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Eukaryotic Cell, December 2006, p. 2174-2183, Vol. 5, No. 12
1535-9778/06/$08.00+0     doi:10.1128/EC.00163-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Targeted Deletion of MIC5 Enhances Trimming Proteolysis of Toxoplasma Invasion Proteins{triangledown}

Susannah D. Brydges,1,{dagger} Xing Wang Zhou,1,{ddagger} My-Hang Huynh,1,§ Jill M. Harper,1,¶ Jeffrey Mital,2 Koku D. Z. Adjogble,3 Walter Däubener,3 Gary E. Ward,2 and Vern B. Carruthers1*

W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205,1 Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont 05405,2 Institute for Medical Microbiology and Hospital Hygiene, Universitaetsstr. 1, D-40225 Düsseldorf, Germany3

Received 3 June 2006/ Accepted 1 September 2006

Limited proteolysis of proteins transiently expressed on the surface of the opportunistic pathogen Toxoplasma gondii accompanies cell invasion and facilitates parasite migration across cell barriers during infection. However, little is known about what factors influence this specialized proteolysis or how these proteolytic events are regulated. Here we show that genetic ablation of the micronemal protein MIC5 enhances the normal proteolytic processing of several micronemal proteins secreted by Toxoplasma tachyzoites. Restoring MIC5 expression by genetic complementation reversed this phenotype, as did treatment with the protease inhibitor ALLN, which was previously shown to block the activity of a hypothetical parasite surface protease called MPP2. We show that, despite its lack of obvious membrane association signals, MIC5 occupies the parasite surface during invasion in the vicinity of the proteins affected by enhanced processing. Proteolysis of other secretory proteins, including GRA1, was also enhanced in MIC5 knockout parasites, indicating that the phenotype is not strictly limited to proteins derived from micronemes. Together, our findings suggest that MIC5 either directly regulates MPP2 activity or it influences MPP2's ability to access substrate cleavage sites on the parasite surface.

* Corresponding author. Present address: Department of Microbiology and Immunology, University of Michigan School of Medicine, 1150 W. Medical Center Drive, Ann Arbor, MI 48109. Phone: (734) 763-2081. Fax: (734) 764-3562. E-mail: vcarruth{at}jhsph.edu.

{triangledown} Published ahead of print on 15 September 2006.

{dagger} Present address: Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892.

{ddagger} Present address: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201.

§ Present address: Department of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109.

Present address: Laboratory of Clinical Investigation, Gerontology Research Center, Baltimore, MD 21224.

Eukaryotic Cell, December 2006, p. 2174-2183, Vol. 5, No. 12
1535-9778/06/$08.00+0     doi:10.1128/EC.00163-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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