Identification of a Human Heme Exporter that Is Essential for Erythropoiesis

Quigley, John G.; Yang, Zhilin; Worthington, Mark T.; Phillips, John D.; Sabo, Kathleen M.; Sabath, Daniel E.; Berg, Carl L.; Sassa, Shigeru; Wood, Brent L.; Abkowitz, Janis L.

doi:10.1016/j.cell.2004.08.014

Cited by 380 publications

(394 citation statements)

References 44 publications

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“…Decreased iron availability likely results in more effective erythropoiesis, as less iron is available during erythroid development to generate free heme or α-globin precipitates, factors associated with shortened rbc survival. Previously presented data demonstrate that the absence of heme-regulated inhibitor (HRI) kinase, which controls Hb synthesis (25), exacerbates the β-thalassemia phenotype (26), while lack of heme exporter feline leukemia virus subgroup C cellular receptor (FLVCR), which controls heme export (27), impairs rbc formation (28). These observations, along with our new data, suggest that an excess of iron and/or heme (in addition to α-globin) in erythroid cells might be deleterious to erythropoiesis.…”

Section: Discussionmentioning

confidence: 99%

Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice

Gardenghi¹,

Ramos²,

Marongiu³

et al. 2010

J. Clin. Invest.

209

216

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Excessive iron absorption is one of the main features of β-thalassemia and can lead to severe morbidity and mortality. Serial analyses of β-thalassemic mice indicate that while hemoglobin levels decrease over time, the concentration of iron in the liver, spleen, and kidneys markedly increases. Iron overload is associated with low levels of hepcidin, a peptide that regulates iron metabolism by triggering degradation of ferroportin, an iron-transport protein localized on absorptive enterocytes as well as hepatocytes and macrophages. Patients with β-thalassemia also have low hepcidin levels. These observations led us to hypothesize that more iron is absorbed in β-thalassemia than is required for erythropoiesis and that increasing the concentration of hepcidin in the body of such patients might be therapeutic, limiting iron overload. Here we demonstrate that a moderate increase in expression of hepcidin in β-thalassemic mice limits iron overload, decreases formation of insoluble membrane-bound globins and reactive oxygen species, and improves anemia. Mice with increased hepcidin expression also demonstrated an increase in the lifespan of their red cells, reversal of ineffective erythropoiesis and splenomegaly, and an increase in total hemoglobin levels. These data led us to suggest that therapeutics that could increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals with β-thalassemia and related disorders.

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Section: Discussionmentioning

confidence: 99%

Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice

Gardenghi¹,

Ramos²,

Marongiu³

et al. 2010

J. Clin. Invest.

209

216

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Section: Balance Of Heme and Globinmentioning

confidence: 99%

“…101 FLVCR is the receptor for the feline leukemia virus, subgroup C (FeLV-C), which causes a red cell aplasia in cats. 101 Pro-erythroblasts may need FLVCR both to prevent heme toxicity and to preserve adequate heme supply. Homozygous conditional inactivation of FLVCR in the murine bone marrow causes a macrocytic anemia, reticulocytopenia, and maturation arrest at the pro-erythroblast stage, phenocopying the hematologic phenotype in DBA patients.…”

Section: Balance Of Heme and Globinmentioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

698

726

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Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, SchwachmanDiamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q؊ syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases. Identification of ribosomal abnormalities in human diseaseIn 1999, Draptchinskaia et al reported recurrent mutations in a ribosomal protein gene, RPS19, in patients with Diamond-Blackfan anemia (DBA), a rare congenital bone marrow failure syndrome with a striking erythroid defect. 1 Since that initial discovery, mutations in a number of ribosomal proteins have been identified in up to 50% of patients with DBA. Moreover, other congenital syndromes have been linked to defective ribosome biogenesis, including Schwachman-Diamond syndrome (SDS), X-linked dyskeratosis congenita (DKC), cartilage hair hypoplasia (CHH), and Treacher Collins syndrome (TCS). 2 In the 5qϪ syndrome, a subtype of adult myelodysplastic syndrome, acquired haploinsufficiency for RPS14 resulting from an interstitial chromosomal deletion causes a severe refractory anemia. 3 Each of these disorders is associated with specific defects in ribosome biogenesis, which cause distinct clinical phenotypes, most often involving bone marrow failure and/or craniofacial or other skeletal defects. The disorders of ribosome dysfunction have become collectively known as ribosomopathies. Overview of ribosome biogenesisThe eukaryotic ribosome is composed of 40S and 60S subunits, which associate to form the translationally active 80S ribosome. This process requires the coordinated synthesis of 4 ribosomal RNAs (rRNAs), approximately 80 core ribosomal proteins, more than 150 associated proteins, and approximately 70 small nucleolar RNAs (snoRNAs). 4,5 The 40S subunit contains 18S rRNA and the 60S subunit contains 28S, 5.8S, and 5S rRNAs. In eukaryotes, assembly of rRNA and ribosomal proteins, along with assoc...

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“…The Feline Leukemia Virus subgroup C receptor (FLVCR or FLVCR1) is the first heme transporter identified in eukaryotes [71]. Two isoforms of FLVCR1, FLVCR1a and FLVCR1b, may play distinct roles in mammalian heme homeostasis.…”

Section: Heme Exportmentioning

confidence: 99%

“…Two isoforms of FLVCR1, FLVCR1a and FLVCR1b, may play distinct roles in mammalian heme homeostasis. FLVCR1a is a heme exporter [71], whereas FLVCR1b may be an intracellular heme transporter [74]. In macrophages of the reticuloendothelial system, FLVCR1a exports heme that is derived from ingested senescent red blood cells [72].…”

Section: Heme Exportmentioning

confidence: 99%

Regulation of heme biosynthesis and transport in metazoa

Sun

Cheng

Chen

2015

Sci. China Life Sci.

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Heme is an iron-containing tetrapyrrole that plays a critical role in regulating a variety of biological processes including oxygen and electron transport, gas sensing, signal transduction, biological clock, and microRNA processing. Most metazoan cells synthesize heme via a conserved pathway comprised of eight enzyme-catalyzed reactions. Heme can also be acquired from food or extracellular environment. Cellular heme homeostasis is maintained through the coordinated regulation of synthesis, transport, and degradation. This review presents the current knowledge of the synthesis and transport of heme in metazoans and highlights recent advances in the regulation of these pathways. heme, iron, synthesis, transport, regulation Citation:Sun FX, Cheng YJ, Chen CY. Regulation of heme biosynthesis and transport in metazoa.

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Identification of a Human Heme Exporter that Is Essential for Erythropoiesis

Cited by 380 publications

References 44 publications

Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice

Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice

Ribosomopathies: human disorders of ribosome dysfunction

Regulation of heme biosynthesis and transport in metazoa

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