The DOI matches its Crossref record; 23 of the 23 references it cites were found in a registry or an index.
Hepcidin-Induced Endocytosis of Ferroportin Is Dependent on Ferroportin Ubiquitination
Open accessAbstract
Ferroportin exports iron into plasma from absorptive enterocytes, erythrophagocytosing macrophages, and hepatic stores. The hormone hepcidin controls cellular iron export and plasma iron concentrations by binding to ferroportin and causing its internalization and degradation. We explored the mechanism of hepcidin-induced endocytosis of ferroportin, the key molecular event in systemic iron homeostasis. Hepcidin binding caused rapid ubiquitination of ferroportin in cell lines overexpressing ferroportin and in murine bone marrow-derived macrophages. No hepcidin-dependent ubiquitination was observed in C326S ferroportin mutant which does not bind hepcidin. Substitutions of lysines between residues 229 and 269 in the third cytoplasmic loop of ferroportin prevented hepcidin-dependent ubiquitination and endocytosis of ferroportin, and promoted cellular iron export even in the presence of hepcidin. The human ferroportin mutation K240E, previously associated with clinical iron overload, caused hepcidin resistance in vitro by interfering with ferroportin ubiquitination. Our study demonstrates that ubiquitination is the functionally relevant signal for hepcidin-induced ferroportin endocytosis.
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“In settings of elevated serum iron levels, liverderived hepcidin negatively regulates cell surface FPN by acutely blocking iron transport 7 and inducing FPN ubiquitination, internalization, and degradation 1,8-10 .”
From Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms (2020) · cites this paper as [9]
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“The cryo-EM density map of FPN enabled building of an atomic model of FPN regions important for iron transport and hepcidin binding 2,7 , and a portion of the intracellular loop 3 (ICL3) important in hepcidin-induced FPN internalization 8-10 (Extended Data Fig. 5).”
From Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms (2020) · cites this paper as [9]
In the citing paper
“Previous studies found that hepcidin binding induces the endocytosis and subsequent ubiquitination of FPN, followed by degradation predominantly in lysosomes.9,11-13”
From RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation (2021) · cites this paper as [13]
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“HAMP regulates systemic iron metabolism through its capacity to bind, occlude and induce the degradation of FPN on the surface of reticuloendothelial macrophages and duodenal enterocytes. 44 , 45”
From The battle for iron in enteric infections (2020) · cites this paper as [45]
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1 retracted
Domenico, I. D., Lo, E., Yang, B., Korolnek, T., Hamza, I., Ward, D. M., & Kaplan, J. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.09.008 · Cited by 27
RetractedHepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization
Nemeth, E., Tuttle, M. S., Powelson, J., Vaughn, M. B., Donovan, A., Ward, D. M., Ganz, T., & Kaplan, J. (2004) · Science · doi:10.1126/science.1104742 · Cited by 4,803
Self-citationSignals for Sorting of Transmembrane Proteins to Endosomes and Lysosomes
Bonifacino, J. S., & Traub, L. M. (2003) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.72.121801.161800 · Cited by 2,040
The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis
Donovan, A., Lima, C. A., Pinkus, J. L., Pinkus, G. S., Zon, L. I., Robine, S., & Andrews, N. C. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.01.003 · Cited by 1,275
Immunoassay for human serum hepcidin
Ganz, T., Olbina, G., Girelli, D., Nemeth, E., & Westerman, M. (2008) · Blood · doi:10.1182/blood-2008-02-139915 · Cited by 688
Self-citationHepcidin and disorders of iron metabolism
Ganz, T., & Nemeth, E. (2011) · Annual Review of Medicine · doi:10.1146/annurev-med-050109-142444 · Cited by 466
Self-citationThe Molecular Mechanism of Hepcidin-mediated Ferroportin Down-Regulation
De Domenico, I., Ward, D. M., Langelier, C., Vaughn, M. B., Nemeth, E., Sundquist, W. I., Ganz, T., Musci, G., & Kaplan, J. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-01-0060 · Cited by 434
Self-citationUBE2S drives elongation of K11-linked ubiquitin chains by the Anaphase-Promoting Complex
Wu, T., Merbl, Y., Huo, Y., Gallop, J. L., Tzur, A., & Kirschner, M. W. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912802107 · Cited by 240
Preza, G. C., Ruchala, P., Pinon, R., Ramos, E., Qiao, B., Peralta, M. A., Sharma, S., Waring, A., Ganz, T., & Nemeth, E. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57693 · Cited by 234
Self-citationMiranda, M., & Sorkin, A. D. (2007) · Molecular Interventions · doi:10.1124/mi.7.3.7 · Cited by 205
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A Red carpet for iron metabolism
Muckenthaler, M. U., Rivella, S., Hentze, M. W., & Galy, B. (2017) · Cell · doi:10.1016/j.cell.2016.12.034 · Cited by 1,319
Ganz, T. (2013) · Physiological Reviews · doi:10.1152/physrev.00008.2013 · Cited by 1,122
Self-citationIron homeostasis and oxidative stress: An intimate relationship
Galaris, D., Barbouti, A., & Pantopoulos, K. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2019.118535 · Cited by 960
Drakesmith, H., Nemeth, E., & Ganz, T. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.09.006 · Cited by 638
Self-citationHepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis
Nemeth, E., & Ganz, T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126493 · Cited by 540
“It appears to require hepcidin-induced conformational change in ferroportin that triggers the ubiquitination of the lysine-rich cytoplasmic segment connecting the two 6-helix domains of ferroportin [19,20].”
BackgroundSelf-citation
Metadata
- Authors
- Qiao, B., Sugianto, P., Fung, E., del-Castillo-Rueda, A., Moran-Jimenez, M.-J., Ganz, T., & Nemeth, E.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Nemeth, Elizabeta
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 15
- Issue
- 6
- Pages
- 918-924
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3372862
- OpenAlex
- W2020932850
- Cited by
- 334
- References
- 23
- Citations by year
- 2026: 18 · 2025: 21 · 2024: 25 · 2023: 28 · 2022: 26 · 2021: 35 · 2020: 25 · 2019: 22 · 2018: 15 · 2017: 26 · 2016: 16 · 2015: 16 · 2014: 28 · 2013: 20 · 2012: 9
- FWCI
- 15.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK082717)
- Jonsson Comprehensive Cancer Center
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- hepcidin, ferroportin, ubiquitination, endocytosis, iron export, iron homeostasis, iron overload, lysine residues, macrophages, enterocytes
- MeSH terms
- Ferroportin, Endocytosis, Humans, Iron, Protein Binding, Protein Processing, Post-Translational, Mutagenesis, Site-Directed, Amino Acid Substitution, Amino Acid Motifs, Protein Transport, Antimicrobial Cationic Peptides, Cation Transport Proteins, Ubiquitination, HEK293 Cells, Hepcidins
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