The role of ubiquitination in hepcidin-independent and hepcidin-dependent degradation of ferroportin.
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.
Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT 84132, USA.
Ivana
I
De Domenico
Eric
E
Lo
Baoli
B
Yang
Tamara
T
Korolnek
Iqbal
I
Hamza
Diane McVey
DM
Ward
Jerry
J
Kaplan
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000172:deficiency / Q000235:genetics; D005075:Biological Evolution; D017173:Caenorhabditis elegans; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D064451:Hepcidins; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007501:Iron / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000075702:Nedd4 Ubiquitin Protein Ligases; D010957:Plasmids; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000098742:Ferroportin
D023181:Antimicrobial Cationic Peptides; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C451223:NDFIP1 protein, human; C499188:Ndfip1 protein, mouse; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D000098742:Ferroportin; D007501:Iron; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618485:Nedd4L protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases