title: Cellular catabolism of the iron-regulatory peptide hormone hepcidin.
abstract: Hepcidin, a 25-amino acid peptide hormone, is the principal regulator of plasma iron concentrations. Hepcidin binding to its receptor, the iron exporter ferroportin, induces ferroportin internalization and degradation, thus blocking iron efflux from cells into plasma. The aim of this study was to characterize the fate of hepcidin after binding to ferroportin. We show that hepcidin is taken up by ferroportin-expressing cells in a temperature- and pH-dependent manner, and degraded together with its receptor. When Texas red-labeled hepcidin (TR-Hep) was added to ferroportin-GFP (Fpn-GFP) expressing cells, confocal microscopy showed co-localization of TR-Hep with Fpn-GFP. Using flow cytometry, we showed that the peptide was almost completely degraded by 24 h after its addition, but that lysosomal inhibitors completely prevented degradation of both ferroportin and hepcidin. In addition, using radio-labeled hepcidin and HPLC analysis we show that hepcidin is not recycled, and that only degradation products are released from the cells. Together these results show that the hormone hepcidin and its receptor ferroportin are internalized together and trafficked to lysosomes where both are degraded.
authors.affiliation: Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Gloria Cuevas
authors.initials: GC
authors.lastname: Preza
authors.forename: Rogelio
authors.initials: R
authors.lastname: Pinon
authors.forename: Tomas
authors.initials: T
authors.lastname: Ganz
authors.forename: Elizabeta
authors.initials: E
authors.lastname: Nemeth
mesh_terms: D027682:Cation Transport Proteins / Q000378:metabolism; D002460:Cell Line; D064451:Hepcidins / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D059748:Proteolysis; D013696:Temperature; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D064451:Hepcidins; D000098742:Ferroportin; D007501:Iron
references.citation: J Mol Biol. 2009 Feb 27;386(3):717-32
references.pmid: 19150361
references.citation: J Biol Chem. 2009 Sep 4;284(36):24155-67
references.pmid: 19553669
references.citation: J Clin Invest. 2011 Dec;121(12):4880-8
references.pmid: 22045566
references.citation: Chemistry. 2004 Jan 5;10(1):257-66
references.pmid: 14695571
references.citation: FEBS Lett. 2000 Sep 1;480(2-3):147-50
references.pmid: 11034317
references.citation: Chem Biol. 2011 Mar 25;18(3):336-43
references.pmid: 21439478
references.citation: Science. 2004 Dec 17;306(5704):2090-3
references.pmid: 15514116
references.citation: Biochem Pharmacol. 1993 Nov 2;46(9):1521-7
references.pmid: 8240406
references.citation: Blood. 2008 Nov 15;112(10):4292-7
references.pmid: 18689548
references.citation: Clin Chem. 2012 Jul;58(7):1158-60
references.pmid: 22586325
references.citation: Biochemistry. 2008 Nov 4;47(44):11647-52
references.pmid: 18847225
references.citation: J Lab Clin Med. 1982 Jul;100(1):1-14
references.pmid: 7045258
references.citation: J Biol Chem. 2001 Mar 16;276(11):7806-10
references.pmid: 11113131
references.citation: Blood. 2006 Jan 1;107(1):328-33
references.pmid: 16141345
references.citation: J Biol Chem. 1979 Apr 25;254(8):2619-25
references.pmid: 218948
references.citation: Experientia. 1986 Jul 15;42(7):734-44
references.pmid: 3015663
references.citation: Clin J Am Soc Nephrol. 2010 Jun;5(6):1010-4
references.pmid: 20299375
references.citation: Haematologica. 2010 Aug;95(8):1269-77
references.pmid: 20220061
references.citation: Blood. 2005 Dec 1;106(12):3979-84
references.pmid: 16081696
references.citation: Cell Metab. 2012 Jun 6;15(6):918-24
references.pmid: 22682227
references.citation: Blood. 2009 Jul 9;114(2):437-43
references.pmid: 19383972
references.citation: Nat Rev Immunol. 2003 Sep;3(9):710-20
references.pmid: 12949495
references.citation: Biochim Biophys Acta. 2012 Sep;1823(9):1434-43
references.pmid: 22306005