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J. Biol. Chem., Vol. 282, Issue 7, 4994-5003, February 16, 2007

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Cathepsin Cs Are Key for the Intracellular Survival of the Protozoan Parasite, Toxoplasma gondii^*

Xuchu Que, Juan C. Engel, David Ferguson^¶, Annette Wunderlich, Stanislas Tomavo^||, and Sharon L. Reed¹

From the Departments of Pathology and Medicine, University of California, San Diego, California 92103-8416, the Department of Pathology, University of California, San Francisco, Veterans Administration Medical Center, San Francisco, California 94121, the ^¶Nuffield Department of Pathology, Oxford University, Oxford OX3 9DU, United Kingdom, and the ^||Equipe de Parasitologie Moleculaire, Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), CNRS UMR 8576, Universite des Sciences et Technologies de Lille, 59655 Villeneuve d'Ascq Cédex, France

Cysteine proteases play key roles in apicomplexan invasion, organellar biogenesis, and intracellular survival. We have now characterized five genes encoding papain family cathepsins from Toxoplasma gondii, including three cathepsin Cs, one cathepsin B, and one cathepsin L. Unlike endopeptidases cathepsin B and L, T. gondii cathepsin Cs are exopeptidases and remove dipeptides from unblocked N-terminal substrates of proteins or peptides. TgCPC1 was the most highly expressed cathepsin mRNA in tachyzoites (by real-time PCR), but three cathepsins, TgCPC1, TgCPC2, and TgCPB, were undetectable in in vivo bradyzoites. The specific cathepsin C inhibitor, Gly-Phe-dimethylketone, selectively inhibited the TgCPCs activity, reducing parasite intracellular growth and proliferation. The targeted disruption of TgCPC1 does not affect the invasion and growth of tachyzoites as TgCPC2 is then up-regulated and may substitute for TgCPC1. TgCPC1 and TgCPC2 localize to constitutive secretory vesicles of tachyzoites, the dense granules. T. gondii cathepsin Cs are required for peptide degradation in the parasitophorous vacuole as the degradation of the marker protein, Escherichia coli -lactamase, secreted into the parasitophorous vacuole of transgenic tachyzoites was completely inhibited by the cathepsin C inhibitor. Cathepsin C inhibitors also limited the in vivo infection of T. gondii in the chick embryo model of toxoplasmosis. Thus, cathepsin Cs are critical to T. gondii growth and differentiation, and their unique specificities could be exploited to develop novel chemotherapeutic agents.

Received for publication, July 17, 2006 , and in revised form, November 8, 2006.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) DQ063593 [GenBank] -DQ063595 [GenBank] .

^* This work was supported by NIAID, National Institutes of Health Grant AI41093 (to S. R.) and AI35707 (to J. E.) and University of California University-wide AIDS Research Program Grant ID04-SD-079 (to S. R.) and by grants from the Rockefeller Brothers Fund (to S. R.) and the UCSD Center for AIDS Research (to X. Q.). 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.

¹ To whom correspondence should be addressed: Division of Infectious Diseases, University of California, San Diego Medical Center, 200 W. Arbor Dr., San Diego, CA 92103-8416. Tel.: 619-543-6146; Fax: 619-543-6614; E-mail: slreed{at}ucsd.edu.

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