Understanding the multiple functions of Nramp1

Nramp1 regulates macrophage activation in infectious and autoimmune disease s. Nramp2 controls anaemia. Both are divalent cation (Fe2+, Zn2+, and Mn2+) transporters; Nramp2 a symporter of H+ and metal ions, Nramp1 a H+/divalen t cation antiporter. This provides a model for metal ion homeostasis in mac rophages. Nramp2, localised to early endosomes, delivers extracellularly ac quired divalent cations into the cytosol. Nramp1, localised to late endosom es/lysosomes, delivers divalent cations from the cytosol to phagolysosomes. Here, Fe2+ generates antimicrobial hydroxyl radicals via the Fenton reacti on. Zn2+ and Mn2+ may also influence endosomal metalloprotease activity and phagolysosome fusion. The many cellular functions dependent on metal ions as cofactors may explain the multiple pleiotropic effects of Nramp1, and it s complex roles in infectious and autoimmune disease. (C) 2000 Editions sci entifiques et medicales Elsevier SAS.