Document Detail

The role of ubiquitination in hepcidin-independent and hepcidin-dependent degradation of ferroportin.
MedLine Citation:
PMID:  22019085     Owner:  NLM     Status:  MEDLINE    
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.
Ivana De Domenico; Eric Lo; Baoli Yang; Tamara Korolnek; Iqbal Hamza; Diane McVey Ward; Jerry Kaplan
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Retracted Publication     Date:  2011-10-20
Journal Detail:
Title:  Cell metabolism     Volume:  14     ISSN:  1932-7420     ISO Abbreviation:  Cell Metab.     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-07     Completed Date:  2012-02-24     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  101233170     Medline TA:  Cell Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  635-46     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Inc. All rights reserved.
Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT 84132, USA.
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MeSH Terms
Antimicrobial Cationic Peptides / deficiency,  genetics
Biological Evolution
Caenorhabditis elegans
Carrier Proteins / genetics,  metabolism*
Cation Transport Proteins / genetics,  metabolism*
Cells, Cultured
Endosomal Sorting Complexes Required for Transport / genetics,  metabolism*
HEK293 Cells
Homeostasis / physiology
Iron / metabolism*
Macrophages / cytology,  metabolism
Membrane Proteins / genetics,  metabolism*
Mice, Knockout
RNA, Small Interfering
Recombinant Fusion Proteins / genetics,  metabolism*
Signal Transduction / physiology*
Ubiquitin-Protein Ligases / genetics,  metabolism*
Grant Support
Reg. No./Substance:
0/Antimicrobial Cationic Peptides; 0/Carrier Proteins; 0/Cation Transport Proteins; 0/Endosomal Sorting Complexes Required for Transport; 0/Membrane Proteins; 0/NDFIP1 protein, human; 0/Ndfip1 protein, mouse; 0/RNA, Small Interfering; 0/Recombinant Fusion Proteins; 0/hepcidin; 0/metal transporting protein 1; 7439-89-6/Iron; EC ubiquitin protein ligases; EC Ligases
Retraction In:
Cell Metab. 2012 Jun 6;15(6):927   [PMID:  22866335 ]

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