Article
- The EMBO Journal (2007) 26, 2823 - 2831
- doi:10.1038/sj.emboj.7601735
Published online: 31 May 2007
Subject Category:
Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin
Ivana De Domenico1, Diane McVey Ward1, Maria Carmela Bonaccorsi di Patti2, Suh Young Jeong3, Samuel David3, Giovanni Musci4 and Jerry Kaplan1
- Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT, USA
- Dipartimento di Scienze Biochimiche, Universita' di Roma La Sapienza, Roma, Italy
- Centre for Research in Neuroscience, McGill University Health Centre, Montreal General Hospital Research Institute, Montreal, Quebec, Canada
- Dipartimento di Scienze e Tecnologie Agro-alimentari, Ambientali e Microbiologiche, Università del Molise, Campobasso, Italy
Correspondence to:
Jerry Kaplan, Department of Pathology, School of Medicine, University of Utah, 50 North Medical Drive, 1900 East, Salt Lake City, UT 84132, USA. Tel.: +1 801 581 7427; Fax: +1 801 581 6001; E-mail: jerry.kaplan@path.utah.edu
Giovanni Musci, Dipartimento di Scienze e Tecnologie Agro-alimentari, Ambientali e Microbiologiche, Università del Molise, Campobasso, Italy. Tel.: +1 39 0874 404879; Fax: +1 39 0874 404652; E-mail: musci@unimol.it
Received 2 March 2007; Accepted 4 May 2007
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.
Keywords:
- ceruloplasmin,
- copper,
- ferroportin,
- iron,
- transport
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