Slc11a1/SLC11A1 (formerly Nramp1/NRAMP1)
Genetic and functional characterization of murine and human
Slc11a1/SCL11A1 (formerly Nramp1/NRAMP1)encoding the natural resistance associated macrophage protein has been a
major focus of our research. The gene encodes a polytopic integral membrane protein with 10-12 membrane spanning
domains. Confocal and EM-gold studies demonstrate that wildtype Slc11a1 localizes to late endosomes/lysosomes of
macrophages. Using GFP-tagged proteins we have demonstrated using transient and stable transfection that the murine
mutant protein that carries a Gly/Asp amino acid substitution at position 169 in putative transmembrane domain 4
is retained and degraded in the ER.
We are also tracking down the motifs in Slc11a1 and the two isoforms of the
related protein Slc11a2 that act as localization signals to target them to late endosomal/lysosomal versus early
endosomal compartments. We used the Xenopus oocyte expression system to demonstrate that Slc11a1 is a H+/Fe2+,Zn2+,
Mn2+ antiporter. We are currently working to establish a functional yeast complementation assay so that we can use
mutagenesis to gain a better understanding of the transport function of the molecule, and to determine the key
amino acids that make Slc11a1 an antiporter while Slc11a2 is a symporter. The action of Slc11a1 as a divalent
cation transporter influences antigen processing for presentation via class II, endosomal fusion, resistance to
infection, response to vaccination, and susceptibility to rheumatoid and juvenile rheumatoid arthritis.