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Papers In Press, published online ahead of print January 2, 2002
Pathology, Northwestern University, Chicago, Illinois 60611
Corresponding Author: b-mcgwire{at}northwestern.edu
The major zinc metalloprotease of Leishmania (gp63), an important determinant of parasite virulence, is attached to the parasite surface via a glycosylphosphatidylinositol (GPI) 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 wildtype gp63 was found in the culture supernatant twelve hrs post synthesis. Biochemical analysis of the extracellular gp63 revealed two forms of the protein—one which is released from the cell surface and another which, apparently, is directly secreted. Release of cell surface gp63 was significantly reduced when the protein's proteolytic activity was inactivated by site-specific mutagenesis, or inhibited by zinc chelation, suggesting that release involves autoproteolysis. The extracellular gp63 does not contain a GPI 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.
J. Biol. Chem, 10.1074/jbc.M109072200
Submitted on September 19, 2001
Revised on January 2, 2002
Accepted on December 30, 2001
Extracellular release of the glycosylphosphatidylinositol (GPI)-linked Leishmania surface metalloprotease, Gp63, is independent of GPI phospholipolysis: implications for parasite virulence
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