Nramp1 locus encodes a 65 kDa interferon-γ-inducible protein in murine macrophages

Atkinson, P. G. P.; Blackwell, Jenefer M.; Barton, Chris

doi:10.1042/bj3250779

Cited by 79 publications

(55 citation statements)

References 33 publications

(42 reference statements)

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“…Nramp2 transports a range of metal ions including Fe, Mn, Zn, Cd, Cu, and Co with about the same efficiency [13]. In addition, recent reports show that Nramp1 is associated with phagocytic vesicles of the late endocytic pathway [16,17]. Taken together, these results suggest that Nramp1 functions to transport metal ions in or out of the macrophage phagosomes after infection with an intracellular pathogen.…”

Section: Introductionmentioning

confidence: 69%

“…Gruenheid et al [16] reported that in resting macrophages Nramp1 is localized to late endocytic vesicles containing lysosomal-associated membrane protein 1 (Lamp1) that on phagocytosis fuse with the phagosomes. Atkinson et al [17] showed that Nramp1 is associated with endosomal vesicles formed in macrophages by phagocytosis of magnetic IgG-coated beads. A more detailed study by this group using M. avium infection produced similar results [24].…”

Section: Discussionmentioning

confidence: 99%

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Differential iron transport into phagosomes isolated from the RAW264.7 macrophage cell lines transfected with Nramp1Gly169 or Nramp1Asp169

Kuhn

Baker

Lafuse

et al. 1999

Journal of Leukocyte Biology

112

104

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The transport of iron by RAW264.7 macrophage cell lines transfected with either Nramp1 Gly169 (resistant) or Nramp1 Asp169 (susceptible) alleles was assessed. We found no difference between resistant and susceptible cells in the rate of Fe import or export when Fe transport was measured in intact cells. In contrast, the rate of Fe import by latex-bead phagosomes isolated from resistant cells was more than double the rate by latex-bead phagosomes from susceptible cells. Similarly, phagosomes isolated from resistant cells that had been pre-labeled with 55 Fe-citrate before phagocytosis contained up to four times as much Fe as the corresponding phagosomes from susceptible cells. Phagocytosis of Mycobacterium avium was accompanied by an increase in the production of hydroxyl radicals by Nramp1 Gly169 -transfected macrophages but not by macrophages transfected with the susceptible allele. These results are consistent with the hypothesis that Nramp1 functions to transport Fe into the bacterium-containing phagosome where it serves as a catalyst for the Haber-Weiss reaction, which accounts for the increased capacity of these cells to limit mycobacterial growth. J. Leukoc. Biol. 66: 113-119; 1999.

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Section: Introductionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Differential iron transport into phagosomes isolated from the RAW264.7 macrophage cell lines transfected with Nramp1Gly169 or Nramp1Asp169

Kuhn

Baker

Lafuse

et al. 1999

Journal of Leukocyte Biology

112

104

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“…Cells were harvested at intervals for Nramp1 expression determination and for cell growth quantitation. N11 microglial cells that express mature 90-to 100-kDa Nramp1 protein were used for analysis of Nramp1 regulation following serum removal and replacement and were maintained as described previously (9).…”

Section: Methodsmentioning

confidence: 99%

c-Myc Represses and Miz-1 Activates the Murine Natural Resistance-associated Protein 1 Promoter

Bowen¹,

Biggs²,

Phillips³

et al. 2002

Journal of Biological Chemistry

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Iron is essential for growth, and impaired iron homoeostasis through a non-conserved mutation within murine Nramp1, also termed Slc11a1, contributes to susceptibility to infection. Nramp1 depletes the macrophage cytosol of iron, with effects on iron-regulated gene expression and iron-dependent processes. Wu and colleagues (Wu, K.-J., Polack, A., and Dalla-Favera, R. A biallelic phenotype in mouse, termed Ity/Lsh/Bcg, was identified in response to infection by obligate intracellular macrophage pathogens (1-3). Nramp1 1 (also termed Slc11a1) was isolated as the positional gene candidate for Ity/Lsh/Bcg (4). In subsequent studies the full-length sequence of the encoded polypeptide was identified (5). Mouse strains resistant to infection encode Gly at codon 169 within Nramp1 whereas susceptible mice encode Asp (6). The G169D polymorphism is sufficient to explain the outcomes of model infections within inbred mouse strains at pre-T cell stages of infection, as confirmed by gene targeting and transgenesis experiments (7,8).Allele D169 is phenotypically null (7). When Nramp1 was cloned, the biochemical basis for its control over the proliferation of intracellular pathogens was not obvious, but the sequence suggested a transporter function (4). Subsequent studies showed the encoded polytopic integral membrane Nramp1 protein was expressed in a perinuclear location, on intracellular late endosomal/lysosomal membranes (9 -11). Nramp1 underwent rapid recruitment to the periphery of a pathogencontaining vesicle (10, 11) and displayed a more peripheral location in response to treatment with interferon-␥ (11). These observations led to the suggestion that growth control of microbial pathogens could be achieved by the transport of some toxin into the lumen of the phagosome or by the sequestration of some essential nutrient. The identity of a candidate transport substrate was revealed from studies on a highly sequencerelated gene, Nramp2 (DMT1/DCT1/SLC11A2). Nramp2 was initially isolated as an orphan gene (12) but was re-isolated by functional cloning through a divalent cation/iron uptake assay (13). In addition, identical mutations, G185R, within Nramp2 in the mk mouse and the Belgrade rat are associated with impaired intestinal and erythroid cell iron uptake (14). Based on the striking sequence similarity between the two polypeptides (15), Nramp1 was also predicted to transport divalent cations or iron within murine macrophages, and infection susceptibility occurs through impaired divalent cation transport. The many pleiotropic effects attributed to Nramp1 (16) should be explained by differential cation transport. Because Nramp1 protein is expressed within internal membranes, the differential partitioning of divalent cations between the cytosol and the lumen of the internal vesicle should contribute to the pleiotropic effects described (16). Inducible nitric-oxide synthase (iNos) is expressed at quantitatively higher levels in functional-Nramp1 macrophages (17)(18)(19)(20). Ferrous iron provides the link between iNos expressio...

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“…60 Increased iron concentrations increase M. avium growth within macrophages, and when excess iron is present the greater ability of Nramp1 G169/G169 mice compared to Nramp1 D169/D169 mice to limit M. avium replication is overcome. 61 This suggests that Nramp1 may be an iron transporter which is saturated at high iron concentration.…”

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confidence: 99%

Susceptibility to mycobacterial infections: the importance of host genetics

2003

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There is substantial evidence that host genetic factors are important in determining susceptibility to mycobacteria. Several different techniques have been used to identify the genes involved. Studies of an inbred strain of mice with increased susceptibility to mycobacteria, salmonella and leishmania infections led to the identification of the natural resistance-associated macrophage protein gene (Nramp1). Case-control studies have confirmed the importance of the human equivalent of this gene, NRAMP1, and have also suggested that the major histocompatibility complex and vitamin-D receptor genes may be involved in determining human susceptibility to mycobacteria. Studies of individuals with the rare condition of increased susceptibility to disseminated bacille Calmette-Guerin and other atypical mycobacterial infections have identified several abnormalities in the genes encoding the interferon gamma receptor (IFNgR) ligand binding chain, IFNgR signal transduction chain, IFNg signal transduction and activation of transcription-1, interleukin 12 receptor b1 subunit and interleukin 12 p40 subunit. A genome-wide linkage study has been performed to identify genes exerting a major effect on tuberculosis susceptibility in the general population. Linkages were found to markers on chromosomes 15 and X. Studies to identify the genes responsible are in progress.

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Nramp1 locus encodes a 65 kDa interferon-γ-inducible protein in murine macrophages

Cited by 79 publications

References 33 publications

Differential iron transport into phagosomes isolated from the RAW264.7 macrophage cell lines transfected with Nramp1Gly169 or Nramp1Asp169

Differential iron transport into phagosomes isolated from the RAW264.7 macrophage cell lines transfected with Nramp1Gly169 or Nramp1Asp169

c-Myc Represses and Miz-1 Activates the Murine Natural Resistance-associated Protein 1 Promoter

Susceptibility to mycobacterial infections: the importance of host genetics

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