NRAMP-1 expression modulates protein-tyrosine phosphatase activity in macrophages: impact on host cell signaling and functions.
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.
Gomez
Maria Adelaida
MA
Department of Medicine, McGill University, Montréal, Québec H3A 2B4, Canada.
Li
Samantha
S
Tremblay
Michel L
ML
Olivier
Martin
M
D000818:Animals; D027682:Cation Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D002413:Cations, Divalent / Q000378:metabolism; D002460:Cell Line; D017136:Ion Transport / Q000235:genetics; D007893:Leishmania donovani; D007898:Leishmaniasis, Visceral / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000469:parasitology; D008670:Metals / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D000099173:Natural Resistance-associated Macrophage Protein 1
D027682:Cation Transport Proteins; D002413:Cations, Divalent; D008670:Metals; D009569:Nitric Oxide; D017027:Protein Tyrosine Phosphatases; D000099173:Natural Resistance-associated Macrophage Protein 1