Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites
- Author(s)
- Sleebs, BE; Lopaticki, S; Marapana, DS; O'Neill, MT; Rajasekaran, P; Gazdik, M; Gunther, S; Whitehead, LW; Lowes, KN; Barfod, L; HVIID, L; Shaw, PJ; Hodder, AN; Smith, BJ; Cowman, AF; Boddey, JA;
- Details
- Publication Year 2014-07,Volume 12,Issue #7,Page e1001897
- Journal Title
- PLoS Biology
- Publication Type
- Journal Article
- 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.
- Publisher
- Public Library of Science
- Research Division(s)
- Chemical Biology; Infection And Immunity
- Publisher's Version
- https://doi.org/10.1371/journal.pbio.1001897
- Open Access at Publisher's Site
http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001897- NHMRC Grants
- NHMRC/1010326,
- Terms of Use/Rights Notice
- Copyright: © 2014 Sleebs et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Creation Date: 2014-07-03 10:22:51