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Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression
Abstract
Hepcidin is a key regulator of systemic iron homeostasis. Hepcidin deficiency induces iron overload, whereas hepcidin excess induces anemia. Mutations in the gene encoding hemojuvelin (HFE2, also known as HJV) cause severe iron overload and correlate with low hepcidin levels, suggesting that hemojuvelin positively regulates hepcidin expression. Hemojuvelin is a member of the repulsive guidance molecule (RGM) family, which also includes the bone morphogenetic protein (BMP) coreceptors RGMA and DRAGON (RGMB). Here, we report that hemojuvelin is a BMP coreceptor and that hemojuvelin mutants associated with hemochromatosis have impaired BMP signaling ability. Furthermore, BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemojuvelin and blunted in Hfe2-/- hepatocytes. Our data suggest a mechanism by which HFE2 mutations cause hemochromatosis: hemojuvelin dysfunction decreases BMP signaling, thereby lowering hepcidin expression.
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“The latter is due to the fact, that several co-factors expressed on the hepatocyte cell membrane such as HFE, hemojuvelin (HJV) or TfR2 impact on hepcidin expression via the BMP-SMAD pathway (Babitt et al., 2006).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Babitt et al., 2006
In the citing paper
“Regulation of hepcidin by iron depends on the hemojuvelin (HJV) and bone morphogenetic protein receptor (BMPR) complex activating the SMAD signaling pathway (Fig 3) [13–15].”
From Hepcidin and Host Defense against Infectious Diseases (2015) · cites this paper as [13]
In the citing paper
“HJV is a BMP co-receptor that enhances iron signaling to hepcidin (Babitt et al., 2006).”
From Pharmacological Targeting of the Hepcidin/Ferroportin Axis (2016) · cites this paper as Babitt et al., 2006
In the citing paper
“BMP6 binds to a heterodimeric receptor complexed with hemojuvelin (HJV) and matriptase-2 (the gene product of TMPRSS6), and stimulates HAMP expression [66, 67].”
From Iron deficiency or anemia of inflammation?: Differential diagnosis and mechanisms of anemia of inflammation (2016) · cites this paper as [67]
In the citing paper
“Nonetheless, BMP treatment is a potent stimulus for hepcidin expression both in cultured cells 113,114,116,117 and in animals.”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [114]
In the citing paper
“They showed that hemojuvelin acts as a BMP coreceptor to stimulate hepcidin transcription.”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [114]
In the citing paper
“Activation of signaling through the hemochromatosis protein HFE, TFR1, TFR2, or hemojuvelin (HJV), which acts as a co-receptor for bone morphogenetic protein 6 (BMP6), increases hepcidin transcription in a SMAD-dependent fashion.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [200]
In the citing paper
“HFE2 is a BMP coreceptor, and its mutation suppresses BMP signaling (14).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
In the citing paper
“An alternative mechanism of hepcidin regulation through a signaling pathway involving hemojuvelin (HFE2, also known as HJV) and bone morphogenetic proteins (BMP) was recently identified (14).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
In the citing paper
“This study showed that BMP could upregulate hepcidin in hepatocytes.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
In the citing paper
“hepatocytes deficient in HFE2 had impaired hepcidin induction by BMP signaling (14).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
In the citing paper
“Overexpression of HFE2 enhanced hepcidin production.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
In the citing paper
“Smad4-knockout mice had lower levels of hepcidin and did not induce hepcidin in response to iron loading or IL-6 stimulation (14).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
In the citing paper
“downstream activation of Smad4 was required for BMP-mediated hepcidin upregulation,”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [14]
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“Evidence suggests TfR2 binding to Holo-Tf activates ERK through phosphorylation,(40,41) whereas SMAD1/5/8 activation by phosphorylation can be triggered by BMP6 binding to a complex, including BMP receptor plus hemojuvelin.(42) To test whether Holo-Tf injection activates SMAD1/5/8 and ERK1/2, we assessed levels of the…”
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“HJV operates as an enhancer of BMP/SMAD signaling and the most frequent pathogenic HJV mutation, a G320V substitution, largely abrogates this function (80).”
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“Hepcidin is transcriptionally induced in response to iron or inflammatory cues via BMP/SMAD and IL-6/STAT3 signaling, respectively [30,31].”
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“The BMP signaling function of HJV was then demonstrated to play a critical role in the transcriptional regulation of hepcidin expression [8] via specific SMAD binding elements on the hepcidin promoter [14–16].”
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“Hemojuvelin (HJV), a GPI-linked membrane protein, appears to be the co-receptor specialized for iron regulation [19].”
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“Animal studies have shown that HJV is indispensable for the induction of hepcidin expression through the BMP signaling pathway.(39)”
BackgroundSmad1/5 is required for erythropoietin-mediated suppression of hepcidin in mice
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“Hepatocyte-specific deletion of Smad4 produces mice with a severe iron overload phenotype, whereas mutations in the HFE2 gene, which encodes a BMP coreceptor hemojuvelin, result in juvenile hemochromatosis, a disease characterized by severe iron overload (Babitt et al. 2006).”
BackgroundFine tuning of hepcidin expression by positive and negative regulators
Muckenthaler, M. U. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.06.009 · Cited by 83
“Hepcidin activators include proteins responsible for heredi- tary hemochromatosis (HFE, TfR2, and hemojuvelin [HFE2]) and the bone morphogenetic proteins (BMPs) that induce hepcidin transcription via the SMAD signaling pathway (e.g., Babitt et al., 2006; Wang et al., 2005) (Figure 1).”
BackgroundTmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice
Finberg, K. E., Whittlesey, R. L., & Andrews, N. C. (2011) · Blood · doi:10.1182/blood-2010-10-315507 · Cited by 81
Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signalling
Rauner, M., Baschant, U., Roetto, A., Pellegrino, R. M., Rother, S., Salbach-Hirsch, J., Weidner, H., Hintze, V., Campbell, G., Petzold, A., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-018-0005-8 · Cited by 87
Biological effects of mutant ceruloplasmin on hepcidin-mediated internalization of ferroportin
Kono, S., Yoshida, K., Tomosugi, N., Terada, T., Hamaya, Y., Kanaoka, S., & Miyajima, H. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2010.07.011 · Cited by 85
Sow, F. B., Alvarez, G. R., Gross, R. P., Satoskar, A. R., Schlesinger, L. S., Zwilling, B. S., & Lafuse, W. P. (2009) · Journal of Leukocyte Biology · doi:10.1189/jlb.1208719 · Cited by 83
Zhang, A.-S., Yang, F., Wang, J., Tsukamoto, H., & Enns, C. A. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.027318 · Cited by 84
Genetic mechanisms and modifying factors in hereditary hemochromatosis
Weiss, G. (2010) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2009.201 · Cited by 82
“Hemojuvelin has been identified as a member of the repulsive guidance molecule family that also includes the bone morphogenetic protein (BMP) co-receptors RGMA and RGMB”
BackgroundRegulation of hepcidin expression at high altitude
Talbot, N. P., Lakhal, S., Smith, T. G., Privat, C., Nickol, A. H., Rivera-Ch, M., León-Velarde, F., Dorrington, K. L., Mole, D. R., & Robbins, P. A. (2012) · Blood · doi:10.1182/blood-2011-03-341776 · Cited by 93
Agarwal, A. K., & Yee, J. (2019) · Advances in Chronic Kidney Disease · doi:10.1053/j.ackd.2019.04.005 · Cited by 83
Zhang, A., Gao, J., Koeberl, D. D., & Enns, C. A. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.109488 · Cited by 85
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
Starzyński, R. R., Laarakkers, C. M., Tjalsma, H., Swinkels, D. W., Pieszka, M., Styś, A., Mickiewicz, M., & Lipiński, P. (2013) · PLoS ONE · doi:10.1371/journal.pone.0064022 · Cited by 81
“Hepatic iron is thought to induce hepcidin expression via bone morphogenetic protein (BMP) signaling [25], [26].”
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
Ma, C. H. E., Brenner, G. J., Omura, T., Samad, O. A., Costigan, M., Inquimbert, P., Niederkofler, V., Salie, R., Sun, C. C., Lin, H. Y.-F., et al. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.4550-11.2011 · Cited by 79
“Our data indicate that RGMb expression in DRG neurons enhances signaling of BMP ligands, and support a role for RGMb as a BMP sensitizer in sensory neurons, similar to the role of hemojuvelin (RGMc)—another member of the RGM family - in hepatocytes (Babitt et al., 2006).”
BackgroundResultIron Overload in Sickle Cell Disease
Raghupathy, R., Manwani, D. G., & Little, J. A. (2010) · Advances in Hematology · doi:10.1155/2010/272940 · Cited by 84
“Hemojuvelin, also expressed in the liver, is believed to positively regulate hepcidin production [8].”
BackgroundComputational identification and analysis of novel sugarcane microRNAs
Thiebaut, F., Grativol, C., Carnavale-Bottino, M., Rojas, C. A., Tanurdžić, M., Farinelli, L., Martienssen, R. A., Hemerly, A. S., & Ferreira, P. C. G. (2012) · BMC Genomics · doi:10.1186/1471-2164-13-290 · Cited by 79
Oligomeric interactions of TGF‐β and BMP receptors
Ehrlich, M., Gutman, O., Knaus, P. I., & Henis, Y. I. (2012) · FEBS Letters · doi:10.1016/j.febslet.2012.01.040 · Cited by 78
“This signaling is subject to modulation by several groups of co-receptors: the type III TGF-b receptor (TbRIII, or betaglycan) and endoglin; the glycosylphosphatidylinositol-linked family of repulsive guidance molecules (RGM); and the EGF-CFC protein family [3,11,16,20–25].”
BackgroundZumbrennen‐Bullough, K. B., & Babitt, J. L. (2013) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gft443 · Cited by 82
“While cell-surface, GPI-anchored HJV functions as a BMP co-receptor to stimulate hepcidin expression (Figure 3) [39], sHJV can function as an inhibitor of BMP signaling and hepcidin expression, presumably by sequestering BMP ligands from interacting with cell surface signaling receptors [45, 72, 135].”
BackgroundThe role of hepatic transferrin receptor 2 in the regulation of iron homeostasis in the body
Worthen, C., & Enns, C. A. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00034 · Cited by 80
“Presumably, HJV regulates BMP-signaling through enhancing binding of BMP ligand to BMP-receptors and promoting the assembly of the BMP-signaling complex (Babitt et al., 2006).”
BackgroundInfluentialThe role of TMPRSS6/matriptase-2 in iron regulation and anemia
Wang, C., Meynard, D., & Lin, H. Y.-F. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00114 · Cited by 75
“It is now well established that Hamp expression is regulated by the bone morphogenetic protein (BMP)/sons of mothers against decapentaplegic (SMAD) signaling pathway (Babitt et al., 2006, 2007).”
BackgroundTheurl, I., Schroll, A., Nairz, M., Seifert, M., Theurl, M., Sonnweber, T., Kulaksiz, H., & Weiss, G. (2011) · Haematologica · doi:10.3324/haematol.2011.048926 · Cited by 77
“Iron mediated induction of hepcidin expression is affected by the membrane bound peptide hemojuvelin (mHJV)(23) which has been characterized as a bone morphogenetic protein (BMP) co-receptor.(24) Recently, the membrane bound serine protease TMPRSS6 (Matriptase 2) has been shown to degrade membrane anchored HJV,(25-27)…”
BackgroundShander, A., & Sazama, K. J. (2010) · Transfusion · doi:10.1111/j.1537-2995.2009.02551.x · Cited by 76
“Hepcidin modulates the ferroportinmediated release of iron from hepatocytes and reticuloendothelial macrophages, just as it does in duodenal enterocytes;(14) the membrane-bound protein hemojuvelin appears to play a role in the regulation of hepcidin expression.(15) There are two forms of hemojuvelin, membranebound (a…”
BackgroundRausa, M., Pagani, A., Nai, A., Campanella, A., Gilberti, M. E., Apostoli, P., Camaschella, C., & Silvestri, L. (2015) · PLoS ONE · doi:10.1371/journal.pone.0122696 · Cited by 80
“The characterization of hemojuvelin (HJV), the protein mutated in type 2A hemochromatosis [2], as Bone Morphogenetic Protein (BMP)-coreceptor, functionally linked the BMP-Sons of Mothers Against Decapentaplegic (SMAD) pathway to hepcidin and iron regulation [3].”
BackgroundRoetto, A., Cunto, F. D., Pellegrino, R. M., Hirsch, E., Azzolino, O., Bondi, A., Defilippi, I., Carturan, S., Miniscalco, B., Riondato, F., et al. (2010) · Blood · doi:10.1182/blood-2009-09-240960 · Cited by 75
“602390) because Hjv regulates hepcidin production through the Smad pathway, acting as a coreceptor that enhances Bmp signaling.(3) HFE HH (type 1 HH, OMIM no.”
Mayeur, C., Leyton, P. A., Kolodziej, S. A., Yu, B., & Bloch, K. D. (2014) · Blood · doi:10.1182/blood-2014-04-572644 · Cited by 74
Iron deficiency in systemic sclerosis patients with and without pulmonary hypertension
Ruiter, G., Lanser, I., de Man, F. S., van der Laarse, W. J., Wharton, J., Wilkins, M. R., Howard, L., Noordegraaf, A. V., & Voskuyl, A. E. (2013) · Rheumatology · doi:10.1093/rheumatology/ket331 · Cited by 78
Fillebeen, C., Wilkinson, N., Charlebois, E., Katsarou, A., Wagner, J., & Pantopoulos, K. (2018) · Blood · doi:10.1182/blood-2018-03-841197 · Cited by 73
“8 Genetic inactivation of HJV diminishes hepcidin expression and causes severe iron overload (early onset juvenile hemochromatosis) in humans 9 and mice.”
Theurl, I., Finkenstedt, A., Schroll, A., Nairz, M., Sonnweber, T., Bellmann‐Weiler, R., Theurl, M., Seifert, M., Wroblewski, V. J., Murphy, A. T., et al. (2010) · British Journal of Haematology · doi:10.1111/j.1365-2141.2009.07961.x · Cited by 72
“Hepcidin is produced by the liver in response to LPS, IL-6 and bone morphogenetic proteins (BMPs)( Nemeth et al, 2003; Babitt et al, 2006; Camaschella & Silvestri, 2008; Muckenthaler, 2008).”
BackgroundIron-Sensing Proteins that Regulate Hepcidin and Enteric Iron Absorption
Knutson, M. D. (2010) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.012809.104801 · Cited by 96
Structural perspective of BMP ligands and signaling
Gipson, G. R., Goebel, E. J., Hart, K. N., Kappes, E. C., Kattamuri, C., McCoy, J. C., & Thompson, T. B. (2020) · Bone · doi:10.1016/j.bone.2020.115549 · Cited by 82
Mutual interaction between iron homeostasis and obesity pathogenesis
Nikonorov, A. А., Геннадиевна, С. М., Tinkov, A. A., & Skalny, A. V. (2014) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2014.05.005 · Cited by 77
“[69] Kovacs P, Klöting N, Böttcher Y, Wolf S, Ruschke K, Schleinitz D, et al. Expression of the bone morphogenetic protein receptor 2 (BMPR2) mRNA in adipose tissue and BMPR2 genetic variation are associated with human obesity.”
BackgroundInfluentialGenetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice
Wang, F., Paradkar, P. N., Custodio, Á. O., Ward, D. M., Fleming, M. D., Campagna, D. R., Roberts, K. A., Boyartchuk, V., Dietrich, W. F., Kaplan, J., et al. (2007) · Nature Genetics · doi:10.1038/ng2059 · Cited by 72
“, and HFE, TFR2 and hemojuvelin regulate production of hepcidi”
BackgroundTruksa, J., Peng, H., Lee, P. L., & Beutler, E. (2007) · British Journal of Haematology · doi:10.1111/j.1365-2141.2007.06728.x · Cited by 70
“One non-inflammatory pathway may involve hemojuvelin, which has been shown to be a co-receptor for BMP (Babitt et al, 2006); stimulation by BMP is also independent of HFE and TRFR2 (Truksa et al, 2006).”
BackgroundIsland, M., Jouanolle, A., Mosser, A., Deugnier, Y., David, V., Brissot, P., & Loréal, O. (2009) · Haematologica · doi:10.3324/haematol.2008.001784 · Cited by 73
“As this BMP-RE mediates the induction of hepcidin gene expression in response to BMP,17 HepG2 cells were transfected with the -1024/BMP-RE wt or mutated Hep/Luc plasmid constructs and were treated with either BMP9 or BMP4 in order to determine if the mutation impaired or not the response to these BMPs.21 As expected,…”
MethodInfluential
Metadata
- Authors
- Babitt, J. L., Huang, F. W., Wrighting, D. M., Xia, Y., Sidis, Y., Samad, T. A., Campagna, J. A., Chung, R. T., Schneyer, A. L., Woolf, C. J., Andrews, N. C., & Lin, H. Y.
- Affiliations
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Lin, Herbert Y
- ORCID
- Venue
- Nature Genetics
- Published
- 2006-04-09
- Volume
- 38
- Issue
- 5
- Pages
- 531-539
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2050833520
- Cited by
- 1,026
- References
- 52
- Citations by year
- 2026: 17 · 2025: 23 · 2024: 21 · 2023: 22 · 2022: 21 · 2021: 54 · 2020: 35 · 2019: 39 · 2018: 39 · 2017: 50 · 2016: 44 · 2015: 50 · 2014: 58 · 2013: 62 · 2012: 67
- FWCI
- 49.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32HL07623, T32HL007623)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-71837, R01DK066373, DK-69533, K08DK075846, R01DK071837, F32DK068997, R01DK069533)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Micronutrient Interactions and Effects
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- hemojuvelin, hepcidin, BMP signaling, iron homeostasis, hemochromatosis, RGMa, dragons, hepatocytes, iron overload, anemia
- MeSH terms
- Hemochromatosis Protein, Amino Acid Sequence, Animals, Gene Expression Regulation, Cricetinae, Humans, Liver, Membrane Proteins, Molecular Sequence Data, Mutation, Signal Transduction, Polymerase Chain Reaction, Transforming Growth Factor beta, CHO Cells, Bone Morphogenetic Proteins, Antimicrobial Cationic Peptides, Bone Morphogenetic Protein 2, GPI-Linked Proteins, Hepcidins
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