The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/3/831/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 5, March 1, 1999 831-841

Articles

The Iron Transport Protein NRAMP2 Is an Integral Membrane Glycoprotein That Colocalizes with Transferrin in Recycling Endosomes

Samantha Gruenheid*, François Canonne-Hergaux*, Susan Gauthier*, David J. Hackam{ddagger}, Sergio Grinstein{ddagger}, and Philippe Gros*

From the * Department of Biochemistry and Center for Host Resistance, McGill University, Montreal, Quebec, Canada H3G 1Y6; and {ddagger} Division of Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8

The natural resistance associated macrophage protein (Nramp) gene family is composed of two members in mammals, Nramp1 and Nramp2. Nramp1 is expressed primarily in macrophages and mutations at this locus cause susceptibility to infectious diseases. Nramp2 has a much broader range of tissue expression and mutations at Nramp2 result in iron deficiency, indicating a role for Nramp2 in iron metabolism. To get further insight into the function and mechanism of action of Nramp proteins, we have generated isoform specific anti-Nramp1 and anti-Nramp2 antisera. Immunoblotting experiments indicate that Nramp2 is present in a number of cell types, including hemopoietic precursors, and is coexpressed with Nramp1 in primary macrophages and macrophage cell lines. Nramp2 is expressed as a 90–100-kD integral membrane protein extensively modified by glycosylation (>40% of molecular mass). Subcellular localization studies by immunofluorescence and confocal microscopy indicate distinct and nonoverlapping localization for Nramp1 and Nramp2. Nramp1 is expressed in the lysosomal compartment, whereas Nramp2 is not detectable in the lysosomes but is expressed primarily in recycling endosomes and also, to a lower extent, at the plasma membrane, colocalizing with transferrin. These findings suggest that Nramp2 plays a key role in the metabolism of transferrin-bound iron by transporting free Fe2+ across the endosomal membrane and into the cytoplasm.

Key Words: iron • anemia • transport • infection • macrophage

Address correspondence to Philippe Gros, Department of Biochemistry, McGill University, 3655 Drummond, Rm. 907, Montreal, Quebec, Canada, H3G-1Y6. Phone: 514-398-7291; Fax: 514-398-2603; E-mail: gros{at}med.mcgill.ca

1 Abbreviations used in this paper: CHO, Chinese hamster ovary; CHON, Nramp-transfected CHO cells; Endo H, Endo-β-acetylglucosaminidase H; GST, glutathione S-transferase; MEL, erythroleukemia; Nramp, natural resistance associated macrophage protein; TM, transmembrane.


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