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

Nat Cell Biol. 2000 Dec;2(12):953-7. doi: 10.1038/35046611.

Abstract

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

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Biological Transport, Active
  • Cell Line
  • Cell Polarity
  • Endocytosis
  • Endosomes / metabolism
  • Epithelial Cells / metabolism
  • Green Fluorescent Proteins
  • HLA Antigens / genetics
  • HLA Antigens / metabolism*
  • Hemochromatosis / genetics
  • Hemochromatosis / immunology
  • Hemochromatosis / metabolism
  • Hemochromatosis Protein
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism*
  • Homeostasis
  • Humans
  • Iron / metabolism*
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Membrane Proteins*
  • Microscopy, Confocal
  • Models, Biological
  • Mutation
  • Protein Binding
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism
  • Receptors, Transferrin / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transfection

Substances

  • HFE protein, human
  • HLA Antigens
  • Hemochromatosis Protein
  • Histocompatibility Antigens Class I
  • Luminescent Proteins
  • Membrane Proteins
  • Receptors, LDL
  • Receptors, Transferrin
  • Recombinant Fusion Proteins
  • Green Fluorescent Proteins
  • Iron