Generic protein structure example
|Locus||Chr. 2 q37.3|
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. Skeletal muscle secreted ERFE has been shown to maintain systemic metabolic homeostasis.
It was identified in 2014 in mice where the transcript was found in bone marrow, encoded by the mouse Fam132b gene. The homologous gene in humans is FAM132B and the sequence is conserved in other species. The protein is synthesized by erythroblasts and secreted. This sequence had previously been found expressed in mouse skeletal muscle, called myonectin (CTRP15), and linked to lipid homeostasis.
Seldin and his colleagues have written: "Myonectin is expressed and secreted predominantly by skeletal muscle.... (Our) results suggest that myonectin is a nutrient-responsive metabolic regulator secreted by skeletal muscle in response to changes in cellular energy state resulting from glucose or fatty acid fluxes. Many metabolically relevant secreted proteins (e.g. adiponectin, leptin, resistin, and RBP) and the signaling pathways they regulate in tissues are known to be dysregulated in the condition of obesity. The reduction in expression and circulating levels of myonectin in the obese state may represent yet another component of the complex metabolic circuitry dysregulated by excess caloric intake. Although exercise has long been known to have profound positive impacts on systemic insulin sensitivity and energy balance, the underlying mechanisms remain incompletely understood. That voluntary exercise dramatically increases the expression and circulating levels of myonectin to promote fatty acid uptake into cells may underlie one of the beneficial effects of physical exercise."
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. Homology is greater at the C-terminal where there is a TNF-alpha-like domain.
Erythroferrone is a hormone that regulates iron metabolism through its actions on hepcidin. 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). This process is governed by the renal hormone, erythropoietin.
Its mechanism of action is to inhibit the expression of the liver hormone, hepcidin. This process is governed by the renal hormone, erythropoietin. 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. Erythroferrone inhibits hepcidin synthesis by binding bone morphogenetic proteins and thereby inhibiting the bone morphogenetic protein pathway that controls hepcidin expression.
In its role as myonectin, it also promotes lipid uptake into adipocytes and hepatocytes.
Synthesis of erythroferrone is stimulated by erythropoietin binding to its receptor and activating the Jak2/Stat5 signaling pathway.
The clinical significance in humans is becoming clear. 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. A role in the recovery from the anemia of inflammation in mice has been shown and involvement in inherited anemias with ineffective erythropoiesis, anemia of chronic kidney diseases and iron-refractory iron-deficiency anemia has been suggested.
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.
- "Erythroferrone: A Missing Link in Iron Regulation". American Society of Hematology. http://www.hematology.org/Thehematologist/Years-Best/3599.aspx.
- "Identification of erythroferrone as an erythroid regulator of iron metabolism". Nature Genetics 46 (7): 678–84. July 2014. doi:10.1038/ng.2996. PMID 24880340.
- Wang, Hui (2017). "Skeletal muscle secreted myonectin maintains systemic metabolic homeostasis" (in en). The FASEB Journal 31 (S1): 1036.17. doi:10.1096/fasebj.31.1_supplement.1036.17. ISSN 1530-6860. https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fasebj.31.1_supplement.1036.17.
- "Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis". The Journal of Biological Chemistry 287 (15): 11968–80. April 2012. doi:10.1074/jbc.M111.336834. PMID 22351773.
- Marcus M. Seldin, Jonathan M. Peterson, Mardi S. Byerly, Zhikui Wei, and G. William Wong. "Myonectin (CTRP15), a Novel Myokine That Links Skeletal Muscle to Systemic Lipid Homeostasis." THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 287, NO. 15, pp. 11968–11980, April 6, 2012, doi: 10.1074/jbc.M111.336834 originally published online February 17, 2012.
- "New insights into iron regulation and erythropoiesis". Current Opinion in Hematology 22 (3): 199–205. May 2015. doi:10.1097/MOH.0000000000000132. PMID 25710710.
- "Erythroferrone inhibits the induction of hepcidin by BMP6". Blood 132 (14): 1473–1477. October 2018. doi:10.1182/blood-2018-06-857995. PMID 30097509.
- "Antibodies against the erythroferrone N-terminal domain prevent hepcidin suppression and ameliorate murine thalassemia". Blood 135 (8): 547–557. February 2020. doi:10.1182/blood.2019003140. PMID 31899794.
- "Regulation of Hepcidin by Erythropoiesis: The Story So Far". Annual Review of Nutrition 36: 417–34. July 2016. doi:10.1146/annurev-nutr-071715-050731. PMID 27146013.
- "Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia". Blood 126 (17): 2031–7. October 2015. doi:10.1182/blood-2015-07-658419. PMID 26276665.
- "Erythroferrone contributes to recovery from anemia of inflammation". Blood 124 (16): 2569–74. October 2014. doi:10.1182/blood-2014-06-584607. PMID 25193872.
- "Immunoassay for human serum erythroferrone". Blood 130 (10): 1243–1246. September 2017. doi:10.1182/blood-2017-04-777987. PMID 28739636.
Original source: https://en.wikipedia.org/wiki/Erythroferrone. Read more