The Fowler Syndrome-Associated Protein FLVCR2 Is an Importer of Heme
- 1 November 2010
- journal article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 30 (22), 5318-5324
- https://doi.org/10.1128/mcb.00690-10
Abstract
Mutations in FLVCR2, a cell surface protein related by homology and membrane topology to the heme exporter/retroviral receptor FLVCR1, have recently been associated with Fowler syndrome, a vascular disorder of the brain. We previously identified FLVCR2 to function as a receptor for FY981 feline leukemia virus (FeLV). However, the cellular function of FLVCR2 remains unresolved. Here, we report the cellular function of FLVCR2 as an importer of heme, based on the following observations. First, FLVCR2 binds to hemin-conjugated agarose, and binding is competed by free hemin. Second, mammalian cells and Xenopus laevis oocytes expressing FLVCR2 display enhanced heme uptake. Third, heme import is reduced after the expression of FLVCR2-specific small interfering RNA (siRNA) or after the binding of the FY981 FeLV envelope protein to the FLVCR2 receptor. Finally, cells overexpressing FLVCR2 are more sensitive to heme toxicity, a finding most likely attributable to enhanced heme uptake. Tissue expression analysis indicates that FLVCR2 is expressed in a broad range of human tissues, including liver, placenta, brain, and kidney. The identification of a cellular function for FLVCR2 will have important implications in elucidating the pathogenic mechanisms of Fowler syndrome and of phenotypically associated disorders.This publication has 61 references indexed in Scilit:
- Bone loss caused by iron overload in a murine model: importance of oxidative stressBlood, 2010
- Mutations in FLVCR2 Are Associated with Proliferative Vasculopathy and Hydranencephaly-Hydrocephaly Syndrome (Fowler Syndrome)American Journal of Human Genetics, 2010
- Identification of a Feline Leukemia Virus Variant That Can Use THTR1, FLVCR1, and FLVCR2 for InfectionJournal of Virology, 2009
- The Transporter Classification Database: recent advancesNucleic Acids Research, 2009
- A Heme Export Protein Is Required for Red Blood Cell Differentiation and Iron HomeostasisScience, 2008
- Genome-wide atlas of gene expression in the adult mouse brainNature, 2006
- Identification of a Human Heme Exporter that Is Essential for ErythropoiesisCell, 2004
- Disruption of a novel MFS transporter gene, DIRC2, by a familial renal cell carcinoma-associated t(2;3)(q35;q21)Human Molecular Genetics, 2002
- Receptors and Entry Cofactors for Retroviruses Include Single and Multiple Transmembrane-Spanning Proteins as well as Newly Described Glycophosphatidylinositol-Anchored and Secreted ProteinsMicrobiology and Molecular Biology Reviews, 2001
- Retrovirus-induced feline pure red cell aplasia. Hematopoietic progenitors are infected with feline leukemia virus and erythroid burst-forming cells are uniquely sensitive to heterologous complement.JCI Insight, 1987