Transferrin receptor is negatively modulated by the hemochromatosis protein HFE: Implications for cellular iron homeostasis

Hereditary hemochromatosis is a common autosomal recessive disorder of iron metabolism. Recent demonstration of an association between transferrin rec eptor (TfR) and HFE, a major histocompatibility complex class I-like molecu le that has been implicated to play a role in hereditary hemochromatosis, f urther strengthens the notion that HFE is involved in iron metabolism. Here in we show that TfR is required for and controls the assembly and the intra cellular transport and surface expression of HFE, Because surface-expressed HFE and TfR remain firmly associated physically, only the fraction of TfR that is associated with HFE during biosynthesis is affected functionally, M oreover, we show that HFE binding reduces the number of functional transfer rin binding sites and impairs TfR internalization, thus reducing the uptake of transferrin-bound iron. Thus, iron homeostasis is indirectly regulated by HFE, a negative modulator of TfR.