Abstract
The iron exporter ferroportin (Fpn) is essential to transfer iron from cells to plasma. Systemic iron homeostasis in vertebrates is regulated by the hepcidin-mediated internalization of Fpn. Here, we demonstrate a second route for Fpn internalization; when cytosolic iron levels are low, Fpn is internalized in a hepcidin-independent manner dependent upon the E3 ubiquitin ligase Nedd4-2 and the Nedd4-2 binding protein Nfdip-1. Retention of cell-surface Fpn through reductions in Nedd4-2 results in cell death through depletion of cytosolic iron. Nedd4-2 is also required for internalization of Fpn in the absence of ferroxidase activity as well as for the entry of hepcidin-induced Fpn into the multivesicular body. C. elegans lacks hepcidin genes, and C. elegans Fpn expressed in mammalian cells is not internalized by hepcidin but is internalized in response to iron deprivation in a Nedd4-2-dependent manner, supporting the hypothesis that Nedd4-2-induced internalization of Fpn is evolutionarily conserved.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Retracted Publication
MeSH terms
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Animals
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Antimicrobial Cationic Peptides / deficiency
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Antimicrobial Cationic Peptides / genetics
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Biological Evolution
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Caenorhabditis elegans
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cation Transport Proteins / genetics
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Cation Transport Proteins / metabolism*
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Cells, Cultured
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Endosomal Sorting Complexes Required for Transport / genetics
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Endosomal Sorting Complexes Required for Transport / metabolism*
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HEK293 Cells
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Hepcidins
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Homeostasis / physiology
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Humans
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Intercellular Signaling Peptides and Proteins
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Iron / metabolism*
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Macrophages / cytology
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Macrophages / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Knockout
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Nedd4 Ubiquitin Protein Ligases
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Plasmids
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RNA, Small Interfering
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism*
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Signal Transduction / physiology*
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Transfection
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination
Substances
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Antimicrobial Cationic Peptides
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Carrier Proteins
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Cation Transport Proteins
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Endosomal Sorting Complexes Required for Transport
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HAMP protein, human
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Hamp protein, mouse
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Hepcidins
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Intercellular Signaling Peptides and Proteins
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Membrane Proteins
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NDFIP1 protein, human
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Ndfip1 protein, mouse
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RNA, Small Interfering
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Recombinant Fusion Proteins
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metal transporting protein 1
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Iron
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Nedd4 Ubiquitin Protein Ligases
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Nedd4 protein, human
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Nedd4L protein, human
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Nedd4l protein, mouse
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Ubiquitin-Protein Ligases