Binding to the transferrin receptor is required for endocytosis of HFE andregulation of iron homeostasis

HFE, the protein that is mutated in hereditary haemochromatosis, binds to t he transferrin receptor (TfR). Here we show that wild-type HFE and TfR loca lize in endosomes and at the basolateral membrane of a polarized duodenal e pithelial cell line, whereas the primary haemochromatosis HFE mutant, and a nother mutant with impaired TfR-binding ability accumulate in the ER/Golgi and at the basolateral membrane, respectively. Levels of the iron-storage p rotein ferritin are greatly reduced and those of TfR ave slightly increased in cells expressing wild-type HFE, but not in cells expressing either muta nt. Addition of an endosomal-targeting sequence derived from the human low- density lipoprotein receptor (LDLR) to the TfR-binding-impaired mutant rest ores its endosomal localization but not ferritin reduction or TfR elevation . Thus, binding to TfR is required for transport of HFE to endosomes and re gulation of intracellular iron homeostasis, but not for basolateral surface expression of HFE.