Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites

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 Shaw, Anthony N Hodder, Brian J Smith, Alan F Cowman, Justin A Boddey

    107 Citationer (Scopus)

    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.

    OriginalsprogEngelsk
    TidsskriftP L o S Biology
    Vol/bind12
    Udgave nummer7
    Sider (fra-til)e1001897
    ISSN1545-7885
    DOI
    StatusUdgivet - jul. 2014

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