Interaction of the Hereditary Hemochromatosis Protein HFE with Transferrin Receptor 2 Is Required for Transferrin-Induced Hepcidin Expression

Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, OR 97239, USA.
Cell metabolism (Impact Factor: 17.57). 04/2009; 9(3):217-27. DOI: 10.1016/j.cmet.2009.01.010
Source: PubMed


The mechanisms that allow the body to sense iron levels in order to maintain iron homeostasis are unknown. Patients with the most common form of hereditary iron overload have mutations in the hereditary hemochromatosis protein HFE. They have lower levels of hepcidin than unaffected individuals. Hepcidin, a hepatic peptide hormone, negatively regulates iron efflux from the intestines into the blood. We report two hepatic cell lines, WIF-B cells and HepG2 cells transfected with HFE, where hepcidin expression responded to iron-loaded transferrin. The response was abolished when endogenous transferrin receptor 2 (TfR2) was suppressed or in primary hepatocytes lacking either functional TfR2 or HFE. Furthermore, transferrin-treated HepG2 cells transfected with HFE chimeras containing only the alpha3 and cytoplasmic domains could upregulate hepcidin expression. Since the HFE alpha3 domain interacts with TfR2, these results supported our finding that TfR2/HFE complex is required for transcriptional regulation of hepcidin by holo-Tf.

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    • "HFE and TFR2 are also postulated to function in iron sensing by the liver. The current working model is that when iron-bound transferrin increases in circulation, it binds to transferrin receptor 1 (TFR1) and displaces HFE, which then signals by some mechanism to stimulate hepcidin expression, possibly through an interaction with TFR2 (Schmidt et al., 2008; Gao et al., 2009). "
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    ABSTRACT: Mutations in hemojuvelin (HJV) are the most common cause of the juvenile-onset form of the iron overload disorder hereditary hemochromatosis. The discovery that HJV functions as a co-receptor for the bone morphogenetic protein (BMP) family of signaling molecules helped to identify this signaling pathway as a central regulator of the key iron hormone hepcidin in the control of systemic iron homeostasis. This review highlights recent work uncovering the mechanism of action of HJV and the BMP-SMAD signaling pathway in regulating hepcidin expression in the liver, as well as additional studies investigating possible extra-hepatic functions of HJV. This review also explores the interaction between HJV, the BMP-SMAD signaling pathway and other regulators of hepcidin expression in systemic iron balance.
    Frontiers in Pharmacology 05/2014; 5:104. DOI:10.3389/fphar.2014.00104 · 3.80 Impact Factor
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    • "However, crystallographic studies have shown that HFE binds TFR1 (Bennett et al., 2000) at the same consensus sequences of diferric transferrin, implying a competition between the two ligands. On the contrary, based on in vitro data, binding of HFE to TFR2 and holo-Tf would occur simultaneously at two different TFR2 sequence motifs (Gao et al., 2009). "
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    ABSTRACT: Transferrin receptor 2 (TFR2), a protein homologous to the cell iron importer TFR1, is expressed in the liver and erythroid cells and is reported to bind diferric transferrin, although at lower affinity than TFR1. TFR2 gene is mutated in type 3 hemochromatosis, a disorder characterized by iron overload and inability to upregulate hepcidin in response to iron. Liver TFR2 is considered a sensor of diferric transferrin, possibly in a complex with hemochromatosis protein. In erythroid cells TFR2 is a partner of erythropoietin receptor (EPOR) and stabilizes the receptor on the cell surface. However, Tfr2 null mice as well as TFR2 hemochromatosis patients do not show defective erythropoiesis and tolerate repeated phlebotomy. The iron deficient Tfr2-Tmprss6 double knock out mice have higher red cells count and more severe microcytosis than the liver-specific Tfr2 and Tmprss6 double knock out mice. TFR2 in the bone marrow might be a sensor of iron deficiency that protects against excessive microcytosis in a way that involves EPOR, although the mechanisms remain to be worked out.
    Frontiers in Pharmacology 05/2014; 5:93. DOI:10.3389/fphar.2014.00093 · 3.80 Impact Factor
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    • "In contrast, Tfr2 mutant mouse primary hepatocytes do not respond to treatment, indicating a role of Tfr2 in Tf-sensitivity (Gao et al., 2009). In addition, deletion of the Tfr2 binding partner, Hfe, also results in loss of Tf- sensitivity, indicating that it may be the TfR2/HFE complex that is involved in iron-sensing (Gao et al., 2009). In human patients with TfR2 HH, urinary hepcidin levels do not respond to iron challenge, and HFE HH patients have a blunted hepcidin response, indicating that both molecules are needed in order to modulate iron uptake in response to dietary iron (Girelli et al., 2011). "
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    ABSTRACT: Fine-tuning of body iron is required to prevent diseases such as iron-overload and anemia. The putative iron sensor, transferrin receptor 2 (TfR2), is expressed in the liver and mutations in this protein result in the iron-overload disease Type III hereditary hemochromatosis (HH). With the loss of functional TfR2, the liver produces about 2-fold less of the peptide hormone hepcidin, which is responsible for negatively regulating iron uptake from the diet. This reduction in hepcidin expression leads to the slow accumulation of iron in the liver, heart, joints, and pancreas and subsequent cirrhosis, heart disease, arthritis, and diabetes. TfR2 can bind iron-loaded transferrin (Tf) in the bloodstream, and hepatocytes treated with Tf respond with a 2-fold increase in hepcidin expression through stimulation of the bone morphogenetic protein (BMP)-signaling pathway. Loss of functional TfR2 or its binding partner, the original HH protein, results in a loss of this transferrin-sensitivity. While much is known about the trafficking and regulation of TfR2, the mechanism of its transferrin-sensitivity through the BMP-signaling pathway is still not known.
    Frontiers in Pharmacology 03/2014; 5:34. DOI:10.3389/fphar.2014.00034 · 3.80 Impact Factor
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