Transferrin receptor 2 is emerging as a major player in the control of iron metabolism

2007 ◽  
Vol 2 (1) ◽  
pp. 34-55 ◽  
Author(s):  
Alessia Calzolari ◽  
Isabella Oliviero ◽  
Ugo Testa
Keyword(s):  
Iron Metabolism ◽  
Transferrin Receptor ◽  
Cellular Localization ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Essential Element ◽  
Biological Properties ◽  
The Body ◽  
Major Player ◽  
Type 3

AbstractOur knowledge of mammalian iron metabolism has advanced dramatically over recent years. Iron is an essential element for virtually all living organisms. Its intestinal absorption and accurate cellular regulation is strictly required to ensure the coordinated synthesis of the numerous iron-containing proteins involved in key metabolic processes, while avoiding the uptake of excess iron that can lead to organ damage. A range of different proteins exist to ensure this fine control within the various tissues of the body. Among these proteins, transferrin receptor (TFR2) seems to play a key role in the regulation of iron homeostasis. Disabling mutations in TFR2 are responsible for type 3 hereditary hemochromatosis (Type 3 HH). This review describes the biological properties of this membrane receptor, with a particular emphasis paid to the structure, function and cellular localization. Although much information has been garnered on TFR2, further efforts are needed to elucidate its function in the context of the iron regulatory network.

scholarly journals Normal systemic iron homeostasis in mice with macrophage-specific deletion of transferrin receptor 2

2016 ◽  
Vol 310 (3) ◽  
pp. G171-G180 ◽  
Author(s):  
Gautam Rishi ◽  
Eriza S. Secondes ◽  
Daniel F. Wallace ◽  
V. Nathan Subramaniam
Keyword(s):  
Iron Metabolism ◽  
Knockout Mice ◽  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Essential Element ◽  
Cellular Growth ◽  
Hepatic Expression ◽  
Specific Deletion ◽  
Transferrin Receptor 2

Iron is an essential element, since it is a component of many macromolecules involved in diverse physiological and cellular functions, including oxygen transport, cellular growth, and metabolism. Systemic iron homeostasis is predominantly regulated by the liver through the iron regulatory hormone hepcidin. Hepcidin expression is itself regulated by a number of proteins, including transferrin receptor 2 (TFR2). TFR2 has been shown to be expressed in the liver, bone marrow, macrophages, and peripheral blood mononuclear cells. Studies from our laboratory have shown that mice with a hepatocyte-specific deletion of Tfr2 recapitulate the hemochromatosis phenotype of the global Tfr2 knockout mice, suggesting that the hepatic expression of TFR2 is important in systemic iron homeostasis. It is unclear how TFR2 in macrophages contributes to the regulation of iron metabolism. We examined the role of TFR2 in macrophages by analysis of transgenic mice lacking Tfr2 in macrophages by crossing Tfr2 f/f mice with LysM-Cre mice. Mice were fed an iron-rich diet or injected with lipopolysaccharide to examine the role of macrophage Tfr2 in iron- or inflammation-mediated regulation of hepcidin. Body iron homeostasis was unaffected in the knockout mice, suggesting that macrophage TFR2 is not required for the regulation of systemic iron metabolism. However, peritoneal macrophages of knockout mice had significantly lower levels of ferroportin mRNA and protein, suggesting that TFR2 may be involved in regulating ferroportin levels in macrophages. These studies further elucidate the role of TFR2 in the regulation of iron homeostasis and its role in regulation of ferroportin and thus macrophage iron homeostasis.

scholarly journals The Functional Versatility of Transferrin Receptor 2 and Its Therapeutic Value

2018 ◽  
Vol 11 (4) ◽  
pp. 115 ◽  
Author(s):  
Antonella Roetto ◽  
Mariarosa Mezzanotte ◽  
Rosa Pellegrino
Keyword(s):  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Iron Regulation ◽  
Role Taking ◽  
Therapeutic Value ◽  
Living Organisms ◽  
Type 3 ◽  
Functional Versatility ◽  
Transferrin Receptor 2

Iron homeostasis is a tightly regulated process in all living organisms because this metal is essential for cellular metabolism, but could be extremely toxic when present in excess. In mammals, there is a complex pathway devoted to iron regulation, whose key protein is hepcidin (Hepc), which is a powerful iron absorption inhibitor mainly produced by the liver. Transferrin receptor 2 (Tfr2) is one of the hepcidin regulators, and mutations in TFR2 gene are responsible for type 3 hereditary hemochromatosis (HFE3), a genetically heterogeneous disease characterized by systemic iron overload. It has been recently pointed out that Hepc production and iron regulation could be exerted also in tissues other than liver, and that Tfr2 has an extrahepatic role in iron metabolism as well. This review summarizes all the most recent data on Tfr2 extrahepatic role, taking into account the putative distinct roles of the two main Tfr2 isoforms, Tfr2α and Tfr2β. Representing Hepc modulation an effective approach to correct iron balance impairment in common human diseases, and with Tfr2 being one of its regulators, it would be worthwhile to envisage Tfr2 as a therapeutic target.

Defective trafficking and localization of mutated transferrin receptor 2: implications for type 3 hereditary hemochromatosis

2008 ◽  
Vol 294 (2) ◽  
pp. C383-C390 ◽  
Author(s):  
Daniel F. Wallace ◽  
Lesa Summerville ◽  
Emily M. Crampton ◽  
V. Nathan Subramaniam
Keyword(s):  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Wild Type ◽  
Mouse Liver Cell ◽  
Functional Consequences ◽  
Consequences Of Disease ◽  
Type 3 ◽  
Mutant Forms ◽  
Transferrin Receptor 2

Transferrin receptor 2 (TfR2), a homologue of transferrin receptor 1 (TfR1), is a key molecule involved in the regulation of iron homeostasis. Mutations in TfR2 result in iron overload with similar features to HFE-associated hereditary hemochromatosis. The precise role of TfR2 in iron metabolism and the functional consequences of disease-causing mutations have not been fully determined. We have expressed wild-type and various mutant forms of TfR2 that are associated with human disease in a mouse liver cell line. Intracellular and surface analysis shows that all the TfR2 mutations analyzed cause the intracellular retention of the protein in the endoplasmic reticulum, whereas the wild-type protein is expressed in endocytic structures and at the cell surface. Our results indicate that the majority of mutations that cause type 3 hereditary hemochromatosis are a consequence of the defective localization of the protein.

A single viral protein HCMV US2 affects antigen presentation and intracellular iron homeostasis by degradation of classical HLA class I and HFE molecules

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2858-2864 ◽  
Author(s):  
Sayeh Vahdati-Ben Arieh ◽  
Nihay Laham ◽  
Chana Schechter ◽  
Jon W. Yewdell ◽  
John E. Coligan ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Cytotoxic T Lymphocyte ◽  
Expression System ◽  
Hereditary Hemochromatosis ◽  
Class I ◽  
Intracellular Iron ◽  
Hek 293 ◽  
Classical Class

HFE is a nonclassical class I molecule that associates with β2-microglobulin (β2m) and with the transferrin receptor. HFE accumulates in transferrin-containing endosomes, and its overexpression in human cell lines correlates with decreased transferrin receptor (TFR)–mediated iron uptake and decreased intracellular iron pools. A mutation that interferes with proper folding and assembly of HFE complexes results in a severe iron-overload disease hereditary hemochromatosis. We previously suggested that viruses could also interfere with iron metabolism through the production of proteins that inactivate HFE, similarly to classical class I proteins. In particular, we demonstrated in a transient expression system that human cytomegalovirus (HCMV) US2 targeted HFE for proteasomal degradation. Here we demonstrate that the stable expression of HCMV US2 in HEK 293 cells constitutively expressing HFE leads to loss of HFE expression both intracellularly and on the cell surface, and the significant reduction of classical class I expression. Both HFE and classical class I molecules are targeted to degradation via a similar pathway. This HCMV US2-mediated degradation of HFE leads to increased intracellular iron pools as indicated by reduced synthesis of TfR and increased ferritin synthesis. Whether this interference with regulation of iron metabolism potentiates viral replication and/or promotes damage of HCMV-infected tissues remains to be determined. Nevertheless, the deleterious effect of US2 on the expression of HFE and classical class I major histo-compatibility complexes (MHC) provides HCMV with an efficient tool for altering cellular metabolic functions, as well as supporting the escape of virus-infected cells from cytotoxic T lymphocyte (CTL)–mediated immune responses.

Iron Homeostasis and Disorders in Dogs and Cats: A Review

2011 ◽  
Vol 47 (3) ◽  
pp. 151-160 ◽  
Author(s):  
Jennifer L. McCown ◽  
Andrew J. Specht
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Iron Homeostasis ◽  
Diagnostic Testing ◽  
Clinical Manifestations ◽  
Essential Element ◽  
The Body ◽  
Deficiency Anemia ◽  
Enzyme Systems ◽  
Living Organisms

Iron is an essential element for nearly all living organisms and disruption of iron homeostasis can lead to a number of clinical manifestations. Iron is used in the formation of both hemoglobin and myoglobin, as well as numerous enzyme systems of the body. Disorders of iron in the body include iron deficiency anemia, anemia of inflammatory disease, and iron overload. This article reviews normal iron metabolism, disease syndromes of iron imbalance, diagnostic testing, and treatment of either iron deficiency or excess. Recent advances in diagnosing iron deficiency using reticulocyte indices are reviewed.

Iron homeostasis: new tales from the crypt

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4020-4027 ◽  
Author(s):  
Cindy N. Roy ◽  
Caroline A. Enns
Keyword(s):  
Iron Uptake ◽  
Iron Transport ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Hereditary Hemochromatosis ◽  
The Body ◽  
Regulatory Proteins ◽  
Iron Regulatory Proteins ◽  
Duodenal Epithelium ◽  
Related Proteins

Abstract The enterocyte is a highly specialized cell of the duodenal epithelium that coordinates iron uptake and transport into the body. Until recently, the molecular mechanisms underlying iron absorption and iron homeostasis have remained a mystery. This review focuses on the proteins and regulatory mechanisms known to be present in the enterocyte precursor cell and in the mature enterocyte. The recent cloning of a basolateral iron transporter and investigations into its regulation provide new insights into possible mechanisms for iron transport and homeostasis. The roles of proteins such as iron regulatory proteins, the hereditary hemochromatosis protein (HFE)–transferrin receptor complex, and hephaestin in regulating this transporter and in regulating iron transport across the intestinal epithelium are discussed. A speculative, but testable, model for the maintenance of iron homeostasis, which incorporates the changes in the iron-related proteins associated with the life cycle of the enterocyte as it journeys from the crypt to the tip of the villous is proposed.

scholarly journals Age-Related Changes and Sex-Related Differences in Brain Iron Metabolism

Nutrients ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2601
Author(s):  
Tanja Grubić Kezele ◽  
Božena Ćurko-Cofek
Keyword(s):  
Iron Metabolism ◽  
Neurological Disorders ◽  
Healthy Aging ◽  
Iron Homeostasis ◽  
Essential Element ◽  
Molecular Alterations ◽  
Age Related ◽  
Faster Development ◽  
Brain Iron Metabolism ◽  
Age Related Changes

Iron is an essential element that participates in numerous cellular processes. Any disruption of iron homeostasis leads to either iron deficiency or iron overload, which can be detrimental for humans’ health, especially in elderly. Each of these changes contributes to the faster development of many neurological disorders or stimulates progression of already present diseases. Age-related cellular and molecular alterations in iron metabolism can also lead to iron dyshomeostasis and deposition. Iron deposits can contribute to the development of inflammation, abnormal protein aggregation, and degeneration in the central nervous system (CNS), leading to the progressive decline in cognitive processes, contributing to pathophysiology of stroke and dysfunctions of body metabolism. Besides, since iron plays an important role in both neuroprotection and neurodegeneration, dietary iron homeostasis should be considered with caution. Recently, there has been increased interest in sex-related differences in iron metabolism and iron homeostasis. These differences have not yet been fully elucidated. In this review we will discuss the latest discoveries in iron metabolism, age-related changes, along with the sex differences in iron content in serum and brain, within the healthy aging population and in neurological disorders such as multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and stroke.

scholarly journals A Short Review of Iron Metabolism and Pathophysiology of Iron Disorders

Medicines ◽  
2019 ◽  
Vol 6 (3) ◽  
pp. 85 ◽  
Author(s):  
Andronicos Yiannikourides ◽  
Gladys Latunde-Dada
Keyword(s):  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Cellular Proliferation ◽  
Peptide Hormone ◽  
Short Review ◽  
Reticuloendothelial System ◽  
Cellular Level ◽  
Feedback Mechanism ◽  
The Body ◽  
Iron Regulatory Proteins

Iron is a vital trace element for humans, as it plays a crucial role in oxygen transport, oxidative metabolism, cellular proliferation, and many catalytic reactions. To be beneficial, the amount of iron in the human body needs to be maintained within the ideal range. Iron metabolism is one of the most complex processes involving many organs and tissues, the interaction of which is critical for iron homeostasis. No active mechanism for iron excretion exists. Therefore, the amount of iron absorbed by the intestine is tightly controlled to balance the daily losses. The bone marrow is the prime iron consumer in the body, being the site for erythropoiesis, while the reticuloendothelial system is responsible for iron recycling through erythrocyte phagocytosis. The liver has important synthetic, storing, and regulatory functions in iron homeostasis. Among the numerous proteins involved in iron metabolism, hepcidin is a liver-derived peptide hormone, which is the master regulator of iron metabolism. This hormone acts in many target tissues and regulates systemic iron levels through a negative feedback mechanism. Hepcidin synthesis is controlled by several factors such as iron levels, anaemia, infection, inflammation, and erythropoietic activity. In addition to systemic control, iron balance mechanisms also exist at the cellular level and include the interaction between iron-regulatory proteins and iron-responsive elements. Genetic and acquired diseases of the tissues involved in iron metabolism cause a dysregulation of the iron cycle. Consequently, iron deficiency or excess can result, both of which have detrimental effects on the organism.

scholarly journals Regulation of Iron Homeostasis and Related Diseases

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Yikun Li ◽  
Xiali Huang ◽  
Jingjing Wang ◽  
Ruiling Huang ◽  
Dan Wan
Keyword(s):  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Iron Concentration ◽  
Gene Mutations ◽  
The Body ◽  
Hereditary Diseases ◽  
Iron Regulation ◽  
Iron Storage ◽  
Smad Pathway ◽  
Infection And Inflammation

The liver is the organ for iron storage and regulation; it senses circulating iron concentrations in the body through the BMP-SMAD pathway and regulates the iron intake from food and erythrocyte recovery into the bloodstream by secreting hepcidin. Under iron deficiency, hypoxia, and hemorrhage, the liver reduces the expression of hepcidin to ensure the erythropoiesis but increases the excretion of hepcidin during infection and inflammation to reduce the usage of iron by pathogens. Excessive iron causes system iron overload; it accumulates in never system and damages neurocyte leading to neurodegenerative diseases such as Parkinson’s syndrome. When some gene mutations affect the perception of iron and iron regulation ability in the liver, then they decrease the expression of hepcidin, causing hereditary diseases such as hereditary hemochromatosis. This review summarizes the source and utilization of iron in the body, the liver regulates systemic iron homeostasis by sensing the circulating iron concentration, and the expression of hepcidin regulated by various signaling pathways, thereby understanding the pathogenesis of iron-related diseases.

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