title: HFE downregulates iron uptake from transferrin and induces iron-regulatory protein activity in stably transfected cells.
abstract: Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder of iron metabolism. More than 80% of HH patients are homozygous for a point mutation in a major histocompatibility complex (MHC) class I type protein (HFE), which results in a lack of HFE expression on the cell surface. A previously identified interaction of HFE and the transferrin receptor suggests a possible regulatory role of HFE in cellular iron absorption. Using an HeLa cell line stably transfected with HFE under the control of a tetracycline-sensitive promoter, we investigated the effect of HFE expression on cellular iron uptake. We demonstrate that the overproduction of HFE results in decreased iron uptake from diferric transferrin. Moreover, HFE expression activates the key regulators of intracellular iron homeostasis, the iron-regulatory proteins (IRPs), implying that HFE can affect the intracellular "labile iron pool." The increase in IRP activity is accompanied by the downregulation of the iron-storage protein, ferritin, and an upregulation of transferrin receptor levels. These findings are discussed in the context of the pathophysiology of HH and a possible role of iron-responsive element (IRE)-containing mRNAs.
authors.affiliation: Department of Medicine, University Hospital of Heidelberg; and the European Molecular Biology Lab (EMBL), Heidelberg, Germany.
authors.forename: H D
authors.initials: HD
authors.lastname: Riedel
authors.forename: M U
authors.initials: MU
authors.lastname: Muckenthaler
authors.forename: S G
authors.initials: SG
authors.lastname: Gehrke
authors.forename: I
authors.initials: I
authors.lastname: Mohr
authors.forename: K
authors.initials: K
authors.lastname: Brennan
authors.forename: T
authors.initials: T
authors.lastname: Herrmann
authors.forename: B A
authors.initials: BA
authors.lastname: Fitscher
authors.forename: M W
authors.initials: MW
authors.lastname: Hentze
authors.forename: W
authors.initials: W
authors.lastname: Stremmel
mesh_terms: D015536:Down-Regulation; D005786:Gene Expression Regulation; D005805:Genes, MHC Class I; D006680:HLA Antigens / Q000235:genetics* / Q000378:metabolism*; D006367:HeLa Cells; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D017354:Point Mutation; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014168:Transferrin / Q000235:genetics / Q000378:metabolism*
chemical_list: C103673:HFE protein, human; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; D014168:Transferrin; D007501:Iron