Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin

Ivana De Domenico, Diane Mc Vey Ward, Maria Carmela Bonaccorsi Di Patti, Suh Young Jeong, Samuel David, Giovanni Musci, Jerry Kaplan

Research output: Contribution to journalArticlepeer-review

261 Scopus citations

Abstract

Ferroportin (Fpn), a ferrous iron Fe(II) transporter responsible for the entry of iron into plasma, is regulated post-translationally through internalization and degradation following binding of the hormone hepcidin. Cellular iron export is impaired in mice and humans with aceruloplasminemia, an iron overload disease due to mutations in the ferroxidase ceruloplasmin (Cp). In the absence of Cp Fpn is rapidly internalized and degraded. Depletion of extracellular Fe(II) by the yeast ferroxidase Fet3p or iron chelators can maintain cell surface Fpn in the absence of Cp. Iron remains bound to Fpn in the absence of multicopper oxidases. Fpn with bound iron is recognized by a ubiquitin ligase, which ubiquitinates Fpn on lysine 253. Mutation of lysine 253 to alanine prevents ubiquitination and maintains Fpn-iron on cell surface in the absence of ferroxidase activity. The requirement for a ferroxidase to maintain iron transport activity represents a new mechanism of regulating cellular iron export, a new function for Cp and an explanation for brain iron overload in patients with aceruloplasminemia.

Original languageEnglish (US)
Pages (from-to)2823-2831
Number of pages9
JournalEMBO Journal
Volume26
Issue number12
DOIs
StatePublished - Jun 20 2007
Externally publishedYes

Keywords

  • Ceruloplasmin
  • Copper
  • Ferroportin
  • Iron
  • Transport

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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