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J. Biol. Chem., Vol. 277, Issue 51, 50190-50197, December 20, 2002
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From the 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-1
Leishmania EF-1
Activates the Src Homology 2 Domain Containing
Tyrosine Phosphatase SHP-1 Leading to Macrophage Deactivation*
§,,, and
**
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
(EF-1) as a
SHP-1-binding protein. Purified Leishmania EF-1, but not
host cell EF-1, bound directly to SHP-1 in vitro leading to its activation. Three independent lines of evidence indicated that
Leishmania EF-1 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-1. Second, confocal, fluorescence
microscopy using Leishmania-specific antisera detected
Leishmania EF-1 in the cytosol of infected cells. Third, co-immunoprecipitation showed that Leishmania EF-1 was
associated with SHP-1 in vivo in infected cells. Finally,
introduction of purified Leishmania EF-1, 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-
. Thus, Leishmania EF-1 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.
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