acad. Sci. U.S.A. 95, 1 472-1477; Parkkila, S., Waheed, A., Britton, R. S., Bacon, B. R., Zhou , X. Y., Tomatsu, S., Fleming, R.E., and Sly, W. S. (1997) Proc. Natl. Acad Sci. U.S.A. 94, 13198-13202) and to decrease the affinity of tra nsferrin for the transferrin receptor (Feder et al.). In this study, H eLa cells were transfected with HFE: under the control of the tetracyc line-repressible promoter. We demonstrate that HFE: and the transferri n receptor are capable of associating with each other within 30 min of their synthesis with pulse-chase experiments. HFE and the transferrin receptor co-immunoprecipitate throughout the biosynthetic pathway. Ex cess HFE is rapidly degraded, whereas the HFE-transferrin receptor com plex is stable. Immunofluorescence experiments indicate that they sals e endocytose into transferrin-positive compartments. Combined, these r esults suggest a role for the transferrin receptor in HFE trafficking, Cells expressing HFE have modestly increased levels of transferrin re ceptor and drastically reduced levels of ferritin. These results impli cate HFE further in the modulation of iron levels in the cell.