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Originally published In Press as doi:10.1074/jbc.M202047200 on May 23, 2002

J. Biol. Chem., Vol. 277, Issue 31, 27968-27974, August 2, 2002
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Processing and Trafficking of Leishmania mexicana GP63
ANALYSIS USING GPI8 MUTANTS DEFICIENT IN GLYCOSYLPHOSPHATIDYLINOSITOL PROTEIN ANCHORING*

Miriam EllisDagger , Deepak K. SharmaDagger §, James D. HilleyDagger , Graham H. Coombs, and Jeremy C. MottramDagger ||

From the Dagger  Wellcome Centre for Molecular Parasitology, University of Glasgow, The Anderson College, Glasgow G11 6NU, United Kingdom and the  Division of Infection & Immunity, Institute of Biomedical and Life Sciences, University of Glasgow, Joseph Black Building, Glasgow G12 8QQ, United Kingdom

GPI8 is a clan CD, family C13 cysteine protease and the catalytic core of the GPI-protein transamidase complex. In Leishmania mexicana, GPI8 is nonessential, and Delta gpi8 mutants lack the GPI-anchored metalloprotease GP63, which is the major surface protein of promastigotes. We have identified the active site histidine and cysteine residues of leishmanial GPI8 and generated Delta gpi8 lines expressing modified GPI8 proteins. This has allowed us to study the processing and trafficking of GP63 in wild type and Delta gpi8 mutants. We show using pulse-chase labeling that in Delta gpi8 non-GPI-anchored GP63 was glycosylated and secreted without further processing from the cell with a t1/2 of 120 min. This secretion was prevented by growth of cells in the presence of tunicamycin, indicating that glycosylation is necessary for secretion of non-GPI-anchored proteins. In contrast, in wild type cells the majority of GP63 was rapidly glycosylated, GPI-anchored, and trafficked to the surface with defined processing intermediate forms. Tunicamycin inhibited glycosylation but did not prevent GPI anchor addition or trafficking. These results show that GPI-anchored and unanchored GP63 are trafficked via different pathways. In addition, the balance between GPI anchor addition and secretion of GP63 in Leishmania can vary depending on the activity of the GPI-protein transamidase, which has implications for the host-parasite interaction.

* This work was supported by a Medical Research Council Studentship (to M. E.) and a Medical Research Council Senior Fellowship (to J. C. M.).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.

§ Recipient of a Wellcome Trust Traveling Fellowship. Present address: Dept. of Biochemistry and Molecular Biology, Thoracic Diseases Research Unit, Mayo Clinic and Foundation, Rochester, MN 55905.

|| To whom correspondence should be addressed: Wellcome Centre for Molecular Parasitology, University of Glasgow, The Anderson College, 56 Dumbarton Rd., Glasgow G11 6NU, UK. Tel.: 44-141-330-3745; Fax: 44-141-330-5422; E-mail: j.mottram@udcf.gla.ac.uk.

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