Trafficking of the major virulence factor to the surface of transfected P falciparum–infected erythrocytes

Knuepfer, Ellen; Rug, Melanie; Klonis, Nectarios; Tilley, Leann; Cowman, Alan F.

doi:10.1182/blood-2004-12-4666

Cited by 127 publications

(166 citation statements)

References 33 publications

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“…Our data suggest, however, that the properties of the membranes of these two compartments are not identical and thus may not be continuous. Our FRAP analysis using REX2-GFP support previous FRAP studies using proteins transiently associating with Maurer's clefts (Knuepfer et al, 2005b) or the resident integral cleft protein MAHRP1 (Spycher et al, 2006). In each case, the data indicate that Maurer's clefts are separate entities.…”

Section: Discussionsupporting

confidence: 74%

“…Early transcribed membrane proteins (ETRAMPs) localize to the parasitophorous vacuole membrane (PVM), which surrounds the parasite inside the host cell (Spielmann et al, , 2006. Skeleton binding protein 1 (SBP1) and membrane-associated protein (MAHRP)1 localize to the Maurer's clefts (Blisnick et al, 2000;Spycher et al, 2003), parasite-induced vesicular structures in the host cell that are involved in the export of cytoadherence determinants to the RBC surface (Wickham et al, 2001;Knuepfer et al, 2005b). Interestingly, SBP1 has now been shown to be essential for export of PfEMP-1 to the RBC surface (Cooke et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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A Cluster of Ring Stage–specific Genes Linked to a Locus Implicated in Cytoadherence inPlasmodium falciparumCodes for PEXEL-negative and PEXEL-positive Proteins Exported into the Host Cell

Spielmann

Hawthorne

Dixon

et al. 2006

MBoC

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117

162

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Blood stages of Plasmodium falciparum export proteins into their erythrocyte host, thereby inducing extensive host cell modifications that become apparent after the first half of the asexual development cycle (ring stage). This is responsible for a major part of parasite virulence. Export of many parasite proteins depends on a sequence motif termed Plasmodium export element (PEXEL) or vacuolar transport signal (VTS). This motif has allowed the prediction of the Plasmodium exportome. Using published genome sequence, we redetermined the boundaries of a previously studied region linked to P. falciparum virulence, reducing the number of candidate genes in this region to 13. Among these, we identified a cluster of four ring stage-specific genes, one of which is known to encode an exported protein. We demonstrate that all four genes code for proteins exported into the host cell, although only two genes contain an obvious PEXEL/VTS motif. We propose that the systematic analysis of ring stage-specific genes will reveal a cohort of exported proteins not present in the currently predicted exportome. Moreover, this provides further evidence that host cell remodeling is a major task of this developmental stage. Biochemical and photobleaching studies using these proteins reveal new properties of the parasiteinduced membrane compartments in the host cell. This has important implications for the biogenesis and connectivity of these structures. INTRODUCTIONPlasmodium falciparum is the causative agent of the most severe form of human malaria, killing 1-2 million people each year (Snow et al., 2005). The symptoms of this disease are associated with the continuous asexual multiplication of P. falciparum parasites within red blood cells (RBCs) (for review, see Miller et al., 2002). In this part of the life cycle, the parasite develops, within 48 h from the ring stage, to the trophozoite stage and finally to the schizont stage after which the infected RBCs (IRBCs) rupture, releasing up to 32 merozoite stage parasites that infect new RBCs.The ring stage lasts for almost half of this cycle (ϳ0-20 h after invasion) and shows low metabolic activity with little change in size and morphology (Zolg et al., 1984;de Rojas and Wasserman, 1985). P. falciparum ring forms are the only stages apparent in the blood circulation of infected humans, because more mature parasites adhere to the endothelium of various organs to avoid clearance by the spleen (Langreth and Peterson, 1985). The subsequent accumulation of infected RBCs in the microvasculature is largely responsible for malaria-associated morbidity and mortality. This sequestration of IRBCs is mediated by the parasite protein P. falciparum erythrocyte membrane protein 1 (PfEMP-1), which is exported to the surface of the IRBCs and is encoded by a family of variant antigens (Baruch et al., 1995;Smith et al., 1995;Su et al., 1995). Because human RBCs are devoid of a functional protein trafficking system, the parasite has to establish a protein export system in the host cell before PfEMP-1 can b...

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

A Cluster of Ring Stage–specific Genes Linked to a Locus Implicated in Cytoadherence inPlasmodium falciparumCodes for PEXEL-negative and PEXEL-positive Proteins Exported into the Host Cell

Spielmann

Hawthorne

Dixon

et al. 2006

MBoC

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117

162

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“…In a P. falciparum-infected erythrocyte, knobs consist of parasite-derived proteins whose synthesis begins at the early ring stage of the parasite's development (Kilejian, 1979). These knob proteins are transported to the erythrocyte surface membrane via Maurer's clefts and other vesicular compartments and incorporated into knobs during the trophozoite and schizont stages (Wickham et al, 2001;Haeggstrom et al, 2004;Knuepfer et al, 2005b;Knuepfer et al, 2005a). The cytosolic vesicle-like structures that we frequently observed in P. gallinaceum-infected erythrocytes may be similarly involved in the transport of parasite-derived furrow proteins.…”

Section: Discussionmentioning

confidence: 99%

The avian malaria parasite Plasmodium gallinaceum causes marked structural changes on the surface of its host erythrocyte

Nagao

Arie

Dorward

et al. 2008

Journal of Structural Biology

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Using a combination of atomic force, scanning and transmission electron microscopy, we found that avian erythrocytes infected with the avian malaria parasite Plasmodium gallinaceum develop ~60 nm wide and ~430 nm long furrow-like structures on the surface. Furrows begin to appear during the early trophozoite stage of the parasite's development. They remain constant in size and density during the course of parasite maturation and are uniformly distributed in random orientations over the erythrocyte surface. In addition, the density of furrows is directly proportional to the number of parasites contained within the erythrocyte. These findings suggest that parasite-induced intraerythrocytic processes are involved in modifying the surface of host erythrocytes. These processes may be analogous to those of the human malaria parasite P. falciparum, which induces knob-like protrusions that mediate the pathogenic adherence of parasitized erythrocytes to microvessels. Although P. gallinaceum-infected erythrocytes do not seem to adhere to microvessels in the host chicken, the furrows might be involved in the pathogenesis of P. gallinaceum infections by some other mechanism involving host-pathogen interactions.

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“…Additionaly, there is no known vesicular transport to the Maurer's clefts because none of the vesicles observed could be labeled with antibodies against any Maurer's clefts protein (21,36). Whether these proteins travel via a nontypical vesicular transport or as soluble chaperoned protein complexes (76,81,114) remains to be shown, and recently described J-dots carrying parasitederived HSP40 and HSP70 proteins might play a role in this process (49,50).…”

Section: Proteins Reach Maurer's Clefts Via a Complex Transport Pathwaymentioning

confidence: 99%

“…In contrast, GFP-tagged Maurer's clefts resident proteins were found only in a punctuate manner at Maurer's clefts, indicating distinct, independent structures. In the case of a continuous network, fluorescent signal would have been observed throughout the network (38)(39)(40)(41)(42)(43)(44)(45), but in photo-bleaching experiments no lateral diffusion of Maurer's clefts resident proteins or lipids (41,44,75,76) was observed. In contrast, the erythrocyte membrane showed a fast recovery after photo-bleaching when BODIPYceramide was used (44).…”

Section: Maurer's Cleft As Sorting Stationsmentioning

confidence: 99%

Maurer's clefts, the enigma of Plasmodium falciparum

Mundwiler-Pachlatko

Beck

2013

Proc. Natl. Acad. Sci. U.S.A.

106

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Plasmodium falciparum, the causative agent of malaria, completely remodels the infected human erythrocyte to acquire nutrients and to evade the immune system. For this process, the parasite exports more than 10% of all its proteins into the host cell cytosol, including the major virulence factor PfEMP1 (P. falciparum erythrocyte surface protein 1). This unusual protein trafficking system involves long-known parasitederived membranous structures in the host cell cytosol, called Maurer's clefts. However, the genesis, role, and function of Maurer's clefts remain elusive. Similarly unclear is how proteins are sorted and how they are transported to and from these structures. Recent years have seen a large increase of knowledge but, as yet, no functional model has been established. In this perspective we review the most important findings and conclude with potential possibilities to shed light into the enigma of Maurer's clefts. Understanding the mechanism and function of these structures, as well as their involvement in protein export in P. falciparum, might lead to innovative control strategies and might give us a handle with which to help to eliminate this deadly parasite.

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Trafficking of the major virulence factor to the surface of transfected P falciparum–infected erythrocytes

Cited by 127 publications

References 33 publications

A Cluster of Ring Stage–specific Genes Linked to a Locus Implicated in Cytoadherence inPlasmodium falciparumCodes for PEXEL-negative and PEXEL-positive Proteins Exported into the Host Cell

A Cluster of Ring Stage–specific Genes Linked to a Locus Implicated in Cytoadherence inPlasmodium falciparumCodes for PEXEL-negative and PEXEL-positive Proteins Exported into the Host Cell

The avian malaria parasite Plasmodium gallinaceum causes marked structural changes on the surface of its host erythrocyte

Maurer's clefts, the enigma of Plasmodium falciparum

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