Functional consequences of ferroportin 1 mutations.
The cellular iron exporter ferroportin 1 is expressed in both the duodenum and in cells of the mononuclear phagocyte system. Expression of ferroportin 1 protein on the cell surface is regulated by the interaction of ferroportin 1 with hepcidin. Hepcidin treatment of cells results in internalization and lysosomal degradation of cell surface ferroportin 1. Recently, ferroportin 1 mutations leading to hemochromatosis (HFE4) have been identified. HFE4 differs from classical hemochromatosis in that there is a greater amount of macrophage iron sequestration. The data presented here demonstrate that HFE4 mutations are heterogeneous in their effects on protein function. Some mutations result in loss of function with partial protein sequestration in the ER. Others are indistinguishable from native ferroportin 1 and have a similar ability to deplete transfected cells of iron as evidenced by activation of the iron-response proteins and cellular ferritin depletion. Significantly, all mutants appear to be unresponsive to hepcidin and do not demonstrate the expected internalization on exposure to hepcidin. The clinical phenotypes observed in patients may be secondary to cell-type-specific defects in hepcidin-mediated inhibition of ferroportin 1 expression.
Liu
Xiao-Bing
XB
Audie Murphy Veterans Administration Hospital, South Texas Veterans Health Care System, San Antonio, TX 78229, USA.
Yang
Funmei
F
Haile
David J
DJ
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006432:Hemochromatosis; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000378:metabolism; D000090463:Iron Deficiencies; D008565:Membrane Proteins / Q000737:chemistry; D051379:Mice; D010449:Peptide Mapping; D021381:Protein Transport; D014162:Transfection; D000098742:Ferroportin
D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D008565:Membrane Proteins; D000098742:Ferroportin; D007501:Iron