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Free Radical Biology & Medicine Mar 2019In vertebrates, transferrin (Tf) safely delivers iron through circulation to cells. Tf-bound iron is incorporated through Tf receptor (TfR) 1-mediated endocytosis. TfR1... (Review)
Review
In vertebrates, transferrin (Tf) safely delivers iron through circulation to cells. Tf-bound iron is incorporated through Tf receptor (TfR) 1-mediated endocytosis. TfR1 can mediate cellular uptake of both Tf and H-ferritin, an iron storage protein. New World arenaviruses, which cause hemorrhagic fever, and Plasmodium vivax use TfR1 for entry into host cells. Human TfR2, another receptor for Tf, is predominantly expressed in hepatocytes and erythroid precursors, and holo-Tf dramatically upregulates its expression. TfR2 forms a complex with hemochromatosis protein, HFE, and serves as a component of the iron sensing machinery in hepatocytes. Defects in TfR2 cause systemic iron overload, hemochromatosis, through down-regulation of hepcidin. In erythroid cells, TfR2 forms a complex with the erythropoietin receptor and regulates erythropoiesis. TfR2 facilitates iron transport from lysosomes to mitochondria in erythroblasts and dopaminergic neurons. Administration of apo-Tf, which scavenges free iron, has been explored for various clinical conditions including atransferrinemia, iron overload, and tissue ischemia. Apo-Tf has also been shown to ameliorate anemia in animal models of β-thalassemia. In this review, I provide an update and summary on our knowledge of mammalian Tf and its receptors.
Topics: Antigens, CD; Gene Expression Regulation; Hepatocytes; Hepcidins; Host-Pathogen Interactions; Humans; Iron; Iron Overload; Plasmodium vivax; Protein Binding; Receptors, Transferrin; Transferrin
PubMed: 29969719
DOI: 10.1016/j.freeradbiomed.2018.06.037 -
Critical Reviews in Oncogenesis 1993Transferrin receptor (TfR) is a membrane receptor involved in the control of iron supply to the cell through the binding of transferrin, the major iron-carrier protein.... (Review)
Review
Transferrin receptor (TfR) is a membrane receptor involved in the control of iron supply to the cell through the binding of transferrin, the major iron-carrier protein. This receptor plays a key role in the control of cell proliferation because iron is essential for sustaining ribonucleotide reductase activity, and is the only enzyme that catalyzes the conversion of ribonucleotides to deoxyribonucleotides. Furthermore, TfR is overexpressed in several tumors. The synthesis of the receptor is controlled through an iron-dependent negative feedback in cells where the receptor is involved in the control of cell proliferation, but through a positive feedback in cell types involved in iron storage (monocytes-macrophages). Recent studies have shed light on the molecular basis by which iron regulates TfR expression. Thus, the 3' untranslated region of TfR mRNA contains a cis-acting RNA element, termed the iron-regulatory element (IRE), that interacts with an IRE-binding protein (IRE-BP). The high-affinity interaction between IRE-BP and IRE in the TfR mRNA leads to repression of mRNA degradation and thus to higher synthesis of TfR. Hence, the study of IRE-BP activity will elucidate the mechanisms that modulate TfR expression in normal and malignant cells.
Topics: Amino Acid Sequence; Base Sequence; Cell Division; DNA; Erythropoiesis; Ferritins; Gene Expression Regulation; Humans; Iron; Iron-Regulatory Proteins; Macrophages; Molecular Sequence Data; Monocytes; RNA Processing, Post-Transcriptional; RNA, Messenger; RNA-Binding Proteins; Receptors, Transferrin; T-Lymphocytes
PubMed: 8485201
DOI: No ID Found -
Proceedings of the National Academy of... May 2023Influenza A virus (IAV) enters host cells mostly through clathrin-dependent receptor-mediated endocytosis. A single bona fide entry receptor protein supporting this...
Influenza A virus (IAV) enters host cells mostly through clathrin-dependent receptor-mediated endocytosis. A single bona fide entry receptor protein supporting this entry mechanism remains elusive. Here we performed proximity ligation of biotin to host cell surface proteins in the vicinity of attached trimeric hemagglutinin-HRP and characterized biotinylated targets using mass spectrometry. This approach identified transferrin receptor 1 (TfR1) as a candidate entry protein. Genetic gain-of-function and loss-of-function experiments, as well as in vitro and in vivo chemical inhibition, confirmed the functional involvement of TfR1 in IAV entry. Recycling deficient mutants of TfR1 do not support entry, indicating that TfR1 recycling is essential for this function. The binding of virions to TfR1 via sialic acids confirmed its role as a directly acting entry factor, but unexpectedly even headless TfR1 promoted IAV particle uptake in . TIRF microscopy localized the entering virus-like particles in the vicinity of TfR1. Our data identify TfR1 recycling as a revolving door mechanism exploited by IAV to enter host cells.
Topics: Transferrin; Influenza A virus; Virus Internalization; Endocytosis; Receptors, Transferrin
PubMed: 37192162
DOI: 10.1073/pnas.2214936120 -
Annual Review of Medicine 1993The transferrin receptor plays a critical role in iron metabolism by precisely controlling the flow of transferrin iron into body cells. A soluble truncated form of the... (Review)
Review
The transferrin receptor plays a critical role in iron metabolism by precisely controlling the flow of transferrin iron into body cells. A soluble truncated form of the receptor can be detected in human serum using sensitive immunoassays, and the initial clinical experience with this new measurement indicates that it reflects the total body mass of tissue receptor. Serum receptor levels rise significantly with tissue iron deficiency and the heightened demand for iron associated with expansion of the erythroid marrow. The serum receptor provides a quantitative measure of functional iron deficiency and distinguishes the associated anemia from that of chronic disease. If iron deficiency is excluded, the serum receptor provides a quantitative measure of total erythropoiesis that is more sensitive and less invasive than bone marrow examination currently used to assess red cell precursor mass. Performed in conjunction with serum ferritin measurements, the serum receptor will be useful in establishing the true prevalence of iron deficiency anemia in population studies.
Topics: Anemia; Erythropoiesis; Humans; Iron; Receptors, Transferrin
PubMed: 8476268
DOI: 10.1146/annurev.me.44.020193.000431 -
Metallomics : Integrated Biometal... Oct 2017The transferrin receptor (TfR1), which mediates cellular iron uptake through clathrin-dependent endocytosis of iron-loaded transferrin, plays a key role in iron... (Review)
Review
The transferrin receptor (TfR1), which mediates cellular iron uptake through clathrin-dependent endocytosis of iron-loaded transferrin, plays a key role in iron homeostasis. Since the number of TfR1 molecules at the cell surface is the rate-limiting step for iron entry into cells and is essential to prevent iron overload, TfR1 expression is precisely controlled at multiple levels. In this review, we have discussed the latest advances in the molecular regulation of TfR1 expression and we have considered current understanding of TfR1 function beyond its canonical role in providing iron for erythroid precursors and rapidly proliferating cells.
Topics: Animals; Biological Transport; Endocytosis; Homeostasis; Humans; Iron; Receptors, Transferrin; Transferrin
PubMed: 28671201
DOI: 10.1039/c7mt00143f -
Biophysical Chemistry Nov 2019The transferrin receptor 1 (TfR1) is one of the key regulators of iron homeostasis for most higher organisms. It mediates cellular iron import through a constitutive... (Review)
Review
The transferrin receptor 1 (TfR1) is one of the key regulators of iron homeostasis for most higher organisms. It mediates cellular iron import through a constitutive clathrin-dependent endocytosis mechanism and by recruiting iron- regulator proteins as transferrin, Hereditary Hemochromatosis factor (HFE) and serum ferritin in response to cellular demand. The receptor is also opportunistically exploited by several viruses and the malaria parasite as a preferential door for cell invasion. In this review, we analyze the structural information available for TfR1 and all its functional complexes to figure out how structural signals in a single receptor can guide the recognition of multiple ligands and how the conservation of key residues in TfR1 might have a role in iron uptake and cell infection.
Topics: Animals; Binding Sites; Humans; Iron; Ligands; Protein Binding; Protein Conformation, alpha-Helical; Receptors, Transferrin
PubMed: 31419721
DOI: 10.1016/j.bpc.2019.106242 -
Progress in Neurobiology Oct 2019Obtaining efficient drug delivery to the brain remains the biggest challenge for the development of therapeutics to treat diseases of the central nervous system. The... (Review)
Review
Obtaining efficient drug delivery to the brain remains the biggest challenge for the development of therapeutics to treat diseases of the central nervous system. The main obstacle is the blood-brain barrier (BBB), which impedes the entrance of most molecules present in the systemic circulation, especially large molecule drugs and nanomedicines. To overcome this obstacle, targeting strategies binding to nutrient receptors present at the luminal membrane of the BBB are frequently employed. Amongst the numerous potential targets at the BBB, the transferrin receptor (TfR) remains the most common target used to ensure sufficient drug delivery to the brain. In this review, we provide a full account on the use of the TfR as a target for brain drug delivery by describing the function of the TfR in the BBB, the historical background of its use in drug delivery, and the most recent evidence suggesting TfR-targeted medicines to be efficient for brain drug delivery with a clear clinical potential.
Topics: Animals; Biological Transport; Blood-Brain Barrier; Drug Delivery Systems; Humans; Receptors, Transferrin
PubMed: 31376426
DOI: 10.1016/j.pneurobio.2019.101665 -
Medicinal Research Reviews May 2002Since transferrin was discovered more than half a century ago, a considerable effort has been made towards understanding tranferrin-mediated iron uptake. However, it was... (Review)
Review
Since transferrin was discovered more than half a century ago, a considerable effort has been made towards understanding tranferrin-mediated iron uptake. However, it was not until recently with the identification and characterization of several new genes related to iron homeostasis, such as the hemochromatosis protein HFE and the iron transporter DMT1, that our knowledge has been advanced dramatically. A major pathway for cellular iron uptake is through internalization of the complex of iron-bound transferrin and the transferrin receptor, which is negatively modulated by HFE, a protein related to hereditary hemochromatosis. Iron is released from transferrin as the result of the acidic pH in endosome and then is transported to the cytosol by DMT1. The iron is then utilized as a cofactor by heme and ribonucleotide reductase or stored in ferritin. Apart from iron, many other metal ions of therapeutic and diagnostic interests can also bind to transferrin at the iron sites and their transferrin complexes can be recognized by many cells. Therefore, transferrin has been thought as a "delivery system" for many beneficial and harmful metal ions into the cells. Transferrin has also be widely applied as a targeting ligand in the active targeting of anticancer agents, proteins, and genes to primary proliferating malignant cells that overexpress transferrin receptors. This is achieved by conjugation of transferrin with drugs, proteins, hybride systems with marcomolecules and as liposomal-coated systems. Conjugates of anticancer drugs with transferrin can significantly improve the selectivity and toxicity and overcome drug resistance, thereby leading to a better treatment. The coupling of DNA to transferrin via a polycation such as polylysine or via cationic liposomes can target and transfer of the extrogenous DNA particularly into proliferating cells through receptor-mediated endocytosis. These kinds of non-viral vectors are potential alternatives to viral vectors for gene therapy, if the transfection efficiency can be improved. Moreover, transferrin receptors have shown potentials in delivery of therapeutic drugs or genes into the brain across blood-brain barrier.
Topics: Animals; Drug Delivery Systems; Endocytosis; Humans; Iron; Protein Conformation; Receptors, Transferrin; Transferrin
PubMed: 11933019
DOI: 10.1002/med.10008 -
Clinica Chimica Acta; International... Apr 2014Determination of serum soluble transferrin receptor (sTfR) has been proposed to identify iron-deficiency anemia (IDA) in patients affected by concurrent inflammatory... (Meta-Analysis)
Meta-Analysis Review
Determination of serum soluble transferrin receptor (sTfR) has been proposed to identify iron-deficiency anemia (IDA) in patients affected by concurrent inflammatory disease that may spuriously increase ferritin concentration. The aim of this study was to critically review the available literature to assess the diagnostic efficacy of sTfR in complicated anemia. The criteria for study selection were: enrolment of patients with complicated anemia; bone marrow examination used as diagnostic gold standard for IDA; evaluation of sTfR vs. ferritin and binary data presentation. Six published studies met the criteria. However, the small size and wide heterogeneity of the studies did not allow us to conduct a meta-analysis. sTfR was overall more sensitive, even though it was evident that the ferritin sensitivity was influenced by selected cut-offs. Well-designed studies are still needed to define the added value, if any, of sTfR to ferritin for IDA detection in complicated anemia.
Topics: Anemia, Iron-Deficiency; Ferritins; Humans; Receptors, Transferrin; Reference Standards
PubMed: 24525213
DOI: 10.1016/j.cca.2014.02.005 -
Drug Discovery Today. Technologies Jun 2016Delivery of large molecule drugs across the blood brain barrier is increasingly being seen as an achievable goal. Several technologies have been described where... (Review)
Review
Delivery of large molecule drugs across the blood brain barrier is increasingly being seen as an achievable goal. Several technologies have been described where following peripheral administration the molecules can be detected in the brain. Foremost amongst these technologies are antibodies against the transferrin receptor. Following a burst of publications in the very early twenty first century, excitement seemed to wane as contrary data started to emerge. Over the last few years antibodies against transferrin receptor have again started to raise hopes of successful drug delivery to the central nervous system, as protein engineering techniques have allowed a more detailed understanding of the antibody properties necessary for successful transport across the blood brain barrier.
Topics: Animals; Antibodies; Blood-Brain Barrier; Drug Delivery Systems; Humans; Pharmaceutical Preparations; Receptors, Transferrin
PubMed: 27986223
DOI: 10.1016/j.ddtec.2016.07.009