Hepcidin-Induced Endocytosis of Ferroportin Is Dependent on Ferroportin Ubiquitination
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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, liver-derived hepcidin negatively regulates cell surface FPN by acutely blocking iron transport and inducing FPN ubiquitination, internalization, and degradation.
“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]
The cryo-EM density map of FPN enabled building of an atomic model of FPN regions important for iron transport and hepcidin binding and a portion of ICL3 important in hepcidin-induced FPN internalization.
“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]
Hepcidin binding induces FPN endocytosis and ubiquitination, followed by degradation mainly in lysosomes.
“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]
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.
“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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- 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
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › 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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