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

J Hepatol. 2009 Feb;50(2):394-401. doi: 10.1016/j.jhep.2008.09.018. Epub 2008 Dec 4.


Background/aims: The iron-regulatory peptide hepcidin is synthesized in the liver as an 84-aa pre-pro-hormone maturated by proteolysis through a consensus furin cleavage site to generate the bioactive 25-aa peptide secreted in the circulation. This peptide regulates iron export from enterocytes and macrophages by binding the membrane iron exporter, ferroportin, leading to its degradation. Whether pro-hepcidin could be secreted and reflect hepcidin levels remains an open question. However, the activity of the pro-peptide on ferroportin degradation has never been addressed.

Methods: To answer this question, we produced recombinant pro-hepcidin, both the wild-type form and a furin cleavage site mutant, and tested their activity on ferroportin levels in macrophagic J774 cells. Furin activity was also modulated using furin inhibitor or siRNA-mediated furin mRNA knockdown.

Results: We found that pro-hepcidin could fully induce ferroportin degradation, but only when processed by furin to generate the mature hepcidin-25 form. Pro-hepcidin activity was abolished in the presence of furin inhibitor and diminished after siRNA-mediated knockdown of furin mRNA. Furthermore, the mutated version of pro-hepcidin was completely inefficient at degrading ferroportin in macrophages.

Conclusions: Our results demonstrate that pro-hepcidin lacks biological activity, unless fully maturated by a furin-dependent process to yield the bioactive 25-aa peptide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides / physiology*
  • Cation Transport Proteins / metabolism*
  • Cell Line
  • Furin / physiology*
  • Hepcidins
  • Macrophages / metabolism
  • Mice
  • Protein Precursors / physiology*


  • Antimicrobial Cationic Peptides
  • Cation Transport Proteins
  • Hamp protein, mouse
  • Hepcidins
  • Protein Precursors
  • metal transporting protein 1
  • Furin