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Gene Review

Slc11a1  -  solute carrier family 11 (proton-coupled...

Mus musculus

Synonyms: Bcg, Ity, Lsh, NRAMP 1, Natural resistance-associated macrophage protein 1, ...
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Disease relevance of Slc11a1


Psychiatry related information on Slc11a1

  • We propose that acquisition of SPI2 by S. enterica not only enabled this bacterium to become an effective intracellular pathogen but also allowed the bacterium to withstand the effects of macrophage defense mechanisms such as Nramp1 early in the evolution of its pathogenic character [6].

High impact information on Slc11a1


Chemical compound and disease context of Slc11a1


Biological context of Slc11a1

  • During macrophage activation, Slc11a1 exerts pleiotropic effects on gene regulation and function, including generation of nitric oxide (NO) via inducible NO synthase (iNOS; encoded by Nos2A) and of reactive oxygen intermediates (ROI) via the phagocyte oxidase complex [13].
  • All together, these results are consistent with an impact of Slc11a1 on Th cell differentiation during chronic S. enterica serovar Enteritidis infection [1].
  • Kinetics of infection in 129S6 mice and Slc11a1-deficient (129S6-Slc11a1(tm1Mcg)) mice demonstrated that the wild-type allele of Slc11a1 contributed to the S. enterica serovar Enteritidis carrier state as early as 7 days postinfection [1].
  • We propose that the G169D mutation causes localized misfolding of Slc11a1, resulting in its retention in the ER and manifestation of the loss of function phenotype [3].
  • Correct endosomal targeting of wild-type Slc11a1 continued despite disruption of N-glycosylation sites, indicating that glycosylation did not influence folding or sorting [3].

Anatomical context of Slc11a1

  • Here, we show that S. typhimurium can persist for as long as 1 yr in the mesenteric lymph nodes (MLNs) of 129sv Nramp1(+)(/)(+) (Slc11a1(+)(/)(+)) mice despite the presence of high levels of anti-S. typhimurium antibody [14].
  • In the present study the role of Slc11a1 in iron turnover is examined in macrophages transfected with Slc11a1(Gly169) (wild-type) or Slc11a1(Asp169) (mutant=functional null) alleles [15].
  • Slc11a1-mediated resistance to Salmonella enterica serovar Typhimurium and Leishmania donovani infections does not require functional inducible nitric oxide synthase or phagocyte oxidase activity [13].
  • We found occasional late endosome/lysosome staining of mutant protein using immunoelectron microscopy, but most of the mutant Slc11a1 was retained within the ER (endoplasmic reticulum) [3].
  • We used the murine macrophage cell line RAW264.7, stably transfected with functional (RAW-37) or nonfunctional (RAW-21) Nramp1, to study for differences in the expression of NO, a central antimicrobial effector molecule of macrophages [16].

Associations of Slc11a1 with chemical compounds


Physical interactions of Slc11a1


Co-localisations of Slc11a1

  • Gold labelling and electron microscopy defines these compartments more precisely as electron-lucent late endosomal and electron-dense lysosomal compartments, with Nramp1 colocalizing with Lamp1 and cathepsins D and L in both compartments, with macrosialin in late endosomes, and with BSA-5 nm gold in pre-loaded lysosomes [22].

Regulatory relationships of Slc11a1

  • Functional gp91phox and iNOS are required to control S. enterica serovar Typhimurium in non-Slc11a1-regulated phases of infection [13].
  • Taken together, these results suggest for the first time that Nramp1 controls macrophage SLPI mRNA and protein expression, and can also have an important effect on the kinetics of wound healing [23].
  • Ity influences the production of IFN-gamma by murine splenocytes stimulated in vitro with Salmonella typhimurium [24].
  • We investigated if c-Myc also regulates Nramp1 expression [25].
  • Induction of Nramp2 in activated mouse macrophages is dissociated from regulation of the Nramp1, classical inflammatory genes, and genes involved in iron metabolism [26].

Other interactions of Slc11a1

  • Delayed cutaneous wound healing in mice lacking solute carrier 11a1 (formerly Nramp1): correlation with decreased expression of secretory leukocyte protease inhibitor [23].
  • In contrast to the previously described macrophage-specific Nramp gene, Nramp2 mRNAs were found to be expressed at low levels in all tissues tested [27].
  • Two of these new marker genes were found very tightly linked to Bcg: Des was located 0.3 +/- 0.3 cM distal from (Vil,Bcg) and 0.3 +/- 0.3 cM proximal to Inha [28].
  • In conclusion, presence of MHCII, but not Tlr4 or Slc11a1 significantly influences prevalence of naturally acquired infection with S. obvelata [29].
  • The presence of a Th2 bias in Slc11a1-deficient mice is associated with improved bacterial clearance [1].

Analytical, diagnostic and therapeutic context of Slc11a1


  1. Influence of Slc11a1 on the outcome of Salmonella enterica serovar Enteritidis infection in mice is associated with Th polarization. Caron, J., Larivière, L., Nacache, M., Tam, M., Stevenson, M.M., McKerly, C., Gros, P., Malo, D. Infect. Immun. (2006) [Pubmed]
  2. Disruption of the Nramp1 (also known as Slc11a1) gene in Kupffer cells attenuates early-phase, warm ischemia-reperfusion injury in the mouse liver. Wyllie, S., Seu, P., Gao, F.Q., Gros, P., Goss, J.A. J. Leukoc. Biol. (2002) [Pubmed]
  3. Incomplete glycosylation and defective intracellular targeting of mutant solute carrier family 11 member 1 (Slc11a1). White, J.K., Stewart, A., Popoff, J.F., Wilson, S., Blackwell, J.M. Biochem. J. (2004) [Pubmed]
  4. A mutation in the Icsbp1 gene causes susceptibility to infection and a chronic myeloid leukemia-like syndrome in BXH-2 mice. Turcotte, K., Gauthier, S., Tuite, A., Mullick, A., Malo, D., Gros, P. J. Exp. Med. (2005) [Pubmed]
  5. Genomic structure, promoter sequence, and induction of expression of the mouse Nramp1 gene in macrophages. Govoni, G., Vidal, S., Cellier, M., Lepage, P., Malo, D., Gros, P. Genomics (1995) [Pubmed]
  6. Host-pathogen interactions: Host resistance factor Nramp1 up-regulates the expression of Salmonella pathogenicity island-2 virulence genes. Zaharik, M.L., Vallance, B.A., Puente, J.L., Gros, P., Finlay, B.B. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  7. Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Vidal, S.M., Malo, D., Vogan, K., Skamene, E., Gros, P. Cell (1993) [Pubmed]
  8. Lsh, a member of the SNF2 family, is required for genome-wide methylation. Dennis, K., Fan, T., Geiman, T., Yan, Q., Muegge, K. Genes Dev. (2001) [Pubmed]
  9. Linkage analysis of the Bcg gene on mouse chromosome 1. Identification of a tightly linked marker. Schurr, E., Skamene, E., Forget, A., Gros, P. J. Immunol. (1989) [Pubmed]
  10. Cytokine-mediated activation of macrophages from Mycobacterium bovis BCG-resistant and -susceptible mice: differential effects of corticosterone on antimycobacterial activity and expression of the Bcg gene (Candidate Nramp). Brown, D.H., LaFuse, W., Zwilling, B.S. Infect. Immun. (1995) [Pubmed]
  11. The full expression of the ity phenotype in ityr mice requires C3 activation by Salmonella lipopolysaccharide. Nishikawa, F., Yoshikawa, S., Harada, H., Kita, M., Kita, E. Immunology (1998) [Pubmed]
  12. Distinct ability to accumulate eosinophils during the inflammatory cellular response to M. bovis BCG in the mouse pleural cavity. Werneck-Barroso, E., Moura, A.C., Monteiro, M.M., Menezes de Lima Júnior, O., de Meirelles, M.N., Henriques, M.G. Inflamm. Res. (2000) [Pubmed]
  13. Slc11a1-mediated resistance to Salmonella enterica serovar Typhimurium and Leishmania donovani infections does not require functional inducible nitric oxide synthase or phagocyte oxidase activity. White, J.K., Mastroeni, P., Popoff, J.F., Evans, C.A., Blackwell, J.M. J. Leukoc. Biol. (2005) [Pubmed]
  14. Salmonella typhimurium persists within macrophages in the mesenteric lymph nodes of chronically infected Nramp1+/+ mice and can be reactivated by IFNgamma neutralization. Monack, D.M., Bouley, D.M., Falkow, S. J. Exp. Med. (2004) [Pubmed]
  15. Solute carrier 11a1 (Slc11a1; formerly Nramp1) regulates metabolism and release of iron acquired by phagocytic, but not transferrin-receptor-mediated, iron uptake. Mulero, V., Searle, S., Blackwell, J.M., Brock, J.H. Biochem. J. (2002) [Pubmed]
  16. Nramp1 functionality increases inducible nitric oxide synthase transcription via stimulation of IFN regulatory factor 1 expression. Fritsche, G., Dlaska, M., Barton, H., Theurl, I., Garimorth, K., Weiss, G. J. Immunol. (2003) [Pubmed]
  17. Nramp transfection transfers Ity/Lsh/Bcg-related pleiotropic effects on macrophage activation: influence on oxidative burst and nitric oxide pathways. Barton, C.H., Whitehead, S.H., Blackwell, J.M. Mol. Med. (1995) [Pubmed]
  18. Interaction with extracellular matrix proteins influences Lsh/Ity/Bcg (candidate Nramp) gene regulation of macrophage priming/activation for tumour necrosis factor-alpha and nitrite release. Formica, S., Roach, T.I., Blackwell, J.M. Immunology (1994) [Pubmed]
  19. Genetic regulation of leishmanial and mycobacterial infections: the Lsh/Ity/Bcg gene story continues. Blackwell, J.M., Barton, C.H., White, J.K., Roach, T.I., Shaw, M.A., Whitehead, S.H., Mock, B.A., Searle, S., Williams, H., Baker, A.M. Immunol. Lett. (1994) [Pubmed]
  20. Nramp1: a link between intracellular iron transport and innate resistance to intracellular pathogens. Barton, C.H., Biggs, T.E., Baker, S.T., Bowen, H., Atkinson, P.G. J. Leukoc. Biol. (1999) [Pubmed]
  21. Resistance ranking of some common inbred mouse strains to Mycobacterium tuberculosis and relationship to major histocompatibility complex haplotype and Nramp1 genotype. Medina, E., North, R.J. Immunology (1998) [Pubmed]
  22. Localisation of Nramp1 in macrophages: modulation with activation and infection. Searle, S., Bright, N.A., Roach, T.I., Atkinson, P.G., Barton, C.H., Meloen, R.H., Blackwell, J.M. J. Cell. Sci. (1998) [Pubmed]
  23. Delayed cutaneous wound healing in mice lacking solute carrier 11a1 (formerly Nramp1): correlation with decreased expression of secretory leukocyte protease inhibitor. Thuraisingam, T., Sam, H., Moisan, J., Zhang, Y., Ding, A., Radzioch, D. J. Invest. Dermatol. (2006) [Pubmed]
  24. Ity influences the production of IFN-gamma by murine splenocytes stimulated in vitro with Salmonella typhimurium. Ramarathinam, L., Niesel, D.W., Klimpel, G.R. J. Immunol. (1993) [Pubmed]
  25. c-Myc represses and Miz-1 activates the murine natural resistance-associated protein 1 promoter. Bowen, H., Biggs, T.E., Phillips, E., Baker, S.T., Perry, V.H., Mann, D.A., Barton, C.H. J. Biol. Chem. (2002) [Pubmed]
  26. Induction of Nramp2 in activated mouse macrophages is dissociated from regulation of the Nramp1, classical inflammatory genes, and genes involved in iron metabolism. Wardrop, S.L., Wells, C., Ravasi, T., Hume, D.A., Richardson, D.R. J. Leukoc. Biol. (2002) [Pubmed]
  27. Identification and characterization of a second mouse Nramp gene. Gruenheid, S., Cellier, M., Vidal, S., Gros, P. Genomics (1995) [Pubmed]
  28. The host resistance locus Bcg is tightly linked to a group of cytoskeleton-associated protein genes that include villin and desmin. Malo, D., Schurr, E., Epstein, D.J., Vekemans, M., Skamene, E., Gros, P. Genomics (1991) [Pubmed]
  29. Role of major histocompatibility complex class II in resistance of mice to naturally acquired infection with Syphacia obvelata. Stewart, P.W., Chapes, S.K. Comp. Med. (2003) [Pubmed]
  30. Physical delineation of the minimal chromosomal segment encompassing the murine host resistance locus Bcg. Malo, D., Vidal, S., Lieman, J.H., Ward, D.C., Gros, P. Genomics (1993) [Pubmed]
  31. Cell-specific and inducible Nramp1 gene expression in mouse macrophages in vitro and in vivo. Govoni, G., Gauthier, S., Billia, F., Iscove, N.N., Gros, P. J. Leukoc. Biol. (1997) [Pubmed]
  32. In vivo RNA interference demonstrates a role for Nramp1 in modifying susceptibility to type 1 diabetes. Kissler, S., Stern, P., Takahashi, K., Hunter, K., Peterson, L.B., Wicker, L.S. Nat. Genet. (2006) [Pubmed]
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