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Vol. 18, Issue 7, 2569-2578, July 2007

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The Molecular Mechanism of Hepcidin-mediated Ferroportin Down-Regulation

Ivana De Domenico^*, Diane McVey Ward^*, Charles Langelier, Michael B. Vaughn^*, Elizabeta Nemeth, Wesley I. Sundquist, Tomas Ganz, Giovanni Musci, and Jerry Kaplan^*

Departments of *Pathology and Biochemistry, School of Medicine, University of Utah, Salt Lake City, UT 84132; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095; and Dipartimento di Scienze e Tecnologie Agro-alimentari, Ambientali e Microbiologiche, Università del Molise, Campobasso, Italy 86100

Submitted January 26, 2007; Revised April 10, 2007; Accepted April 19, 2007
Monitoring Editor: Sandra Schmid

Ferroportin (Fpn) is the only known iron exporter in vertebrates. Hepcidin, a peptide secreted by the liver in response to iron or inflammation, binds to Fpn, inducing its internalization and degradation. We show that after binding of hepcidin, Fpn is tyrosine phosphorylated at the plasma membrane. Mutants of human Fpn that do not get internalized or that are internalized slowly show either absent or impaired phosphorylation. We identify adjacent tyrosines as the phosphorylation sites and show that mutation of both tyrosines prevents hepcidin-mediated Fpn internalization. Once internalized, Fpn is dephosphorylated and subsequently ubiquitinated. An inability to ubiquitinate Fpn does not prevent hepcidin-induced internalization, but it inhibits the degradation of Fpn. Ubiquitinated Fpn is trafficked through the multivesicular body pathway en route to degradation in the late endosome/lysosome. Depletion of proteins involved in multivesicular body trafficking (Endosome Sorting Complex Required for Transport proteins), by small-interfering RNA, reduces the trafficking of Fpn-green fluorescent to the lysosome.

Address correspondence to: Jerry Kaplan (jerry.kaplan{at}path.utah.edu)

Abbreviations used: ESCRT, endosome sorting complex required for transport; Fpn, ferroportin; GFP, green fluorescent protein; MVB, multivesicular body.