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Regulation of prohepcidin processing and activity by the subtilisin-like proprotein convertases Furin, PC5, PACE4 and

N Scamuffa1, A Basak, C Lalou

  • 1INSERM U 716/Equipe AVENIR, Institut de Génétique Moléculaire, 27 rue Juliette Dodu, 75010 Paris, France.

Gut
|July 31, 2008
PubMed

Insights

This study reveals that specific proprotein convertases (PCs), including Furin, PACE4, PC5, and PC7, are crucial for processing hepcidin. This discovery offers potential therapeutic targets for iron disorders and related diseases.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Genetics

Background:

  • Hepcidin regulates iron homeostasis; its dysfunction causes hemochromatosis or anemia.
  • The conversion of preprohepcidin to mature hepcidins is not fully understood.
  • The initial cleavage site suggests involvement of proprotein convertase (PC) enzymes.

Purpose of the Study:

  • To elucidate the mechanism of preprohepcidin processing.
  • To identify the specific proprotein convertases involved in hepcidin maturation.
  • To explore therapeutic strategies targeting hepcidin processing.

Main Methods:

  • Cell transfection experiments using Huh-7 and LoVo cell lines.
  • Site-directed mutagenesis to analyze the preprohepcidin cleavage site (RRRRR(59)DT).
  • In vitro digestion assays and analysis of hepcidin and Furin expression during mouse embryonic development.

Main Results:

  • Furin inhibitors (alpha1-PDX, ppFurin) blocked preprohepcidin processing in Huh-7 cells.
  • Expression of Furin, PACE4, PC5, or PC7 restored processing in PC-deficient LoVo cells.
  • Hepcidin expression in mouse liver during development correlated with Furin expression.

Conclusions:

  • Furin, PACE4, PC5, and/or PC7 are key enzymes in generating active hepcidin.
  • Targeting hepcidin processing presents a potential therapeutic and diagnostic strategy for hepcidin-related disorders.
  • Mutating the cleavage site (RRRRR(59) to SSSSS(59)) inactivates hepcidin's function.
Abstract

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