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Vol. 17, Issue 10, 4551-4563, October 2006

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A Cleavable Propeptide Influences Toxoplasma Infection by Facilitating the Trafficking and Secretion of the TgMIC2–M2AP Invasion Complex

Jill M. Harper^*,, My-Hang Huynh^*,, Isabelle Coppens^*, Fabiola Parussini^*,, Silvia Moreno^||, and Vern B. Carruthers^*,

*W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205; and ^||Cellular Biology and Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA 30602

Submitted January 24, 2006; Revised August 1, 2006; Accepted August 3, 2006
Monitoring Editor: Ralph Isberg

Propeptides regulate protein function and trafficking in many eukaryotic systems and have emerged as important features of regulated secretory proteins in parasites of the phylum Apicomplexa. Regulated protein secretion from micronemes and host cell invasion are inextricably linked and essential processes for the apicomplexan parasite Toxoplasma gondii. TgM2AP is a propeptide-containing microneme protein found in a heterohexameric complex with the microneme protein TgMIC2, a protein that has a demonstrated fundamental role in gliding motility and invasion. TgM2AP function is also central to these processes, because disruption of TgM2AP (m2apKO) results in secretory retention of TgMIC2, leading to reduced TgMIC2 secretion from the micronemes and impaired invasion. Because the TgM2AP propeptide is predicted to be processed in an intracellular site near where TgMIC2 is retained in m2apKO parasites, we hypothesized that the propeptide and its proteolytic removal influence trafficking and secretion of the complex. We found that proTgM2AP traffics through endosomal compartments and that deletion of the propeptide leads to defective trafficking of the complex within or near this site, resulting in aberrant processing and decreased secretion of TgMIC2, impaired invasion, and reduced virulence in vivo, mirroring the phenotypes observed in m2apKO parasites. In contrast, mutation of several cleavage site residues resulted in normal localization, but it affected the stability and secretion of the complex from the micronemes. Therefore, the propeptide and its cleavage site influence distinct aspects of TgMIC2–M2AP function, with both impacting the outcome of infection.

Present addresses: National Institute on Aging, Laboratory of Clinical Investigation, Gerontology Research Center, 5600 Nathan Shock Drive, Room 4D18, Baltimore, MD 21224;

Department of Microbiology and Immunology, University of Michigan School of Medicine, 1150 W. Medical Center Drive, Ann Arbor, MI 48109;

Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT 05405.

Address correspondence to: Vern B. Carruthers (vcarruth{at}umich.edu)

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