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Originally published In Press as doi:10.1074/jbc.M209210200 on October 15, 2002

J. Biol. Chem., Vol. 277, Issue 51, 50190-50197, December 20, 2002
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Leishmania EF-1alpha Activates the Src Homology 2 Domain Containing Tyrosine Phosphatase SHP-1 Leading to Macrophage Deactivation*

Devki NandanDagger §, Taolin Yi, Martin LopezDagger , Crystal LaiDagger , and Neil E. ReinerDagger ||**

From the Dagger  Department of Medicine, Division of Infectious Diseases, and the || Department of Microbiology and Immunology, The University of British Columbia, Faculties of Medicine and Science, The Research Institute of the Vancouver Hospital and Health Sciences Center, Vancouver, British Columbia V5Z 3J5, Canada and the  Lerner Research Institute NB4-67, Cleveland Clinic Foundation, Cleveland, Ohio 44195

The human leishmaniasis are persistent infections of macrophages caused by protozoa of the genus Leishmania. The chronic nature of these infections is in part related to induction of macrophage deactivation, linked to activation of the Src homology 2 domain containing tyrosine phosphatase-1 (SHP-1) in infected cells. To investigate the mechanism of SHP-1 activation, lysates of Leishmania donovani promastigotes were subjected to SHP-1 affinity chromatography and proteins bound to the matrix were sequenced by mass spectrometry. This resulted in the identification of Leishmania elongation factor-1alpha (EF-1alpha ) as a SHP-1-binding protein. Purified Leishmania EF-1alpha , but not host cell EF-1alpha , bound directly to SHP-1 in vitro leading to its activation. Three independent lines of evidence indicated that Leishmania EF-1alpha may be exported from the phagosome thereby enabling targeting of host SHP-1. First, cytosolic fractions prepared from macrophages infected with [35S]methionine-labeled organisms contained Leishmania EF-1alpha . Second, confocal, fluorescence microscopy using Leishmania-specific antisera detected Leishmania EF-1alpha in the cytosol of infected cells. Third, co-immunoprecipitation showed that Leishmania EF-1alpha was associated with SHP-1 in vivo in infected cells. Finally, introduction of purified Leishmania EF-1alpha , but not the corresponding host protein into macrophages activated SHP-1 and blocked the induction of inducible nitric-oxide synthase expression in response to interferon-gamma . Thus, Leishmania EF-1alpha is identified as a novel SHP-1-binding and activating protein that recapitulates the deactivated phenotype of infected macrophages.

* This work was supported by Canadian Institutes of Health Research Grants FRN-38005 (to D. N.) and MOP-8633 (to N. R.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence may be addressed: Div. of Infectious Diseases, University of British Columbia, Rm. 452D, 2733 Heather St., Vancouver, British Columbia V5Z 3J5, Canada. E-mail: dnandan@interchange.ubc.ca.

** To whom correspondence may be addressed: Div. of Infectious Diseases, University of British Columbia, Rm. 452D, 2733 Heather St., Vancouver, British Columbia V5Z 3J5, Canada. Tel.: 604-875-4347; Fax: 604-875-4013; E-mail: ethan@interchange.ubc.ca.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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