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J. Exp. Med.,
Volume 189, Number 5, March 1, 1999 831-841
By
From the * Department of Biochemistry and Center for Host Resistance, McGill University, Montreal,
Quebec, Canada H3G 1Y6; and 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.
Division of Cell Biology, The Hospital for Sick Children, Toronto,
Ontario, Canada M5G 1X8
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