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Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing.
Open accessAbstract
HFE and transferrin receptor 2 (TFR2) are membrane proteins integral to mammalian iron homeostasis and associated with human hereditary hemochromatosis. Here we demonstrate that HFE and TFR2 interact in cells, that this interaction is not abrogated by disease-associated mutations of HFE and TFR2, and that TFR2 competes with TFR1 for binding to HFE. We propose a new model for the mechanism of iron status sensing that results in the regulation of iron homeostasis.
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“Taking this into account, we have proposed a model in which TFR2 escorts HFE away from TFR1 when the serum iron level (reflected in the transferrin saturation) is elevated.149,150”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [150]
In the citing paper
“Like TFR1, TFR2 interacts with HFE to form a stable protein complex.150”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [150]
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“For instance, hemochromatosis patients suffer a chronic mal-accumulation of iron within various tissues of the body (Goswami and Andrews 2006).”
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“HFE is expressed strongly with the TfR2 on Kupffer cells, circulating monocytes and macrophages, as well as duodenal epithelial cells (280).”
BackgroundMolecular Mechanisms of Hepcidin Regulation: Implications for the Anemia of CKD
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“Importantly, HFE can also bind to TfR2 (129), and HFE that is competitively displaced from TfR1 by holo-Tf then becomes available to interact with TfR2, the latter of which is expressed highly in the liver (61).”
Zhao, N., Zhang, A., & Enns, C. A. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67225 · Cited by 215
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“To confirm that the conditions of the immunoprecipitation assay mirror the physiological competition between TfR1 and TfR2 for HFE [16], we co-expressed increasing amounts of either TfR2HA or Flag-HFE, together with a constant amount of Flag-HFE or TfR2-HA, respectively.”
BackgroundMethodGinzburg, Y., & Rivella, S. (2011) · Blood · doi:10.1182/blood-2011-03-283614 · Cited by 201
Hepcidin Regulation of Iron Transport
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“acts with transferrin receptors 1 and 2, likely linking the sensing of serum iron with hepcidin production (14,15).”
BackgroundA fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates
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BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression
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“HFE and TfR2 may interact and function as an iron sensor [33], whereas hemojuvelin acts as a BMP co-receptor and likely regulates hepcidin transcription through the BMP/SMAD pathway [25].”
BackgroundRegulation of iron pathways in response to hypoxia
Chepelev, N. L., & Willmore, W. G. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.12.023 · Cited by 106
“Interestingly, HFE was found to induce hepcidin expression when HFE was dissociated from TfR1 [136] such that HFE was proposed to act as a serum iron sensor [137].”
BackgroundCorradini, E., Rozier, M., Meynard, D., Odhiambo, A., Lin, H. Y.-F., Feng, Q., Migas, M. C., Britton, R. S., Babitt, J. L., & Fleming, R. E. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.06.077 · Cited by 102
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“The recent proposal [11] that a complex consisting of HFE, transferrin receptor 2, and hemojuvelin serves as a receptor for a bone morphogenetic protein (BMP) has attractive features, but does not explain our finding that the response to BMPs is undiminished in cells deficient either in HFE or transferrin receptor 2 […”
BackgroundHereditary hemochromatosis in the post- HFE era
Olynyk, J. K., Trinder, D., Ramm, G. A., Britton, R. S., & Bacon, B. R. (2008) · Hepatology · doi:10.1002/hep.22507 · Cited by 97
Iron metabolism: current facts and future decisions
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Iron metabolism and drug resistance in cancer
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“…hemochromatosis protein and drug resistance Hereditary hemochromatosis protein (HFE) is an atypical major histocompatibility class I molecule that acts as an iron sensor by interacting with TfR1 and TfR2 and regulates cellular iron uptake and whole body iron homeostasis (Goswami and Andrews 2006).”
Iron and the liver: Update 2008
Deugnier, Y., Brissot, P., & Loréal, O. (2008) · Journal of Hepatology · doi:10.1016/j.jhep.2008.01.014 · Cited by 98
Interacting signals in the control of hepcidin expression
Darshan, D., & Anderson, G. J. (2009) · BioMetals · doi:10.1007/s10534-008-9187-y · Cited by 95
“When TfR2 and HFE are overexpressed in the same cell, they are able to interact ( Goswami and Andrews 2006 ).”
BackgroundGardenghi, S., Grady, R. W., & Rivella, S. (2010) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2010.08.003 · Cited by 98
“When the concentration of holoTf in the serum increases, both holoTf and Hfe bind to Tfr2, which is a protein homologous to Tfr1, although the relative affinity of Tfr2 for holoTf and Hfe is reduced compared to that of Tfr1 (67-69).”
BackgroundInfluentialVolke, M., Gale, D. P., Maegdefrau, U., Schley, G., Klanke, B., Bosserhoff, A.-K., Maxwell, P. H., Eckardt, K.-U., & Warnecke, C. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007875 · Cited by 93
“expression by reducing TfR2 signalling [37,38].”
Ineffective Erythropoiesis: Anemia and Iron Overload
Gupta, R., Musallam, K. M., Taher, A. T., & Rivella, S. (2017) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2017.11.009 · Cited by 94
Hepcidin and iron disorders: new biology and clinical approaches
Arezes, J., & Nemeth, E. (2015) · International Journal of Laboratory Hematology · doi:10.1111/ijlh.12358 · Cited by 88
“iron transferrin, by associating with and stabilizing other hepcidin regulators—transferrin receptor 2 [11]”
BackgroundBone morphogenic proteins in iron homeostasis
Xiao, X., Alfaro-Magallanes, V. M., & Babitt, J. L. (2020) · Bone · doi:10.1016/j.bone.2020.115495 · Cited by 89
“The iron proteins HFE, TFR2, TMPRSS6 modulate BMP-SMAD signaling to regulate hepcidin In addition to mutations in HJV, mutations in HFE (encoding human homeostatic iron regulator protein) and TFR2 (encoding transferrin receptor 2) also cause hemochromatosis characterized by hepcidin deficiency and iron overload [56–59…”
BackgroundInfluentialTargeting the Hepcidin-Ferroportin Axis in the Diagnosis and Treatment of Anemias
Nemeth, E. (2009) · Advances in Hematology · doi:10.1155/2010/750643 · Cited by 88
“HFE, a protein similar to MHC I type molecules, appears to function as a shuttle between TfR1 and TfR2 depending on iron-transferrin concentrations [27].”
Sanad, M., Osman, M., & Gharib, A. (2011) · Italian Journal of Pediatrics · doi:10.1186/1824-7288-37-34 · Cited by 85
“All are found to interact with liver cells to initiate the production of sufficient hepcidin for correct maintenance of iron homeostasis [14-17].”
BackgroundRegulators of hepcidin expression
Roth, M., Meynard, D., & Coppin, H. (2019) · Vitamins and hormones · doi:10.1016/bs.vh.2019.01.005 · Cited by 86
Nemeth, E. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05585.x · Cited by 91
Chen, J., Chloupková, M., Gao, J., Arvedson, T., & Enns, C. A. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m706720200 · Cited by 86
Poli, M., Luscieti, S., Gandini, V., Maccarinelli, F., Finazzi, D., Silvestri, L., Roetto, A., & Arosio, P. (2010) · Haematologica · doi:10.3324/haematol.2010.027003 · Cited by 81
Pathophysiological consequences and benefits of HFE mutations: 20 years of research
Hollerer, I., Bachmann, A., & Muckenthaler, M. U. (2017) · Haematologica · doi:10.3324/haematol.2016.160432 · Cited by 81
A time course of hepcidin response to iron challenge in patients with HFE and TFR2 hemochromatosis
Girelli, D., Trombini, P., Busti, F., Campostrini, N., Sandri, M. F., Pelucchi, S., Westerman, M., Ganz, T., Nemeth, E., Piperno, A., et al. (2010) · Haematologica · doi:10.3324/haematol.2010.033449 · Cited by 81
“The HFETFR2 complex is proposed to trigger hepcidin activation in response to increased holotransferrin concentration.(16,17) Loss of both HFE and TFR2 activity was reported to cause the phenotype of severe juvenile hemochromatosis in a single patient.”
BackgroundHepatocyte-targeted HFE and TFR2 control hepcidin expression in mice
Gao, J., Chen, J., Domenico, I. D., Koeller, D. M., Harding, C. O., Fleming, R. E., Koeberl, D. D., & Enns, C. A. (2010) · Blood · doi:10.1182/blood-2009-09-245209 · Cited by 81
Zumbrennen‐Bullough, K. B., & Babitt, J. L. (2013) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gft443 · Cited by 82
Olynyk, J. K., & Ramm, G. A. (2022) · New England Journal of Medicine · doi:10.1056/nejmra2119758 · Cited by 84
Khalil, S., Holy, M., Grado, S., Fleming, R. E., Kurita, R., Nakamura, Y., & Goldfarb, A. N. (2017) · Blood Advances · doi:10.1182/bloodadvances.2016003772 · Cited by 85
Metadata
- Authors
- Goswami, T., & Andrews, N. C.
- Affiliations
- Boston Children's Hospital (US)
- Corresponding author
- Andrews, Nancy C.
- ORCID
- Andrews, Nancy C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-09
- Volume
- 281
- Issue
- 39
- Pages
- 28494-28498
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1983970155
- Cited by
- 352
- References
- 20
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 1 · 2023: 6 · 2022: 4 · 2021: 15 · 2020: 13 · 2019: 12 · 2018: 12 · 2017: 18 · 2016: 16 · 2015: 16 · 2014: 18 · 2013: 31 · 2012: 17
- FWCI
- 19.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK53813, R01DK053813)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- hereditary hemochromatosis, HFE gene, transferrin receptor 2, transferrin receptor 1, protein-protein interaction, iron homeostasis, iron sensing, disease-associated mutations
- MeSH terms
- Hemochromatosis Protein, Animals, Hemochromatosis, Homeostasis, Humans, Iron, Membrane Proteins, Models, Biological, Mutation, Receptors, Transferrin, Histocompatibility Antigens Class I, Antigens, CD, Mice
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