Activation and inactivation of the iron hormone hepcidin: Biochemical characterization of prohepcidin cleavage and sequential degradation to N-terminally truncated hepcidin isoforms

  • Schranz M
  • Bakry R
  • Creus M
 et al. 
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Abstract

The hormone hepcidin is produced mainly in the liver in response to iron loading and inflammation and secreted into the circulation as a 25-amino acid peptide. The 84-amino acid prohormone undergoes limited proteolytic cleavage at a conserved proprotein convertase (PC) recognition site. In addition to the 25-amino acid hepcidin, N-terminally truncated isoforms of lower biological activity are found in plasma and urine. Here we show that a redundant system of proprotein convertases cleaves prohepcidin at the predicted site releasing active hepcidin-25 from the proprotein. In addition to furin mediated cleavage of prohepcidin, we found prohepcidin peptidase activity of proprotein convertases PC5/6, PC7/LPC, PC1/3 and PC2 which was specific for the release of hepcidin-25 from prohepcidin as shown by mass spectrometry. In native tissue extracts, a calcium-dependent prohepcidin peptidase activity is present specifically releasing the 25-mer hepcidin isoform from the recombinant prohormone. In contrast, the 20-mer isoform of hepcidin is generated by a calcium-independent tissue activity which cleaves the 25-mer peptide but has no activity on the entire prohormone. This finding demonstrates the presence of an additional peptidase in this inactivation mechanism for hepcidin. An inhibitor of prohepcidin cleavage was designed and synthesized from d-amino acids (QRRRRR). Biochemical studies indicated that this is a potent and generic inhibitor of prohepcidin cleavage. Biochemical and inhibitor studies of endogenous tissue peptidase activities support the implication of proprotein convertases in the activation of hepcidin. Inactivation of the peptide hormone by N-terminal truncation is mediated by other distinct peptidases, which appear to act sequentially to initial release of hepcidin-25 from the proprotein. © 2009 Elsevier Inc.

Author-supplied keywords

  • Hemochromatosis
  • Hepcidin
  • Iron
  • Proprotein convertases

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Authors

  • Melanie Schranz

  • Rania Bakry

  • Marc Creus

  • Günther Bonn

  • Wolfgang Vogel

  • Heinz Zoller

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