Erythroferrone
| ERFE | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | ERFE, C1QTNF15, CTRP15, FAM132B, Erythroferrone, family with sequence similarity 132 member B | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 615099; MGI: 3606476; HomoloGene: 87245; GeneCards: ERFE; OMA:ERFE - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Erythroferrone | |||||||
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| Identifiers | |||||||
| Symbol | ERFE | ||||||
| NCBI gene | 151176 | ||||||
| HGNC | 26727 | ||||||
| OMIM | 615099 | ||||||
| RefSeq | NM_001291832.1 | ||||||
| UniProt | Q4G0M1 | ||||||
| Other data | |||||||
| Locus | Chr. 2 q37.3 | ||||||
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Erythroferrone is a protein hormone encoded in humans by the ERFE gene. Erythroferrone is produced by erythroblasts, inhibits the production of hepcidin in the liver, and so increases the amount of iron available for hemoglobin synthesis.[5][6]
Discovery
It was identified in 2014 in mice where the transcript was found in bone marrow, encoded by the mouse Fam132b gene.[6] The homologous gene in humans is FAM132B and the sequence is conserved in other species. The protein is synthesized by erythroblasts and secreted.[6] This sequence had previously been found expressed in mouse skeletal muscle, called myonectin (CTRP15), and linked to lipid homeostasis.[7]
Structure
Erythroferrone in humans is transcribed as a precursor of 354 amino acids, with a signal peptide of 28 amino acids. The mouse gene encodes a 340 amino acid protein which is 71% identical.[6] Homology is greater at the C-terminal where there is a TNF-alpha-like domain.
Function
Erythroferrone is a hormone that regulates iron metabolism through its actions on hepcidin.[5] As shown in mice and humans, it is produced in erythroblasts, which proliferate when new red cells are synthesized, such as after hemorrhage when more iron is needed (so-called stress erythropoiesis).[8] This process is governed by the renal hormone, erythropoietin.[6]
Its mechanism of action is to inhibit the expression of the liver hormone, hepcidin.[8] This process is governed by the renal hormone, erythropoietin.[6] By suppressing hepcidin, ERFE increases the function of the cellular iron export channel, ferroportin. This then results in increased iron absorption from the intestine and mobilization of iron from stores, which can then be used in the synthesis of hemoglobin in new red blood cells.[6] Erythroferrone inhibits hepcidin synthesis by binding bone morphogenetic proteins and thereby inhibiting the bone morphogenetic protein pathway that controls hepcidin expression.[9][10]
Mice deficient in the gene encoding erythroferrone have transient maturational hemoglobin deficits and impaired hepcidin suppression in response to phlebotomy with a delayed recovery from anemia.[6]
In its role as myonectin, it also promotes lipid uptake into adipocytes and hepatocytes.[7]
Regulation
Synthesis of erythroferrone is stimulated by erythropoietin binding to its receptor and activating the Jak2/Stat5 signaling pathway.[6]
Clinical significance
The clinical significance in humans is becoming clear.[11] From parallels in the mouse studies, there may be diseases where its function could be relevant. In a mouse model of thalassemia, its expression is increased, resulting in iron overload, which is also a feature of the human disease.[12] A role in the recovery from the anemia of inflammation in mice has been shown[13] and involvement in inherited anemias with ineffective erythropoiesis, anemia of chronic kidney diseases and iron-refractory iron-deficiency anemia has been suggested.[6][11]
Erythroferrone levels in blood have been shown by immunoassay to be higher after blood loss or erythropoetin administration. Patients with beta-thalassemia have very high levels, and these decrease after blood transfusion.[14]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000178752 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000047443 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b Koury, M.J. "Erythroferrone: A Missing Link in Iron Regulation". The Hematologist. American Society of Hematology. Retrieved 26 August 2015.
- ^ a b c d e f g h i j Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T (July 2014). "Identification of erythroferrone as an erythroid regulator of iron metabolism". Nature Genetics. 46 (7): 678–84. doi:10.1038/ng.2996. PMC 4104984. PMID 24880340.
- ^ a b Seldin MM, Peterson JM, Byerly MS, Wei Z, Wong GW (April 2012). "Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis". The Journal of Biological Chemistry. 287 (15): 11968–80. doi:10.1074/jbc.M111.336834. PMC 3320944. PMID 22351773.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b Kim A, Nemeth E (May 2015). "New insights into iron regulation and erythropoiesis". Current Opinion in Hematology. 22 (3): 199–205. doi:10.1097/MOH.0000000000000132. PMC 4509743. PMID 25710710.
- ^ Arezes J, Foy N, McHugh K, Sawant A, Quinkert D, Terraube V, et al. (October 2018). "Erythroferrone inhibits the induction of hepcidin by BMP6". Blood. 132 (14): 1473–1477. doi:10.1182/blood-2018-06-857995. PMC 6238155. PMID 30097509.
- ^ Arezes J, Foy NJ, Mchugh K, Quinkert D, Benard S, Sawant A, et al. (January 2020). "Antibodies against the erythroferrone N-terminal domain prevent hepcidin suppression and ameliorate murine thalassemia". Blood: blood.2019003140. doi:10.1182/blood.2019003140. PMID 31899794.
- ^ a b Pasricha SR, McHugh K, Drakesmith H (July 2016). "Regulation of Hepcidin by Erythropoiesis: The Story So Far". Annual Review of Nutrition. 36: 417–34. doi:10.1146/annurev-nutr-071715-050731. PMID 27146013.
- ^ Kautz L, Jung G, Du X, Gabayan V, Chapman J, Nasoff M, Nemeth E, Ganz T (October 2015). "Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia". Blood. 126 (17): 2031–7. doi:10.1182/blood-2015-07-658419. PMC 4616236. PMID 26276665.
- ^ Kautz L, Jung G, Nemeth E, Ganz T (October 2014). "Erythroferrone contributes to recovery from anemia of inflammation". Blood. 124 (16): 2569–74. doi:10.1182/blood-2014-06-584607. PMC 199959. PMID 25193872.
- ^ Ganz T, Jung G, Naeim A, Ginzburg Y, Pakbaz Z, Walter PB, Kautz L, Nemeth E (September 2017). "Immunoassay for human serum erythroferrone". Blood. 130 (10): 1243–1246. doi:10.1182/blood-2017-04-777987. PMC 5606005. PMID 28739636.