Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte

Nature volume 463, pages 632–636 (2010)Cite this article

Subjects

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Sargeant, T. J. et al. Lineage-specific expansion of proteins exported to erythrocytes in malaria parasites. Genome Biol. 7, R12 (2006)

    Article  Google Scholar 

  2. van Ooij, C. et al. The malaria secretome: from algorithms to essential function in blood stage infection. PLoS Pathog. 4, e1000084 (2008)

    Article  Google Scholar 

  3. Haldar, K. & Mohandas, N. Erythrocyte remodeling by malaria parasites. Curr. Opin. Hematol. 14, 203–209 (2007)

    Article  Google Scholar 

  4. Maier, A. G., Cooke, B. M., Cowman, A. F. & Tilley, L. Malaria parasite proteins that remodel the host erythrocyte. Nature Rev. Microbiol. 7, 341–354 (2009)

    Article  CAS  Google Scholar 

  5. Hiller, N. L. et al. A host-targeting signal in virulence proteins reveals a secretome in malarial infection. Science 306, 1934–1937 (2004)

    Article  ADS  CAS  Google Scholar 

  6. Marti, M. et al. Targeting malaria virulence and remodeling proteins to the host erythrocyte. Science 306, 1930–1933 (2004)

    Article  ADS  CAS  Google Scholar 

  7. Chang, H. H. et al. N-terminal processing of proteins exported by malaria parasites. Mol. Biochem. Parasitol. 160, 107–115 (2008)

    Article  CAS  Google Scholar 

  8. Boddey, J. A., Moritz, R. L., Simpson, R. J. & Cowman, A. F. Role of the Plasmodium export element in trafficking parasite proteins to the infected erythrocyte. Traffic 10, 285–299 (2009)

    Article  CAS  Google Scholar 

  9. Klemba, M. & Goldberg, D. E. Characterization of plasmepsin V, a membrane-bound aspartic protease homolog in the endoplasmic reticulum of Plasmodium falciparum . Mol. Biochem. Parasitol. 143, 183–191 (2005)

    Article  CAS  Google Scholar 

  10. Tang, J. in Handbook of Proteolytic Enzymes 2nd edn, Vol. 1 (eds Barrett, A. J., Rawlings, N. D. & Woessner, J. F.) Ch. 13 (Elsevier, 2004)

    Google Scholar 

  11. Bhattacharjee, S. et al. The malarial host-targeting signal is conserved in the Irish potato famine pathogen. PLoS Pathog. 2, e50 (2006)

    Article  Google Scholar 

  12. Russo, I., Oksman, A., Vaupel, B. & Goldberg, D. E. A calpain unique to alveolates is essential in Plasmodium falciparum and its knockdown reveals an involvement in pre-S-phase development. Proc. Natl Acad. Sci. USA 106, 1554–1559 (2009)

    Article  ADS  CAS  Google Scholar 

  13. Klemba, M., Gluzman, I. & Goldberg, D. E. A Plasmodium falciparum dipeptidyl aminopeptidase I participates in vacuolar hemoglobin degradation. J. Biol. Chem. 279, 43000–43007 (2004)

    Article  CAS  Google Scholar 

  14. Klemba, M., Beatty, W., Gluzman, I. & Goldberg, D. E. Trafficking of plasmepsin II to the food vacuole of the malaria parasite Plasmodium falciparum . J. Cell Biol. 164, 47–56 (2004)

    Article  CAS  Google Scholar 

  15. Maier, A. G. et al. Exported proteins required for virulence and rigidity of Plasmodium falciparum-infected human erythrocytes. Cell 134, 48–61 (2008)

    Article  CAS  Google Scholar 

  16. Kim, J. H. et al. Noninvasive measurement of the pH of the endoplasmic reticulum at rest and during calcium release. Proc. Natl Acad. Sci. USA 95, 2997–3002 (1998)

    Article  ADS  CAS  Google Scholar 

  17. Boddey, J. A. et al. An aspartyl protease directs malaria effector proteins to the host cell. Nature 10.1038/nature08728 (this issue)

  18. de Koning-Ward, T. F. et al. A newly discovered protein export machine in malaria parasites. Nature 459, 945–949 (2009)

    Article  ADS  CAS  Google Scholar 

  19. Skinner-Adams, T. S. et al. Antiretrovirals as antimalarial agents. J. Infect. Dis. 190, 1998–2000 (2004)

    Article  CAS  Google Scholar 

  20. Parikh, S. et al. Antimalarial activity of human immunodeficiency virus type 1 protease inhibitors. Antimicrob. Agents Chemother. 49, 2983–2985 (2005)

    Article  CAS  Google Scholar 

  21. Russo, I., Oksman, A. & Goldberg, D. E. Fatty acid acylation regulates trafficking of the unusual Plasmodium falciparum calpain to the nucleolus. Mol. Microbiol. 72, 229–245 (2009)

    Article  CAS  Google Scholar 

  22. Sullivan, D. J., Gluzman, I. Y. & Goldberg, D. E. Plasmodium hemozoin formation mediated by histidine-rich proteins. Science 271, 219–222 (1996)

    Article  ADS  CAS  Google Scholar 

  23. Drew, M. E. et al. Plasmodium food vacuole plasmepsins are activated by falcipains. J. Biol. Chem. 283, 12870–12876 (2008)

    Article  CAS  Google Scholar 

  24. Shevchenko, A., Wilm, M., Vorm, O. & Mann, M. Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels. Anal. Chem. 68, 850–858 (1996)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Author notes

  1. Ilaria Russo

    Present address: Present address: Department of Experimental Medicine and Biochemical Science, University of Perugia, 06126 Perugia, Italy.,

  2. Shalon Babbitt and Vasant Muralidharan: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Molecular Microbiology and Medicine, Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, Missouri 63110, USA,

    Ilaria Russo, Shalon Babbitt, Vasant Muralidharan, Tamira Butler, Anna Oksman & Daniel E. Goldberg

Authors
  1. Ilaria Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shalon Babbitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vasant Muralidharan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tamira Butler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anna Oksman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniel E. Goldberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel E. Goldberg.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-3 with Legends and Supplementary Table 1. (PDF 1194 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Russo, I., Babbitt, S., Muralidharan, V. et al. Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte. Nature 463, 632–636 (2010). https://doi.org/10.1038/nature08726

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature08726

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing