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Sci. Signal., 29 September 2009
Vol. 2, Issue 90, p. ra58
[DOI: 10.1126/scisignal.2000213]

RESEARCH ARTICLES

Leishmania GP63 Alters Host Signaling Through Cleavage-Activated Protein Tyrosine Phosphatases

Maria Adelaida Gomez1,2, Irazu Contreras1,2, Maxime Hallé3, Michel L. Tremblay3, Robert W. McMaster4, and Martin Olivier1,2*

1 Departments of Experimental Medicine and of Microbiology and Immunology, McGill University, Montréal, Québec, Canada H3A 2B4.
2 Centre for the Study of Host Resistance and the Research Institute of the McGill University Health Centre, Montréal, Québec, Canada H3G 1A4.
3 Department of Biochemistry, McGill University, Montréal, Québec, Canada H3G 1Y6.
4 Department of Medical Genetics, University of British Columbia, Vancouver Hospital, 2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6.

Abstract: With more than 12 million people affected worldwide, 2 million new cases occurring per year, and the rapid emergence of drug resistance and treatment failure, leishmaniasis is an infectious disease for which research on drug and vaccine development, host-pathogen, and vector-parasite interactions are current international priorities. Upon Leishmania-macrophage interaction, activation of the protein tyrosine phosphatase (PTP) SHP-1 rapidly leads to the down-regulation of Janus kinase and mitogen-activated protein kinase signaling, resulting in the attenuation of host innate inflammatory responses and of various microbicidal macrophage functions. We report that, in addition to SHP-1, the PTPs PTP1B and TCPTP are activated and posttranslationally modified in infected macrophages, and we identify an essential role for PTP1B in the in vivo progression of Leishmania infection. The mechanism underlying PTP modulation involves the proteolytic activity of the Leishmania surface protease GP63. Access of GP63 to macrophage PTP1B, TCPTP, and SHP-1 is mediated in part by a lipid raft–dependent mechanism, resulting in PTP cleavage and stimulation of phosphatase activity. Collectively, our data present a mechanism of cleavage-dependent activation of macrophage PTPs by an obligate intracellular pathogen and show that internalization of GP63, a key Leishmania virulence factor, into host macrophages is a strategy the parasite uses to interact and survive within its host.

* To whom correspondence should be addressed. E-mail: martin.olivier{at}mcgill.ca

Citation: M. A. Gomez, I. Contreras, M. Hallé, M. L. Tremblay, R. W. McMaster, M. Olivier, Leishmania GP63 Alters Host Signaling Through Cleavage-Activated Protein Tyrosine Phosphatases. Sci. Signal. 2, ra58 (2009).

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