Journal of Hepatology
Volume 50, Issue 2 , Pages 394-401 , February 2009

Pro-hepcidin is unable to degrade the iron exporter ferroportin unless maturated by a furin-dependent process

  • Bruno Gagliardo

      Affiliations

    • Université Paris Descartes, CNRS (UMR 8601), Paris, France
    • These authors contributed equally to this work.
  • ,
  • Nicole Kubat

      Affiliations

    • Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
    • Inserm, U567, Paris, France
    • These authors contributed equally to this work.
  • ,
  • Audrey Faye

      Affiliations

    • Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
    • Inserm, U567, Paris, France
  • ,
  • Maryse Jaouen

      Affiliations

    • Université Paris Descartes, CNRS (UMR 8601), Paris, France
  • ,
  • Béatrice Durel

      Affiliations

    • Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
    • Inserm, U567, Paris, France
  • ,
  • Jean-Christophe Deschemin

      Affiliations

    • Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
    • Inserm, U567, Paris, France
  • ,
  • François Canonne-Hergaux

      Affiliations

    • CNRS, Institut de Chimie des Substances Naturelles, Gif-Sur-Yvette, France
  • ,
  • Marie-Agnès Sari

      Affiliations

    • Université Paris Descartes, CNRS (UMR 8601), Paris, France
  • ,
  • Sophie Vaulont

      Affiliations

    • Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
    • Inserm, U567, Paris, France
    • Département de Génétique, Développement et Pathologie Moléculaire, Institut Cochin, Faculté de Médecine Cochin-Port Royal, 24, rue du Fg St Jacques, 75014 Paris, France
    • Corresponding Author InformationCorresponding author. Tel.: +33 1 44412408; fax: +33 1 44412421.

Received 8 August 2008 ,Revised 11 September 2008 ,Accepted 15 September 2008.

References 

  1. Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, et al. A new mouse liver specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276:7811–7819
  2. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin: a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806–7810
  3. Krause A, Neitz S, Magert HJ, Schulz A, Forssmann WG, Schulz-Knappe P, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000;480:147–150
  4. Ganz T. Hepcidin and its role in regulating systemic iron metabolism. Hematol Am Soc Hematol Educ Program. 2006;507:29–35
  5. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090–2093
  6. Delaby C, Pilard N, Goncalves AS, Beaumont C, Canonne-Hergaux F. The presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and downregulated by hepcidin. Blood. 2005;106:3979–3984
  7. De Domenico I, Ward DM, Langelier C, Vaughn MB, Nemeth E, Sundquist WI, et al. The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell. 2007;18:2569–2578
  8. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271–1276
  9. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110:1037–1044
  10. Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest. 2007;117:1926–1932
  11. Vaulont S, Lou DQ, Viatte L, Kahn A. Of mice and men: the iron age. J Clin Invest. 2005;115:2079–2082
  12. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102:783–788
  13. Tomosugi N, Kawabata H, Wakatabe R, Higuchi M, Yamaya H, Umehara H, et al. Detection of serum hepcidin in renal failure and inflammation by using ProteinChip System. Blood. 2006;108:1381–1387
  14. Kemna EH, Tjalsma H, Podust VN, Swinkels DW. Mass spectrometry-based hepcidin measurements in serum and urine: analytical aspects and clinical implications. Clin Chem. 2007;53:620–628
  15. Murphy AT, Witcher DR, Luan P, Wroblewski VJ. Quantitation of hepcidin from human and mouse serum using liquid chromatography tandem mass spectrometry. Blood. 2007;110:1048–1054
  16. Kulaksiz H, Gehrke SG, Janetzko A, Rost D, Bruckner T, Kallinowski B, et al. Pro-hepcidin: expression and cell specific localisation in the liver and its regulation in hereditary haemochromatosis, chronic renal insufficiency, and renal anaemia. Gut. 2004;53:735–743
  17. Walker AP, Partridge J, Dooley JS. Hepcidin: what every gastroenterologist should know. Gut. 2004;53:624–627
  18. Brookes MJ, Sharma NK, Tselepis C, Iqbal TH. Serum pro-hepcidin: measuring active hepcidin or a non-functional precursor?. Gut. 2005;54:169–170
  19. Kemna EH, Pickkers P, Nemeth E, van der Hoeven H, Swinkels D. Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood. 2005;106:51864–51866
  20. Molloy SS, Anderson ED, Jean F, Thomas G. Bi-cycling the furin pathway: from TGN localization to pathogen activation and embryogenesis. Trends Cell Biol. 1999;9:28–35
  21. Prinz WA, Aslund F, Holmgren A, Beckwith J. The role of the thioredoxin and glutaredoxin pathways in reducing protein disulfide bonds in the Escherichia coli cytoplasm. J Biol Chem. 1997;272:15661–15667
  22. Stewart EJ, Aslund F, Beckwith J. Disulfide bond formation in the Escherichia coli cytoplasm: an in vivo role reversal for the thioredoxins. EMBO J. 1998;17:5543–5550
  23. Gagliardo B, Faye A, Jaouen M, Deschemin JC, Canonne-Hergaux F, Vaulont S, et al. Production of biologically active forms of recombinant hepcidin, the iron-regulatory hormone. FEBS J. 2008;275:3793–3803
  24. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding. Anal Biochem. 1976;72:248–254
  25. Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys. 1959;82:70–77
  26. Molloy SS, Thomas L, VanSlyke JK, Stenberg PE, Thomas G. Intracellular trafficking and activation of the furin proprotein convertase: localization to the TGN and recycling from the cell surface. EMBO J. 1994;13:18–33
  27. Valore EV, Ganz T. Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin. Blood Cells Mol Dis. 2007;40:132–138
  28. Silvestri L, Pagani A, Camaschella C. Furin mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis. Blood. 2007;15:924–931
  29. Scamuffa N, Basak A, Lalou C, Wargnier A, Marcinkiewicz J, Siegfried G, et al. Regulation of prohepcidin processing and activity by the subtilisin-like proprotein convertases Furin, PC5, PACE4 and PC7. Gut. 2008;57:1573–1582

 The authors who have taken part in the research of this paper declared that they do not have a relationship with the manufacturers of the materials involved either in the past or present and they did not receive funding from the manufacturers to carry out their research.

☆☆ Financial support: This work was supported by ANR, Institut National de la Santé et de la Recherche Médicale and CNRS.

PII: S0168-8278(08)00716-2

doi: 10.1016/j.jhep.2008.09.018

Journal of Hepatology
Volume 50, Issue 2 , Pages 394-401 , February 2009