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J. Biol. Chem., Vol. 282, Issue 50, 36190-36198, December 14, 2007

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NRAMP-1 Expression Modulates Protein-tyrosine Phosphatase Activity in Macrophages

IMPACT ON HOST CELL SIGNALING AND FUNCTIONS^*

Maria Adelaida Gomez¹, Samantha Li, Michel L. Tremblay^¶, and Martin Olivier²

From the Departments of Medicine and of Microbiology and Immunology, McGill University, Montréal, Québec H3A 2B4, Canada, the Centre for the Study of Host Resistance and the Research Institute of the McGill University Health Centre, Montréal, Québec H3G 1A4, Canada, and the ^¶Department of Biochemistry, McGill University, Montréal, Québec H3G 1Y6, Canada

NRAMP-1 (natural resistance-associated macrophage protein-1) has been associated with innate resistance to unrelated intracellular pathogen infections, up-regulation of proinflammatory phagocyte functions, and susceptibility to autoimmune diseases. It is still unclear how the divalent cation transport function of NRAMP-1 accounts for the associated pleiotropic effects. In this study, we evaluated the impact of murine macrophage NRAMP-1 expression on the activity of protein-tyrosine phosphatases (PTPs) as an upstream event contributing to the NRAMP-1 regulation of signal transduction and control of effector macrophage functions. Functional expression of NRAMP-1 results in lower macrophage PTP activity and increased protein phosphorylation. Decreased PTP activity is not a result of changes in protein expression but rather a reversible regulatory mechanism involving the interaction with NRAMP-1 metal substrates. In the context of intracellular infections, NRAMP-1 expression prevents full macrophage PTP induction by Leishmania infection, correlating with higher nitric oxide production and lower parasite survival. We suggest that NRAMP-1 divalent cation transport leads to transient inhibition of PTPs via direct PTP-metal interaction and/or by reactive oxygen species-dependent PTP oxidation, consequently promoting positive signal transduction, as a backbone for the induction of proinflammatory phagocyte functions.

Received for publication, April 13, 2007 , and in revised form, September 21, 2007.

^* This work was supported in part by Canadian Institute of Health Research (CIHR) Operating Grant MOP-12671 (to M. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a CIHR training grant Ph.D. student award from the Centre for the Study of Host Resistance at McGill University Health Centre.

² Member of the CIHR group on host-pathogen interaction. To whom correspondence should be addressed: Dept. of Microbiology and Immunology, McGill University, Duff Medical Bldg., Rm. 610, 3775 University St., Montréal, Québec, H3A 2B4, Canada. Tel.: 514-398-5592/1302; Fax: 514-398-7052; E-mail: martin.olivier{at}mcgill.ca.

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