title: Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin.
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.
authors.affiliation: Department of Pathology, School of Medicine, University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: De Domenico
authors.forename: Diane McVey
authors.initials: DM
authors.lastname: Ward
authors.forename: Maria Carmela Bonaccorsi
authors.initials: MC
authors.lastname: di Patti
authors.forename: Suh Young
authors.initials: SY
authors.lastname: Jeong
authors.forename: Samuel
authors.initials: S
authors.lastname: David
authors.forename: Giovanni
authors.initials: G
authors.lastname: Musci
authors.forename: Jerry
authors.initials: J
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism*; D002570:Ceruloplasmin / Q000378:metabolism*; D004705:Endocytosis; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D006801:Humans; D051379:Mice; D034741:RNA, Small Interfering; D051381:Rats; D014407:Tumor Cells, Cultured; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D017261:Glycosylphosphatidylinositols; D034741:RNA, Small Interfering; D000098742:Ferroportin; D002570:Ceruloplasmin