Divalent transition metal (iron and manganese) transporter involved in iron metabolism and host resistance to certain pathogens. Macrophage-specific membrane transport function. Controls natural resistance to infection with intracellular parasites. Pathogen resistance involves sequestration of Fe(2+) and Mn(2+), cofactors of both prokaryotic and eukaryotic catalases and superoxide dismutases, not only to protect the macrophage against its own generation of reactive oxygen species, but to deny the cations to the pathogen for synthesis of its protective enzymes.
CuratedUniProtKB
According to TCDB this is a transporter from family:
metal ion (Mn2+-iron) transporter (Nramp) family 2.A.55.2.3
Catalysis of the transfer of a solute or solutes from one side of a membrane to the other according to the reaction: metal ion(in) + H+(out) = metal ion(out) + H+(in).
Evidence
1:
Inferred from Genetic InteractionBHF-UCL
Slc11a1 (formerly Nramp1) is a proton/divalent cation transporter that regulates cation homeostasis in macrophages. Slc11a2 mediates divalent cation uptake via the gut and delivery into cells. The mode of action of the two transporters remains controversial. Heterologous expression in frog oocytes shows Slc11a2 is a symporter, whereas Slc11a1 is an antiporter fluxing divalent cations against the proton gradient. This explains why Slc11a2, but not Slc11a1, can complement EGTA sensitivity in smf1Delta/smf2Delta/smf3Delta yeast. However, some studies of transport in mammalian cells suggest Slc11a1 is a symporter. We now demonstrate that Slc11a1, but not Slc11a2, complements a divalent cation stress phenotype in bsd2Delta/rer1Delta yeast. This is the first description of a yeast complementation assay for Slc11a1 function. Given the prior demonstration in frog oocytes that Slc11a1 acts as an antiporter, the most plausible interpretation of the data is that Slc11a1 is rescuing bsd2Delta/rer1Delta yeast by exporting divalent cations. Chimaeras define the N terminus, and a segment of the protein core preceding transmembrane domain 9 through transmembrane domain 12, as important in rescuing the divalent cation stress phenotype. EGTA sensitivity and divalent cation stress phenotypes in yeast expressing Slc11a orthologues show that symport activity is ancestral. Molecular changes that mediate rescue of the divalent cation stress phenotype post-date frogs and co-evolved with Slc11a1 orthologues that regulate divalent cation homeostasis in macrophages and resistance to infection in chickens and mammals.
Natural resistance-associated macrophage protein gene (Nramp) was isolated from the gene locus Lsh/Ity/Bcg, which regulates macrophage activation for antimicrobial activity against intracellular pathogens. The deduced protein sequence encodes an integral membrane protein that has structural homology with known prokaryotic and eukaryotic transport systems. In the present study, a polyclonal antibody was raised with the synthetic peptide of the carboxy-terminal 17 amino acids of human Nramp. The protein product of the gene is apparently present in human peripheral blood lymphocyte (PBL) as a 60 kD a protein recognized by the antibody, which is consistent with the calculated molecular mass. Bacterial lipopolysaccharide or interferon-gamma did not appear to stimulate the level of Nramp expression in PBL.
Catalysis of the transfer of transition metal ions from one side of a membrane to the other. A transition metal is an element whose atom has an incomplete d-subshell of extranuclear electrons, or which gives rise to a cation or cations with an incomplete d-subshell. Transition metals often have more than one valency state. Biologically relevant transition metals include vanadium, manganese, iron, copper, cobalt, nickel, molybdenum and silver.
Evidence
1:
Inferred from Genetic InteractionBHF-UCL
Slc11a1 (formerly Nramp1) is a proton/divalent cation transporter that regulates cation homeostasis in macrophages. Slc11a2 mediates divalent cation uptake via the gut and delivery into cells. The mode of action of the two transporters remains controversial. Heterologous expression in frog oocytes shows Slc11a2 is a symporter, whereas Slc11a1 is an antiporter fluxing divalent cations against the proton gradient. This explains why Slc11a2, but not Slc11a1, can complement EGTA sensitivity in smf1Delta/smf2Delta/smf3Delta yeast. However, some studies of transport in mammalian cells suggest Slc11a1 is a symporter. We now demonstrate that Slc11a1, but not Slc11a2, complements a divalent cation stress phenotype in bsd2Delta/rer1Delta yeast. This is the first description of a yeast complementation assay for Slc11a1 function. Given the prior demonstration in frog oocytes that Slc11a1 acts as an antiporter, the most plausible interpretation of the data is that Slc11a1 is rescuing bsd2Delta/rer1Delta yeast by exporting divalent cations. Chimaeras define the N terminus, and a segment of the protein core preceding transmembrane domain 9 through transmembrane domain 12, as important in rescuing the divalent cation stress phenotype. EGTA sensitivity and divalent cation stress phenotypes in yeast expressing Slc11a orthologues show that symport activity is ancestral. Molecular changes that mediate rescue of the divalent cation stress phenotype post-date frogs and co-evolved with Slc11a1 orthologues that regulate divalent cation homeostasis in macrophages and resistance to infection in chickens and mammals.
The process in which an antigen-presenting cell expresses peptide antigen in association with an MHC protein complex on its cell surface, including proteolysis and transport steps for the peptide antigen both prior to and following assembly with the MHC protein complex. The peptide antigen is typically, but not always, processed from an endogenous or exogenous protein.
Slc11a1 (formerly Nramp1) is a proton/divalent cation transporter that regulates cation homeostasis in macrophages. Slc11a2 mediates divalent cation uptake via the gut and delivery into cells. The mode of action of the two transporters remains controversial. Heterologous expression in frog oocytes shows Slc11a2 is a symporter, whereas Slc11a1 is an antiporter fluxing divalent cations against the proton gradient. This explains why Slc11a2, but not Slc11a1, can complement EGTA sensitivity in smf1Delta/smf2Delta/smf3Delta yeast. However, some studies of transport in mammalian cells suggest Slc11a1 is a symporter. We now demonstrate that Slc11a1, but not Slc11a2, complements a divalent cation stress phenotype in bsd2Delta/rer1Delta yeast. This is the first description of a yeast complementation assay for Slc11a1 function. Given the prior demonstration in frog oocytes that Slc11a1 acts as an antiporter, the most plausible interpretation of the data is that Slc11a1 is rescuing bsd2Delta/rer1Delta yeast by exporting divalent cations. Chimaeras define the N terminus, and a segment of the protein core preceding transmembrane domain 9 through transmembrane domain 12, as important in rescuing the divalent cation stress phenotype. EGTA sensitivity and divalent cation stress phenotypes in yeast expressing Slc11a orthologues show that symport activity is ancestral. Molecular changes that mediate rescue of the divalent cation stress phenotype post-date frogs and co-evolved with Slc11a1 orthologues that regulate divalent cation homeostasis in macrophages and resistance to infection in chickens and mammals.
Slc11a1 (formerly Nramp1) is a proton/divalent cation transporter that regulates cation homeostasis in macrophages. Slc11a2 mediates divalent cation uptake via the gut and delivery into cells. The mode of action of the two transporters remains controversial. Heterologous expression in frog oocytes shows Slc11a2 is a symporter, whereas Slc11a1 is an antiporter fluxing divalent cations against the proton gradient. This explains why Slc11a2, but not Slc11a1, can complement EGTA sensitivity in smf1Delta/smf2Delta/smf3Delta yeast. However, some studies of transport in mammalian cells suggest Slc11a1 is a symporter. We now demonstrate that Slc11a1, but not Slc11a2, complements a divalent cation stress phenotype in bsd2Delta/rer1Delta yeast. This is the first description of a yeast complementation assay for Slc11a1 function. Given the prior demonstration in frog oocytes that Slc11a1 acts as an antiporter, the most plausible interpretation of the data is that Slc11a1 is rescuing bsd2Delta/rer1Delta yeast by exporting divalent cations. Chimaeras define the N terminus, and a segment of the protein core preceding transmembrane domain 9 through transmembrane domain 12, as important in rescuing the divalent cation stress phenotype. EGTA sensitivity and divalent cation stress phenotypes in yeast expressing Slc11a orthologues show that symport activity is ancestral. Molecular changes that mediate rescue of the divalent cation stress phenotype post-date frogs and co-evolved with Slc11a1 orthologues that regulate divalent cation homeostasis in macrophages and resistance to infection in chickens and mammals.
Hypoxia-inducible factor (HIF) is a transcription factor with major roles in many cellular and systemic responses to hypoxia. Activation of HIF pathways under hypoxia is mediated by suppression of the Fe(2+)- and O(2)-dependent HIF hydroxylase enzymes that normally inactivate HIFalpha subunits. Mechanisms underlying induction of HIF in normoxic conditions are less clearly understood. In human cancers, infiltrating macrophages show up-regulation of HIF and it has recently been shown that normoxic expression of HIF-1alpha is essential for macrophage function. Here, we report studies of HIF-1alpha induction following phorbol-12-myristate 13-acetate (PMA)-induced differentiation of monocytic U937 and THP1 cells. HIF-1alpha was markedly up-regulated under normoxia in this setting and this involved failure of HIF-1alpha prolyl hydroxylation despite the presence of O(2). Fluorescence measurements showed that differentiation was associated with marked reduction of the labile iron pool. Both the reduction in labile iron pool and the up-regulation of HIF-1alpha were suppressed by RNA interference-mediated down-regulation of the iron transporter natural resistance-associated macrophage protein 1. Up-regulation of HIF-1alpha following PMA-induced differentiation was also abolished by addition of Fe(2+) or ascorbate. These results indicate that physiologic changes in macrophage iron metabolism have an important effect on HIF hydroxylase pathways and suggest means by which the system could be manipulated for therapeutic benefit.
Slc11a1 (formerly Nramp1) is a proton/divalent cation transporter that regulates cation homeostasis in macrophages. Slc11a2 mediates divalent cation uptake via the gut and delivery into cells. The mode of action of the two transporters remains controversial. Heterologous expression in frog oocytes shows Slc11a2 is a symporter, whereas Slc11a1 is an antiporter fluxing divalent cations against the proton gradient. This explains why Slc11a2, but not Slc11a1, can complement EGTA sensitivity in smf1Delta/smf2Delta/smf3Delta yeast. However, some studies of transport in mammalian cells suggest Slc11a1 is a symporter. We now demonstrate that Slc11a1, but not Slc11a2, complements a divalent cation stress phenotype in bsd2Delta/rer1Delta yeast. This is the first description of a yeast complementation assay for Slc11a1 function. Given the prior demonstration in frog oocytes that Slc11a1 acts as an antiporter, the most plausible interpretation of the data is that Slc11a1 is rescuing bsd2Delta/rer1Delta yeast by exporting divalent cations. Chimaeras define the N terminus, and a segment of the protein core preceding transmembrane domain 9 through transmembrane domain 12, as important in rescuing the divalent cation stress phenotype. EGTA sensitivity and divalent cation stress phenotypes in yeast expressing Slc11a orthologues show that symport activity is ancestral. Molecular changes that mediate rescue of the divalent cation stress phenotype post-date frogs and co-evolved with Slc11a1 orthologues that regulate divalent cation homeostasis in macrophages and resistance to infection in chickens and mammals.
The immediate defensive reaction (by vertebrate tissue) to infection or injury caused by chemical or physical agents. The process is characterized by local vasodilation, extravasation of plasma into intercellular spaces and accumulation of white blood cells and macrophages.
The appearance of interleukin-2 due to biosynthesis or secretion following a cellular stimulus, resulting in an increase in its intracellular or extracellular levels.
The appearance of interleukin-3 due to biosynthesis or secretion following a cellular stimulus, resulting in an increase in its intracellular or extracellular levels.
Hypoxia-inducible factor (HIF) is a transcription factor with major roles in many cellular and systemic responses to hypoxia. Activation of HIF pathways under hypoxia is mediated by suppression of the Fe(2+)- and O(2)-dependent HIF hydroxylase enzymes that normally inactivate HIFalpha subunits. Mechanisms underlying induction of HIF in normoxic conditions are less clearly understood. In human cancers, infiltrating macrophages show up-regulation of HIF and it has recently been shown that normoxic expression of HIF-1alpha is essential for macrophage function. Here, we report studies of HIF-1alpha induction following phorbol-12-myristate 13-acetate (PMA)-induced differentiation of monocytic U937 and THP1 cells. HIF-1alpha was markedly up-regulated under normoxia in this setting and this involved failure of HIF-1alpha prolyl hydroxylation despite the presence of O(2). Fluorescence measurements showed that differentiation was associated with marked reduction of the labile iron pool. Both the reduction in labile iron pool and the up-regulation of HIF-1alpha were suppressed by RNA interference-mediated down-regulation of the iron transporter natural resistance-associated macrophage protein 1. Up-regulation of HIF-1alpha following PMA-induced differentiation was also abolished by addition of Fe(2+) or ascorbate. These results indicate that physiologic changes in macrophage iron metabolism have an important effect on HIF hydroxylase pathways and suggest means by which the system could be manipulated for therapeutic benefit.
Prevention of degradation of mRNA molecules. In the absence of compensating changes in other processes, the slowing of mRNA degradation can result in an overall increase in the population of active mRNA molecules.
An endocytosis process that results in the engulfment of external particulate material by phagocytes. The particles are initially contained within phagocytic vacuoles (phagosomes), which then fuse with primary lysosomes to effect digestion of the particles.
Any process that increases the frequency, rate or extent of gene expression. Gene expression is the process in which a gene's coding sequence is converted into a mature gene product or products (proteins or RNA). This includes the production of an RNA transcript as well as any processing to produce a mature RNA product or an mRNA (for protein-coding genes) and the translation of that mRNA into protein. Some protein processing events may be included when they are required to form an active form of a product from an inactive precursor form.
Any process that activates or increases the frequency, rate, or extent of interferon-gamma production. Interferon-gamma is also known as type II interferon.
A protein transport process that contributes to protein import into the nucleus, and that results in the vectorial transfer of a cargo-carrier protein complex through the nuclear pore complex from the cytoplasmic side to the nucleoplasmic side of the nuclear envelope.
A phase of elevated metabolic activity, during which oxygen consumption increases; this leads to the production, by an NADH dependent system, of hydrogen peroxide (H2O2), superoxide anions and hydroxyl radicals.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus from a bacterium.
Am. J. Hum. Genet. 56, 845-853 (1995)[PubMed:7717395]
The most common mycobacterial disease in humans is tuberculosis, and there is evidence for genetic factors in susceptibility to tuberculosis. In the mouse, the Bcg gene controls macrophage priming for activation and is a major gene for susceptibility to infection with mycobacteria. A candidate gene for Bcg was identified by positional cloning and was designated "natural resistance-associated macrophage protein gene" (Nramp1), and the human homologue (NRAMP1) has recently been cloned. Here we report on (1) the physical mapping of NRAMP1 close to VIL in chromosome region 2q35 by PCR analysis of somatic cell hybrids and YAC cloning and (2) the identification of nine sequence variants in NRAMP1. Of the four variants in the coding region, there were two missense mutations and two silent substitutions. The missense mutations were a conservative alanine-to-valine substitution at codon 318 in exon 9 and an aspartic acid-to-asparagine substitution at codon 543 in the predicted cytoplasmic tail of the NRAMP1 protein. A microsatellite was located in the immediate 5' region of the gene, three variants were in introns, and one variant was located in the 3' UTR. The allele frequencies of each of the nine variants were determined in DNA samples of 60 Caucasians and 20 Asians. In addition, we have physically linked two highly polymorphic microsatellite markers, D2S104 and D2S173, to NRAMP1 on a 1.5-Mb YAC contig. These molecular markers will be useful to assess the role of NRAMP1 is susceptibility to tuberculosis and other macrophage-mediated diseases.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an interferon-gamma stimulus. Interferon-gamma is also known as type II interferon.
Any process that results in a change in state or activity of an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a lipopolysaccharide stimulus; lipopolysaccharide is a major component of the cell wall of gram-negative bacteria.
Protein involved in the transport of ions. Such proteins are usually transmembrane and mediate a movement of ions across cell membranes. Transport may be passive (facilitated diffusion; down the electrochemical gradient), or active (against the electrochemical gradient). Active transport requires energy which may come from light, oxidation reactions, ATP hydrolysis, or cotransport of other ions or molecules.
Protein involved in the transport of a molecule (metabolite, protein, etc), a ion or an electron across cell membranes, inside the cell or in a tissue fluid.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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