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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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
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).
Miller, L. H. & Greenwood, B. Malaria — a shadow over Africa. Science 298, 121–122 (2002).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Glenister, F. K. et al. Functional alteration of red blood cells by a megadalton protein of Plasmodium falciparum. Blood 113, 919–928 (2009).
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).
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).
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).
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).
Lingelbach, K. R. Plasmodium falciparum: a molecular view of protein transport from the parasite into the host erythrocyte. Exp. Parasitol. 76, 318–327 (1993).
Wickham, M. E. et al. Trafficking and assembly of the cytoadherence complex in Plasmodium falciparum-infected human erythrocytes. EMBO J. 20, 5636–5649 (2001).
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).
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).
Hiller, N. L. et al. A host-targeting signal in virulence proteins reveals a secretome in malarial infection. Science 306, 1934–1937 (2004).
Sargeant, T. J. et al. Lineage-specific expansion of proteins exported to erythrocytes in malaria parasites. Genome Biol. 7, R12 (2006).
van Ooij, C. et al. The malaria secretome: from algorithms to essential function in blood stage infection. PLoS Pathog. 4, e1000084 (2008).
Singh, A. P. et al. Plasmodium circumsporozoite protein promotes the development of the liver stages of the parasite. Cell 131, 492–504 (2007).
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).
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).
Chang, H. H. et al. N-terminal processing of proteins exported by malaria parasites. Mol. Biochem. Parasitol. 160, 107–115 (2008).
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).
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).
Russo, I. et al. Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte. Nature 463, 632–636 (2010).
Boddey, J. A. et al. An aspartyl protease directs malaria effector proteins to the host cell. Nature 463, 627–631 (2010).
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).
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).
Banumathy, G., Singh, V. & Tatu, U. Host chaperones are recruited in membrane-bound complexes by Plasmodium falciparum. J. Biol. Chem. 277, 3902–3912 (2002).
de Koning-Ward, T. F. et al. A newly discovered protein export machine in malaria parasites. Nature 459, 945–949 (2009).
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).
Haase, S. et al. Sequence requirements for the export of the Plasmodium falciparum Maurer's clefts protein REX2. Mol. Microbiol. 71, 1003–1017 (2009).
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).
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).
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).
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).
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).
Maier, A. G. et al. Exported proteins required for virulence and rigidity of Plasmodium falciparum-infected human erythrocytes. Cell 134, 48–61 (2008).
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).
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).
Charpian, S. & Przyborski, J. M. Protein transport across the parasitophorous vacuole of Plasmodium falciparum: into the great wide open. Traffic 9, 157–165 (2008).
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).
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).
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).
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.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
DATABASES
FURTHER INFORMATION
Rights and permissions
About this article
Cite this article
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
Issue Date:
DOI: https://doi.org/10.1038/nrmicro2420
This article is cited by
-
Serum proteome profiling of naturally acquired Babesia rossi infection in dogs
Scientific Reports (2023)
-
RhopH2 and RhopH3 export enables assembly of the RhopH complex on P. falciparum-infected erythrocyte membranes
Communications Biology (2022)
-
Investigating a Plasmodium falciparum erythrocyte invasion phenotype switch at the whole transcriptome level
Scientific Reports (2020)
-
EXP2 is a nutrient-permeable channel in the vacuolar membrane of Plasmodium and is essential for protein export via PTEX
Nature Microbiology (2018)
-
Genome-wide analysis of gene expression and protein secretion of Babesia canis during virulent infection identifies potential pathogenicity factors
Scientific Reports (2017)