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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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In the citing paper
“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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Crichton, R. R., Dexter, D. T., & Ward, R. J. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0470-z · Cited by 247
“... a- and b-secretases is modulated by furin, a member of the subtilisin-like proprotein convertase family which catalyses the cleavage of precursor proteins into their biologically active forms (Seidah et al. 1994) Furin is also involved in modulation of systemic iron homeostasis through the production of soluble ha…”
BackgroundThe liver-specific microRNA miR-122 controls systemic iron homeostasis in mice
Castoldi, M., Spasić, M. V., Altamura, S., Elmén, J., Lindow, M., Kiss, J., Stolte, J., Sparla, R., D’Alessandro, L. A., Klingmüller, U., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44883 · Cited by 248
“Elevated expression of Hfe, Hjv, and Bmpr1a would be expected to stimulate the Bmp/Smad signaling pathway in mice (44).”
BackgroundHepcidin and Anemia: A Tight Relationship
Pagani, A., Nai, A., Silvestri, L., & Camaschella, C. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01294 · Cited by 268
The long history of iron in the Universe and in health and disease
Sheftel, A. D., Mason, A. B., & Ponka, P. (2011) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2011.08.002 · Cited by 244
Molecular Mechanisms of Hepcidin Regulation: Implications for the Anemia of CKD
Babitt, J. L., & Lin, H. Y.-F. (2010) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2009.12.030 · Cited by 245
The Spectrum of Achalasia: Lessons From Studies of Pathophysiology and High-Resolution Manometry
Kahrilas, P. J., & Boeckxstaens, G. E. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.08.038 · Cited by 236
Song, S.-N. J., Tomosugi, N., Kawabata, H., Ishikawa, T., Nishikawa, T., & Yoshizaki, K. (2010) · Blood · doi:10.1182/blood-2010-03-271791 · Cited by 228
Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice
Guo, S., Casu, C., Gardenghi, S., Booten, S. L., Aghajan, M., Peralta, R. Q., Watt, A., Freier, S., Monia, B. P., & Rivella, S. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66969 · Cited by 233
“At the molecular level, Hamp expression is controlled by the activation of the SMAD1,5,8/SMAD4 complex, which in turn is triggered by the association between the BMP6 ligand, whose expression is proportional to intracellular hepatic iron concentrations, and the BMP-receptor complex (10–12).”
The role of iron homeostasis in remodeling immune function and regulating inflammatory disease
Mu, Q., Chen, L., Gao, X., Shen, S., Sheng, W., Min, J., & Wang, F. (2021) · 中国科学通报：英文版 · doi:10.1016/j.scib.2021.02.010 · Cited by 232
Xia, Y. Y., Babitt, J. L., Sidis, Y., Chung, R. T., & Lin, H. Y.-F. (2008) · Blood · doi:10.1182/blood-2007-09-111567 · Cited by 230
Targeting BMP signalling in cardiovascular disease and anaemia
Morrell, N. W., Bloch, D. B., ten Dijke, P., Goumans, M., Hata, A., Smith, J., Yu, P. B., & Bloch, K. D. (2015) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2015.156 · Cited by 229
“181 Ferroportin is the sole molecule responsible for exporting iron from intracel‑ lular stores within intestinal epithelial cells, hepatocytes, and macrophages into the circulation.”
Hepcidin: regulation of the master iron regulator
Rishi, G., Wallace, D. F., & Subramaniam, V. N. (2015) · Bioscience Reports · doi:10.1042/bsr20150014 · Cited by 223
Fraenkel, P. G. (2016) · Medical Clinics of North America · doi:10.1016/j.mcna.2016.09.005 · Cited by 230
Anderson, E. R., & Shah, Y. M. (2012) · Comprehensive physiology · doi:10.1002/cphy.c120016 · Cited by 262
“HJV binds to BMPs and enhances the activity of the SMAD signaling cascade (10).”
Hemochromatosis: An endocrine liver disease
Pietrangelo, A. (2007) · Hepatology · doi:10.1002/hep.21886 · Cited by 212
Lawen, A., & Lane, D. J. R. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4271 · Cited by 220
“Importantly, the GPI-linked form of HJV appears to function as a coreceptor for BMP6, and facilitates the BMP6-dependent upregulation of hepcidin expression (13).”
Hepcidin and Host Defense against Infectious Diseases
Michels, K., Nemeth, E., Ganz, T., & Mehrad, B. (2015) · PLOS Pathogens · doi:10.1371/journal.ppat.1004998 · Cited by 205
“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].”
BackgroundOstroff, R. M., Bigbee, W. L., Franklin, W. A., Gold, L., Mehan, M., Miller, Y. E., Pass, H. I., Rom, W. N., Siegfried, J. M., Stewart, A., et al. (2010) · Nature Precedings · doi:10.1371/journal.pone.0015003 · Cited by 213
“Unlike the membrane bound form, soluble RGM-C inhibits hepcidin expression [50,51].”
BackgroundEndothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice
Canali, S., Zumbrennen‐Bullough, K. B., Core, A. B., Wang, C., Nairz, M., Bouley, R., Świrski, F. K., & Babitt, J. L. (2016) · Blood · doi:10.1182/blood-2016-06-721571 · Cited by 226
Zhao, N., Zhang, A., & Enns, C. A. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67225 · Cited by 215
“In the liver, HJV is exclusively expressed in hepatocytes (16, 26) and acts as a coreceptor for BMP6 to induce hepcidin expression via the BMP signaling pathway (11, 20, 27), presumably by using ActRIIA in combination with either ALK2 or ALK3 (28).”
Biochemistry and Biology of GDF11 and Myostatin
Walker, R. G., Poggioli, T., Katsimpardi, L., Buchanan, S. M., Oh, J., Wattrus, S. J., Heidecker, B., Fong, Y. W., Rubin, L. L., Ganz, P., et al. (2016) · Circulation Research · doi:10.1161/circresaha.116.308391 · Cited by 217
Wallace, D. F., Summerville, L., Crampton, E. M., Frazer, D. M., Anderson, G. J., & Subramaniam, V. N. (2009) · Hepatology · doi:10.1002/hep.23198 · Cited by 212
D’Alessio, F., Hentze, M. W., & Muckenthaler, M. U. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.06.015 · Cited by 200
“While HJV is a BMP co-receptor that enhances BMP/SMAD signaling [24], the mechanism(s) of how HFE and TfR2 contribute to the control of hepcidin activation remain(s) elusive.”
BackgroundMethodInfluentialHepcidin regulation in prostate and its disruption in prostate cancer
Tesfay, L., Clausen, K. A., Kim, J. W., Hegde, P., Wang, X., Miller, L. D., Deng, Z., Blanchette, N., Arvedson, T., Miranti, C. K., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-2465 · Cited by 186
“1 mg TCF/LEF firefly luciferase (Qiagen) or hepcidin luciferase construct (17) and constitutively active Renilla luciferase.”
BackgroundGinzburg, Y., & Rivella, S. (2011) · Blood · doi:10.1182/blood-2011-03-283614 · Cited by 201
Iron Regulation: Macrophages in Control
Sukhbaatar, N., & Weichhart, T. (2018) · Pharmaceuticals · doi:10.3390/ph11040137 · Cited by 213
“On the contrary, pathological hepcidin excess caused by inflammatory disorders induces hypoferremia, anemia of inflammation, or anemia of chronic disease [31,63,64].”
Background
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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