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J. Biol. Chem., Vol. 278, Issue 27, 24665-24672, July 4, 2003

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Surface Coat Remodeling during Differentiation of Trypanosoma brucei^*

Amy E. Gruszynski  , Andrew DeMaster ¶, Nigel M. Hooper || and James D. Bangs ¶ **

From the Department of Biomolecular Chemistry and the ^¶Department of Medical Microbiology and Immunology, University of Wisconsin Medical School, Madison, Wisconsin 53706 and the ^||Proteolysis Research Group, School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom

African trypanosomes (Trypanosoma brucei) are digenetic parasites whose lifecycle alternates between the mammalian bloodstream and the midgut of the tsetse fly vector. In mammals, proliferating long slender parasites transform into non-diving short stumpy forms, which differentiate into procyclic forms when ingested by the tsetse fly. A hallmark of differentiation is the replacement of the bloodstream stage surface coat composed of variant surface glycoprotein (VSG) with a new coat composed of procylin. An undefined endoprotease and endogenous glycosylphosphatidylinositol-specific phospholipase C (GPI-PLC) have been implicated in releasing the old VSG coat. However, GPI hydrolysis has been considered unimportant because (i) GPI-PLC null mutants are fully viable and (ii) cytosolic GPI-PLC is localized away from cell surface VSG. Utilizing an in vitro differentiation assay with pleomorphic strains we have investigated these modes of VSG release. Shedding is initially by GPI hydrolysis, which ultimately accounts for a substantial portion of total release. Surface biotinylation assays indicate that GPI-PLC does gain access to extracellular VSG, suggesting that this mode is primed in the starting short stumpy population. Proteolytic release is up-regulated during differentiation and is stereoselectively inhibited by peptidomimetic collagenase inhibitors, implicating a zinc metalloprotease. This protease may be related to TbMSP-B, a trypanosomal homologue of Leishmania major surface protease (MSP) described in the accompanying paper (LaCount, D. J., Gruszynski, A. E., Grandgenett, P. M., Bangs, J. D., and Donelson, J. E. (2003) J. Biol. Chem. 278, 24658–24664). Overall, our results demonstrate that surface coat remodeling during differentiation has multiple mechanisms and that GPI-PLC plays a more significant role in VSG release than previously thought.

Received for publication, February 11, 2003 , and in revised form, April 11, 2003.

^* This work supported in part by National Institutes of Health (NIH) Grant AI35739 (to J. D. B.) and in part by NATO Collaborative Research Grant 972491 (to J. D. B. and N. M. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by NIH Cellular and Molecular Parasitology Training Grant AI07414.

^** A Burroughs Welcome Fund New Investigator in Molecular Parasitology. To whom correspondence should be addressed: Dept. of Medical Microbiology and Immunology, University of Wisconsin Medical School, 1300 University Ave., Madison, WI 53706. Tel.: 608-262-3110; Fax: 608-262-8418; E-mail: jdbangs{at}facstaff.wisc.edu.

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