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An aspartyl protease directs malaria effector proteins to the host cell

Nature volume 463, pages 627–631 (2010)Cite this article

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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.

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Figure 1: PEXEL processing is sensitive to HIV protease inhibitors.
Figure 2: PMV cleaves PEXEL.
Figure 3: Activity of PMV and cleavage of PEXEL.
Figure 4: Cleavage by PMV is essential for export.

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Acknowledgements

We thank the Australian Red Cross Blood Bank for the provision of human blood and serum, the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH for providing HIV protease inhibitors and MR4 (ATCC) for plasmepsin V antibodies, contributed by D. Goldberg. This work was supported by the National Health and Medical Research Council, and a grant from the National Institutes of Health (RO1 AI44008). J.A.B. is an NHMRC Peter Doherty postdoctoral Fellow and A.F.C. is an International Research Scholar of the Howard Hughes Medical Institute and an Australia Fellow.

Author Contributions J.A.B. performed the biochemical and cell biological experiments. A.N.H. performed HPLC, biochemical analysis and purification of recombinant plasmepsin V. S.G. made 3D7-PMIXHA, purified recombinant GBP130 proteins and analysed their processing. H.P. and E.A.K. performed the proteomics analysis. T.F.d.K.-W. attempted the knockouts of plasmepsin V in P. berghei and analysed the results. A.F.C. designed and interpreted experiments. All authors contributed to the study design and to writing the manuscript.

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Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia

    Justin A. Boddey, Anthony N. Hodder, Svenja Günther, J. Andrew Pearce, Richard J. Simpson & Alan F. Cowman

  2. Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne 3004, Australia

    Paul R. Gilson & Brendan S. Crabb

  3. Joint Proteomics Facility, Ludwig Institute for Cancer Research, Melbourne 3050, Australia

    Heather Patsiouras, Eugene A. Kapp & Richard J. Simpson

  4. Deakin University, Waurn Ponds 3217, Australia

    Tania F. de Koning-Ward

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  1. Justin A. Boddey
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Correspondence to Alan F. Cowman.

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Boddey, J., Hodder, A., Günther, S. et al. An aspartyl protease directs malaria effector proteins to the host cell. Nature 463, 627–631 (2010). https://doi.org/10.1038/nature08728

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