Trends in Microbiology
Volume 9, Issue 8, 1 August 2001, Pages 397-403
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Review
Divalent-metal transport by NRAMP proteins at the interface of host–pathogen interactions

https://doi.org/10.1016/S0966-842X(01)02098-4Get rights and content

Abstract

The NRAMP family of divalent-metal transporters plays a key role in the homeostasis of iron and other metals. NRAMP2 (DMT1) acts as an iron-uptake protein in both the duodenum and in peripheral tissues. NRAMP1 functions as a divalent-metal efflux pump at the phagosomal membrane of macrophages and neutrophils, and mutations in NRAMP1 cause susceptibility to several intracellular pathogens. NRAMP homologues have been identified in bacteria and are involved in acquiring divalent metals from the extracellular environment. Interestingly, bacterial and mammalian NRAMP proteins would compete for the same essential substrates within the microenvironment of the phagosome, at the interface of host–pathogen interactions.

Section snippets

Nramp1 expression in phagocytes

In mice, Nramp1 mRNA is expressed in primary macrophages and in granulocytic lineages 2. In the mouse RAW264.7 macrophage cell line, the expression of Nramp1 mRNA is strongly induced by treatment with lipopolysaccharide and interferon (IFN)-γ, and also by exposure to inflammatory stimuli 10. Studies in human primary cells indicate that NRAMP1 mRNA is expressed in granulocytes and monocytes, and migration of immature macrophages to tissues is associated with an increase in NRAMP1 expression 7.

A family of divalent-metal transporters

NRAMP1 is not an isolated gene but a member of a very large gene family, the structure and function of which have been remarkably conserved throughout evolution. In humans and rodents, a second NRAMP gene (NRAMP2, OMIM No. 600523; now designated SLC11A2, but referred to here as NRAMP2) has been identified, and the corresponding protein shares 64% amino acid sequence identity (78% overall similarity) with NRAMP1 (Refs 15, 16). As opposed to its monocyte/macrophage-specific NRAMP1 counterpart,

NRAMP2 is a transferrin-independent iron transporter

Functionally, NRAMP2 (divalent metal transporter 1, DMT1) is the best characterized member of the NRAMP family. In mice and rats, Nramp2 mRNA 15, 16 and protein 38 is expressed in multiple tissues but expression levels are highest in the duodenum and kidney. The expression of Nramp2 mRNA and protein is drastically upregulated by deprivation of dietary iron, resulting in strong expression at the duodenum brush border 39. Iron-dependent regulation of Nramp2 appears to occur through

Divalent-metal transport by NRAMP1 at the phagosomal membrane

A possible role for NRAMP1 in the transport of divalent metals has been investigated. In one study, dietary iron loading of Bcgr mice was found to increase M. avium replication in vivo 48. This finding was interpreted as excess iron overwhelming the NRAMP1 advantage, indirectly suggesting NRAMP1-mediated iron transport is important in anti-mycobacterial host defences. Conversely, Zwilling et al. reported that addition of extracellular iron, over a very narrow concentration range (0.005–0.05

Nramp homologues in bacteria

The recent sequencing of many bacterial genomes has revealed the presence of Nramp homologues in bacteria, including human pathogens such as Mycobacteria, Salmonella and many Gram-positive bacteria 57. These Nramp homologues (given the temporary designation MntH) have been cloned from 15 genera of bacteria, including green sulfur, Thermus spp., Gram-negative and Gram-positive bacteria. These sequences show 26–29% sequence identity (overall similarity of 40–45%) with each other and with their

Conclusion and perspectives

How does the removal of divalent metals from the phagosomal lumen by NRAMP1 contribute to defence against invading organisms? The short answer is that this process is not yet well understood; however, several non-mutually exclusive hypotheses can be made based on available data. Divalent metals such as Zn2+, Cu2+, Fe2+ and Mn2+ (all potential substrates for NRAMP proteins) are essential micronutrients for all life forms as they are cofactors in many enzymatic reactions. Therefore, depletion of

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