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Regulation of prohepcidin processing and activity by the subtilisin-like pro-protein convertases Furin, PC5, PACE4 and PC7.
  1. Nathalie Scamuffa (nathalie.scamuffa{at}inserm.fr)
  1. INSERM, France
    1. Ajoy Basak (abasak{at}ohri.ca)
    1. OHRI, Canada
      1. Claude Lalou (claude.lalou{at}inserm.fr)
      1. INSERM, France
        1. Alain Wargnier (alain.wargnier{at}sls.ap-hop-paris.fr)
        1. Hopital St Louis, France
          1. Marcinkiewicz Jadwiga (marcinkiewiczj{at}ircm.qc.ca)
          1. IRCM, Canada
            1. Geraldine Siegfried (geraldine.siegfried{at}inserm.fr)
            1. INSERM, France
              1. Michel Chretien (mchretien{at}ohri.ca)
              1. OHRI, Canada
                1. Fabien Calvo (fcalvo{at}institutcancer.fr)
                1. INSERM, France
                  1. Nabil Seidah (seidahn{at}ircm.qc.ca)
                  1. OHRI, Canada
                    1. Abdel-Majid Khatib (majid.khatib{at}inserm.fr)
                    1. INSERM, France

                      Abstract

                      Background and Aims: Hepcidin is an iron homoeostasis regulator peptide. Loss-of-function mutations cause juvenile hemochromatosis while its overexpression results in anemia. However, the mechanism and function of preprohepcidin conversion to mature hepcidins (25, 22 and 20 amino acids C-terminal peptides) are not well known. After the signal peptide removal, the first proteolytic cleavage occurs within the basic motif RRRRR59DT, suggesting the involvement of the proprotein convertases (PCs) family members in this process.

                      Methods and Results: Using cell transfection experiments, the processing of preprohepcidin in the human hepatocyte line Huh-7 was found to be inhibited by the Furin inhibitors α1-PDX and ppFurin. Site-directed mutagenesis analysis confirmed the RRRRR59DT preprohepcidin cleavage site. In parallel, the lack of preprohepcidin processing found in the PCs activity-deficient cell line LoVo was restored by the expression of Furin, PACE4, PC5 or PC7. This finding is consistent with the in vitro digestions of a synthetic peptide mimicking the cleavage site of preprohepcidin. In addition, during mouse embryonic development the major expression of hepcidin found in the liver coincided with that of Furin. While hepcidin induces the degradation of the iron transporter ferroportin, its RRRRR59 to SSSSS59 mutant is not active.

                      Conclusions: These results demonstrate the key role of the convertases Furin, PACE4, PC5 and/or PC7 in the generation and secretion of active hepcidin and suggest that the control of hepcidin processing as a potential therapeutic/diagnostic strategy in hepcidin-related disorders such as hemochromatosis, inflammatory diseases, anemia and cancer.

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