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J. Biol. Chem., Vol. 277, Issue 11, 8802-8809, March 15, 2002
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From the The major zinc metalloprotease of
Leishmania (gp63), an important determinant of parasite
virulence, is attached to the parasite surface via a
glycosylphosphatidylinositol anchor. Here we report the spontaneous
release of proteolytically active gp63 from a number of
Leishmania isolates, causing cutaneous and visceral disease. To investigate the mechanism(s) of gp63 release, we
transfected a gp63-deficient variant of Leishmania
amazonensis with constructs expressing gp63 and various mutants
thereof. Surprisingly, approximately half of wild type gp63 was found
in the culture supernatant 12 h post-synthesis. Biochemical
analysis of the extracellular gp63 revealed two forms of the protein,
one that is released from the cell surface, and another, that
apparently is directly secreted. Release of cell surface gp63 was
significantly reduced when the proteolytic activity of the protein was
inactivated by site-specific mutagenesis or inhibited by zinc
chelation, suggesting that release involves autoproteolysis. The
extracellular gp63 does not contain a glycosylphosphatidylinositol
moiety or ethanolamine, indicating that phospholipolysis is not
involved in the release process. Release of gp63 is also independent of
glycosylation. The finding of proteolytically active, extracellular
gp63 produced by multiple Leishmania isolates suggests a
potential role of the extracellular enzyme in substrate degradation
relevant to their survival in both the mammalian host and the insect vector.
Extracellular Release of the Glycosylphosphatidylinositol
(GPI)-linked Leishmania Surface Metalloprotease, gp63,
Is Independent of GPI Phospholipolysis
IMPLICATIONS FOR PARASITE VIRULENCE*
§¶,,
, and
Departments of Pathology and
Microbiology-Immunology, Northwestern University Medical School,
Chicago, Illinois 60611, § Section of Infectious Diseases,
College of Medicine, University of Illinois, Chicago, Illinois 60612, and Department of Microbiology and Immunology, University of
Health Sciences/Chicago Medical School,
North Chicago, Illinois 60064
*
This work was supported in part by grants from the
National Institutes of Health and the American Heart Association,
including a Physician-Scientist Postdoctoral Fellowship (to B. S. M.)
and an Established Investigator Award (to D. M. E.).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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