Mycobacterium tuberculosis Expresses a Novel Ph-Dependent Divalent Cation Transporter Belonging to the Nramp Family

doi:10.1084/jem.190.5.717

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© The Rockefeller University Press, 0022-1007/1999/9/717/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 5, September 6, 1999 717-724

Original Article

Mycobacterium tuberculosis Expresses a Novel Ph-Dependent Divalent Cation Transporter Belonging to the Nramp Family

Daniel Agranoff^a, Irene M. Monahan^b, Joseph A. Mangan^b, Philip D. Butcher^b, and Sanjeev Krishna^a

^a From the Department of Infectious Diseases, St. George's Hospital Medical School, London SW17 ORE, United Kingdom
^b From the Department of Medical Microbiology, St. George's Hospital Medical School, London SW17 ORE, United Kingdom
Department of Infectious Diseases, St. George's Hospital Medical School, Cranmer Terrace, London SW20 ORE, UK.181-725-3487181-725-5836

s.krishna{at}sghms.ac.uk

Mammalian natural resistance–associated macrophage protein(Nramp) homologues are important determinants of susceptibilityto infection by diverse intracellular pathogens including mycobacteria.Eukaryotic Nramp homologues transport divalent cations suchas Fe²⁺, Mn²⁺, Zn²⁺, and Cu²⁺. Mycobacterium tuberculosis andMycobacterium bovis (bacillus Calmette-Guérin [BCG])also encode an Nramp homologue (Mramp).

RNA encoding Mramp induces $~$ 20-fold increases in ⁶⁵Zn²⁺ and ⁵⁵Fe²⁺uptake when injected into Xenopus laevis oocytes. Transportis dependent on acidic extracellular pH and is maximal betweenpH 5.5 and 6.5. Mramp-mediated ⁶⁵Zn²⁺ and ⁵⁵Fe²⁺ transport isabolished by an excess of Mn²⁺ and Cu²⁺, confirming that Mrampinteracts with a broad range of divalent transition metal cations.

Using semiquantitative reverse transcription PCR, we show thatMramp mRNA levels in M. tuberculosis are upregulated in responseto increases in ambient Fe²⁺ and Cu²⁺ between <1 and 5 µMconcentrations and that this upregulation occurs in parallelwith mRNA for y39, a putative metal-transporting P-type ATPase.Using a quantitative ratiometric PCR technique, we demonstratea fourfold decrease in Mramp/y39 mRNA ratios from organismsgrown in 5–70 µM Cu²⁺. M. bovis BCG cultured axenicallyand within THP-1 cells also expresses mRNA encoding Mramp.

Mramp exemplifies a novel prokaryotic class of metal ion transporter.Within phagosomes, Mramp and Nramp1 may compete for the samedivalent cations, with implications for intracellular survivalof mycobacteria.

Key Words: bacillus Calmette-Guérin • Xenopus oocyte • metal ion • phagosome • intracellular pathogen

1used in this paper: BCG, bacillus Calmette-Guérin; 2-DOG,2'-deoxy-[14C]d-glucose; Mramp, mycobacterial homologue of Nramp;Nramp, natural resistance–associated macrophage protein;ORF, open reading frame; RT, reverse transcription; SUM, standarduptake medium; TC, tandem competitive

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