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Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte


During their intraerythrocytic development, malaria parasites export hundreds of proteins to remodel their host cell. Nutrient acquisition, cytoadherence and antigenic variation are among the key virulence functions effected by this erythrocyte takeover. Proteins destined for export are synthesized in the endoplasmic reticulum (ER) and cleaved at a conserved (PEXEL) motif, which allows translocation into the host cell via an ATP-driven translocon called the PTEX complex. We report that plasmepsin V, an ER aspartic protease with distant homology to the mammalian processing enzyme BACE, recognizes the PEXEL motif and cleaves it at the correct site. This enzyme is essential for parasite viability and ER residence is essential for its function. We propose that plasmepsin V is the PEXEL protease and is an attractive enzyme for antimalarial drug development.

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Figure 1: The transmembrane region of plasmepsin V confers ER localization.
Figure 2: Plasmepsin V is essential for intraerythrocytic parasite viability.
Figure 3: Episomal expression of wild-type and catalytic mutant PMV.
Figure 4: Plasmepsin V activity.
Figure 5: Analysis of substrate cleavage.
Figure 6: Proteomic analysis of PMV-associated proteins.

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This work was supported by NIH grant AI-047798. We thank A. Cowman, B. Crabb and S. Lindquist for suggestions, J. Adams and ATCC (MR4) for BiP antibody, D. Taylor for HRPII antibody, R. Anders for RESA antibody, A. Miller and M. Ndonwi for HRPII protein, P. Hruz for HIV protease inhibitors, J. Tang and S. Romeo for BACE inhibitors, W. Beatty for fluorescence analysis, S. Beverley for fluorimeter access, B. Vaupel for technical assistance and J. Turk for mass spectrometer access. Proteomics analysis was carried out at the ‘Fingerprints’ Proteomics Facility, College of Life Sciences, University of Dundee.

Author Contributions I.R. designed and executed most of the experiments and wrote the paper; S.B., V.M., T.B. and A.O. designed and executed experiments; D.E.G. designed experiments and wrote the paper.

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Correspondence to Daniel E. Goldberg.

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Russo, I., Babbitt, S., Muralidharan, V. et al. Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte. Nature 463, 632–636 (2010).

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