An aspartyl protease directs malaria effector proteins to the host cell

Justin A. Boddey, Anthony N. Hodder, Svenja Günther, Paul R. Gilson, Heather Patsiouras, Eugene A. Kapp, J. Andrew Pearce, Tania F. de Koning-Ward, Richard J. Simpson, Brendan S. Crabb and Alan F. Cowman ()
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Justin A. Boddey: The Walter and Eliza Hall Institute of Medical Research
Anthony N. Hodder: The Walter and Eliza Hall Institute of Medical Research
Svenja Günther: The Walter and Eliza Hall Institute of Medical Research
Paul R. Gilson: Macfarlane Burnet Institute for Medical Research and Public Health
Heather Patsiouras: Joint Proteomics Facility, Ludwig Institute for Cancer Research
Eugene A. Kapp: Joint Proteomics Facility, Ludwig Institute for Cancer Research
J. Andrew Pearce: The Walter and Eliza Hall Institute of Medical Research
Tania F. de Koning-Ward: Deakin University
Richard J. Simpson: The Walter and Eliza Hall Institute of Medical Research
Brendan S. Crabb: Macfarlane Burnet Institute for Medical Research and Public Health
Alan F. Cowman: The Walter and Eliza Hall Institute of Medical Research

Nature, 2010, vol. 463, issue 7281, 627-631

Abstract: Abstract Plasmodium falciparum causes the virulent form of malaria and disease manifestations are linked to growth inside infected erythrocytes. To survive and evade host responses the parasite remodels the erythrocyte by exporting several hundred effector proteins beyond the surrounding parasitophorous vacuole membrane. A feature of exported proteins is a pentameric motif (RxLxE/Q/D) that is a substrate for an unknown protease. Here we show that the protein responsible for cleavage of this motif is plasmepsin V (PMV), an aspartic acid protease located in the endoplasmic reticulum. PMV cleavage reveals the export signal (xE/Q/D) at the amino terminus of cargo proteins. Expression of an identical mature protein with xQ at the N terminus generated by signal peptidase was not exported, demonstrating that PMV activity is essential and linked with other key export events. Identification of the protease responsible for export into erythrocytes provides a novel target for therapeutic intervention against this devastating disease.

Date: 2010
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DOI: 10.1038/nature08728

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