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Moving in and renovating: exporting proteins from Plasmodium into host erythrocytes

Nature Reviews Microbiology volume 8, pages 617–621 (2010)Cite this article

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Abstract

Malaria parasites live within erythrocytes in the host bloodstream and induce crucial changes to these cells. By so doing, they can obtain the nutrients that they require for growth and can effect the evasion and perturbation of host defences. In order to accomplish this extensive host cell remodelling, the intracellular parasite exports hundreds of proteins to commandeer the erythrocyte for its own purposes. An export motif, a processing enzyme that specifies protein targeting and a translocon that mediates the export of proteins from the parasite into the host erythrocyte have been identified. However, important questions remain regarding the secretory pathway and the function of the translocon. In addition, this export pathway provides potentially useful targets for the development of inhibitors to interfere with functions that are vital for the virulence and survival programmes of the parasite.

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Figure 1: Plasmodium falciparum life cycle.
Figure 2: Proposed components of the export translocon complex.
Figure 3: Two possible models for protein export specificity.

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Change history

  • 13 August 2010

    The following sentence was added to the legend for figure 2: "Part b image is reproduced, with permission, from Nature REF. 36 © (2010) Macmillan Publishers Ltd. All rights reserved."

References

  1. Snow, R. W., Guerra, C. A., Noor, A. M., Myint, H. Y. & Hay, S. I. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 434, 214–217 (2005).

    Article  CAS  Google Scholar 

  2. Miller, L. H. & Greenwood, B. Malaria — a shadow over Africa. Science 298, 121–122 (2002).

    Article  CAS  Google Scholar 

  3. Marti, M., Baum, J., Rug, M., Tilley, L. & Cowman, A. F. Signal-mediated export of proteins from the malaria parasite to the host erythrocyte. J. Cell Biol. 171, 587–592 (2005).

    Article  CAS  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. Baruch, D. I. et al. Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell 82, 77–87 (1995).

    Article  CAS  Google Scholar 

  6. Su, X. Z. et al. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes. Cell 82, 89–100 (1995).

    Article  CAS  Google Scholar 

  7. Smith, J. D. et al. Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell 82, 101–110 (1995).

    Article  CAS  Google Scholar 

  8. Raventos-Suarez, C., Kaul, D. K., Macaluso, F. & Nagel, R. L. Membrane knobs are required for the microcirculatory obstruction induced by Plasmodium falciparum-infected erythrocytes. Proc. Natl Acad. Sci. USA 82, 3829–3833 (1985).

    Article  CAS  Google Scholar 

  9. Pologe, L. G. & Ravetch, J. V. A chromosomal rearrangement in a P. falciparum histidine-rich protein gene is associated with the knobless phenotype. Nature 322, 474–477 (1986).

    Article  CAS  Google Scholar 

  10. Crabb, B. S. et al. Targeted gene disruption shows that knobs enable malaria-infected red cells to cytoadhere under physiological shear stress. Cell 89, 287–296 (1997).

    Article  CAS  Google Scholar 

  11. Schneider, A. G. & Mercereau-Puijalon, O. A new Apicomplexa-specific protein kinase family: multiple members in Plasmodium falciparum, all with an export signature. BMC Genomics 6, 30 (2005).

    Article  Google Scholar 

  12. Waller, K. L. et al. Interactions of Plasmodium falciparum erythrocyte membrane protein 3 with the red blood cell membrane skeleton. Biochim. Biophys. Acta 1768, 2145–2156 (2007).

    Article  CAS  Google Scholar 

  13. Glenister, F. K. et al. Functional alteration of red blood cells by a megadalton protein of Plasmodium falciparum. Blood 113, 919–928 (2009).

    Article  CAS  Google Scholar 

  14. Glenister, F. K., Coppel, R. L., Cowman, A. F., Mohandas, N. & Cooke, B. M. Contribution of parasite proteins to altered mechanical properties of malaria-infected red blood cells. Blood 99, 1060–1063 (2002).

    Article  CAS  Google Scholar 

  15. Kutner, S., Breuer, W. V., Ginsburg, H., Aley, S. B. & Cabantchik, Z. I. Characterization of permeation pathways in the plasma membrane of human erythrocytes infected with early stages of Plasmodium falciparum: association with parasite development. J. Cell Physiol. 125, 521–527 (1985).

    Article  CAS  Google Scholar 

  16. Tonkin, C. J., Pearce, J. A., McFadden, G. I. & Cowman, A. F. Protein targeting to destinations of the secretory pathway in the malaria parasite Plasmodium falciparum. Curr. Opin. Microbiol. 9, 381–387 (2006).

    Article  CAS  Google Scholar 

  17. 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 

  18. Lingelbach, K. R. Plasmodium falciparum: a molecular view of protein transport from the parasite into the host erythrocyte. Exp. Parasitol. 76, 318–327 (1993).

    Article  CAS  Google Scholar 

  19. Wickham, M. E. et al. Trafficking and assembly of the cytoadherence complex in Plasmodium falciparum-infected human erythrocytes. EMBO J. 20, 5636–5649 (2001).

    Article  CAS  Google Scholar 

  20. Lopez-Estraño, C., Bhattacharjee, S., Harrison, T. & Haldar, K. Cooperative domains define a unique host cell-targeting signal in Plasmodium falciparum-infected erythrocytes. Proc. Natl Acad. Sci. USA 100, 12402–12407 (2003).

    Article  Google Scholar 

  21. Marti, M., Good, R. T., Rug, M., Knuepfer, E. & Cowman, A. F. Targeting malaria virulence and remodeling proteins to the host erythrocyte. Science 306, 1930–1933 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  24. 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 

  25. Singh, A. P. et al. Plasmodium circumsporozoite protein promotes the development of the liver stages of the parasite. Cell 131, 492–504 (2007).

    Article  CAS  Google Scholar 

  26. Silvestrini, F. et al. Protein export marks the early phase of gametocytogenesis of the human malaria parasite Plasmodium falciparum. Mol. Cell. Proteomics 9, 1437–1448 (2010).

    Article  CAS  Google Scholar 

  27. 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 

  28. 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 

  29. Wiek, S., Cowman, A. F. & Lingelbach, K. Double cross-over gene replacement within the sec 7 domain of a GDP-GTP exchange factor from Plasmodium falciparum allows the generation of a transgenic brefeldin A-resistant parasite line. Mol. Biochem. Parasitol. 138, 51–55 (2004).

    Article  CAS  Google Scholar 

  30. Osborne, A. R. et al. The host targeting motif in exported Plasmodium proteins is cleaved in the parasite endoplasmic reticulum. Mol. Biochem. Parasitol. 171, 25–31 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  32. Boddey, J. A. et al. An aspartyl protease directs malaria effector proteins to the host cell. Nature 463, 627–631 (2010).

    Article  CAS  Google Scholar 

  33. 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 

  34. Gehde, N. et al. Protein unfolding is an essential requirement for transport across the parasitophorous vacuolar membrane of Plasmodium falciparum. Mol. Microbiol. 71, 613–628 (2009).

    Article  CAS  Google Scholar 

  35. Banumathy, G., Singh, V. & Tatu, U. Host chaperones are recruited in membrane-bound complexes by Plasmodium falciparum. J. Biol. Chem. 277, 3902–3912 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. Spielmann, T. & Gilberger, T.-W. Protein export in malaria parasites: do multiple export motifs add up to multiple export pathways? Trends Parasitol. 26, 6–10 (2010).

    Article  CAS  Google Scholar 

  38. Haase, S. et al. Sequence requirements for the export of the Plasmodium falciparum Maurer's clefts protein REX2. Mol. Microbiol. 71, 1003–1017 (2009).

    Article  CAS  Google Scholar 

  39. Brown, G. V. et al. Localization of the ring-infected erythrocyte surface antigen (RESA) of Plasmodium falciparum in merozoites and ring-infected erythrocytes. J. Exp. Med. 162, 774–779 (1985).

    Article  CAS  Google Scholar 

  40. Waterkeyn, J. G. et al. Targeted mutagenesis of Plasmodium falciparum erythrocyte membrane protein 3 (PfEMP3) disrupts cytoadherence of malaria-infected red blood cells. EMBO J. 19, 2813–2823 (2000).

    Article  CAS  Google Scholar 

  41. Hanssen, E. et al. Targeted mutagenesis of the ring-exported protein-1 of Plasmodium falciparum disrupts the architecture of Maurer's cleft organelles. Mol. Microbiol. 69, 938–953 (2008).

    Article  CAS  Google Scholar 

  42. Knuepfer, E., Rug, M., Klonis, N., Tilley, L. & Cowman, A. F. Trafficking of the major virulence factor to the surface of transfected P. falciparum-infected erythrocytes. Blood 105, 4078–4087 (2005).

    Article  CAS  Google Scholar 

  43. Kriek, N. et al. Characterization of the pathway for transport of the cytoadherence-mediating protein, PfEMP1, to the host cell surface in malaria parasite-infected erythrocytes. Mol. Microbiol. 50, 1215–1227 (2003).

    Article  CAS  Google Scholar 

  44. 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 

  45. Cooke, B. M. et al. A Maurer's cleft-associated protein is essential for expression of the major malaria virulence antigen on the surface of infected red blood cells. J. Cell Biol. 172, 899–908 (2006).

    Article  CAS  Google Scholar 

  46. Maier, A. G. et al. Skeleton-binding protein 1 functions at the parasitophorous vacuole membrane to traffic PfEMP1 to the Plasmodium falciparum-infected erythrocyte surface. Blood 109, 1289–1297 (2007).

    Article  CAS  Google Scholar 

  47. Charpian, S. & Przyborski, J. M. Protein transport across the parasitophorous vacuole of Plasmodium falciparum: into the great wide open. Traffic 9, 157–165 (2008).

    CAS  Google Scholar 

  48. Crabb, B. S., de Koning-Ward, T. F. & Gilson, P. R. Protein export in Plasmodium parasites: from the endoplasmic reticulum to the vacuolar export machine. Int. J. Parasitol. 40, 509–513 (2010).

    Article  CAS  Google Scholar 

  49. Struck, N. S. et al. Spatial dissection of the cis- and trans-Golgi compartments in the malaria parasite Plasmodium falciparum. Mol. Microbiol. 67, 1320–1330 (2008).

    Article  CAS  Google Scholar 

  50. Lingelbach, K. & Przyborski, J. M. The long and winding road: protein trafficking mechanisms in the Plasmodium falciparum infected erythrocyte. Mol. Biochem. Parasitol. 147, 1–8 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors are supported, in part, by a grant to D.E.G. from the US National Institutes of Health (grant AI047798) and by grants to A.F.C. from the Australian National Health and Medical Research Council.

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Authors and Affiliations

  1. Departments of Medicine and Molecular Microbiology, Daniel E. Goldberg is at the Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, Missouri 63110, USA. goldberg@borcim.wustl.edu,

    Daniel E. Goldberg

  2. and at the Department of Medical Biology, Alan F. Cowman is at The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne 3050, Australia, University of Melbourne, Melbourne 3050, Australia. cowman@wehi.edu.au,

    Alan F. Cowman

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Goldberg, D., Cowman, A. Moving in and renovating: exporting proteins from Plasmodium into host erythrocytes. Nat Rev Microbiol 8, 617–621 (2010). https://doi.org/10.1038/nrmicro2420

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