NRAMP-1 expression modulates protein-tyrosine phosphatase activity in macrophages: impact on host cell signaling and functions.

Abstract

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.

• Authors: Maria Adelaida Gomez, Samantha Li, Michel L Tremblay, Martin Olivier
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 50 Pg. 36190-8 (Dec 14 2007) ISSN: 0021-9258 [Print] United States
• PMID: 17942403 (Publication Type: Journal Article)

Chemical References

• Cation Transport Proteins
• Cations, Divalent
• Metals
• natural resistance-associated macrophage protein 1
• Nitric Oxide
• Protein Tyrosine Phosphatases

Topics

• Animals
• Cation Transport Proteins (biosynthesis, genetics)
• Cations, Divalent (metabolism)
• Cell Line
• Ion Transport (genetics)
• Leishmania donovani
• Leishmaniasis, Visceral (genetics, metabolism)
• Macrophages (metabolism, parasitology)
• Metals (metabolism)
• Mice
• Nitric Oxide (biosynthesis)
• Oxidation-Reduction
• Phosphorylation
• Protein Processing, Post-Translational (genetics)
• Protein Tyrosine Phosphatases (genetics, metabolism)
• Signal Transduction (genetics)