Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin.
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.
De Domenico
Ivana
I
Department of Pathology, School of Medicine, University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132, USA.
Ward
Diane McVey
DM
di Patti
Maria Carmela Bonaccorsi
MC
Jeong
Suh Young
SY
David
Samuel
S
Musci
Giovanni
G
Kaplan
Jerry
J
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
D027682:Cation Transport Proteins; D017261:Glycosylphosphatidylinositols; D034741:RNA, Small Interfering; D000098742:Ferroportin; D002570:Ceruloplasmin