Inhibition of Plasmepsin V Activity Demonstrates Its Essential Role in Protein Export,PfEMP1 Display,and Survival of Malaria Parasites |
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| Authors: | Brad E. Sleebs Sash Lopaticki Danushka S. Marapana Matthew T. O'Neill Pravin Rajasekaran Michelle Gazdik Svenja Günther Lachlan W. Whitehead Kym N. Lowes Lea Barfod Lars Hviid Philip J. Shaw Anthony N. Hodder Brian J. Smith Alan F. Cowman Justin A. Boddey |
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| Affiliation: | 1.The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia;2.Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia;3.University of Copenhagen and Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark;4.National Center for Genetic Engineering and Biotechnology (BIOTEC), Pathum Thani, Thailand;5.Department of Chemistry, La Trobe University, Victoria, Australia;University of Georgia, United States of America |
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| Abstract: | The malaria parasite Plasmodium falciparum exports several hundred proteins into the infected erythrocyte that are involved in cellular remodeling and severe virulence. The export mechanism involves the Plasmodium export element (PEXEL), which is a cleavage site for the parasite protease, Plasmepsin V (PMV). The PMV gene is refractory to deletion, suggesting it is essential, but definitive proof is lacking. Here, we generated a PEXEL-mimetic inhibitor that potently blocks the activity of PMV isolated from P. falciparum and Plasmodium vivax. Assessment of PMV activity in P. falciparum revealed PEXEL cleavage occurs cotranslationaly, similar to signal peptidase. Treatment of P. falciparum–infected erythrocytes with the inhibitor caused dose-dependent inhibition of PEXEL processing as well as protein export, including impaired display of the major virulence adhesin, PfEMP1, on the erythrocyte surface, and cytoadherence. The inhibitor killed parasites at the trophozoite stage and knockdown of PMV enhanced sensitivity to the inhibitor, while overexpression of PMV increased resistance. This provides the first direct evidence that PMV activity is essential for protein export in Plasmodium spp. and for parasite survival in human erythrocytes and validates PMV as an antimalarial drug target. |
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