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Originally published In Press as doi:10.1074/jbc.M109072200 on January 2, 2002

J. Biol. Chem., Vol. 277, Issue 11, 8802-8809, March 15, 2002
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Extracellular Release of the Glycosylphosphatidylinositol (GPI)-linked Leishmania Surface Metalloprotease, gp63, Is Independent of GPI Phospholipolysis
IMPLICATIONS FOR PARASITE VIRULENCE*

Bradford S. McGwireDagger §, William A. O'ConnellDagger , Kwang-Poo Chang||, and David M. EngmanDagger

From the Dagger  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

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.

* 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.

To whom correspondence should be addressed: Northwestern University, Dept. of Pathology Ward 6-140 303 E. Chicago Ave. Chicago, IL 60611. Tel.: 312-503-1267; Fax: 312-503-1265; E-mail: b-mcgwire@northwestern.edu.

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