A Maurer's cleft–associated protein is essential for expression of the major malaria virulence antigen on the surface of infected red blood cells

Cooke, Brian M.; Buckingham, Donna; Glenister, Fiona Kim; Fernandez, Kate Marie; Bannister, L. H.; Marti, Matthias; Mohandas, Narla; Coppel, Ross L.

doi:10.1083/jcb.200509122

Cited by 162 publications

(227 citation statements)

References 40 publications

(63 reference statements)

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“…Mutating residues 2-9, 10-14, 21-26, 27-31 and 32-35, respectively, did not affect trafficking of the chimeric protein to the Maurer's clefts ( Figure 5B). In comparison, introducing alanines at positions 16-20 (A [16][17][18][19][20] seemed to reduce the trafficking efficiency. Now, fluorescence was seen in a dotted pattern surrounding the parasite body and in the Maurer's clefts ( Figure 5B).…”

Section: Dmentioning

confidence: 99%

“…To test this hypothesis, we extended the alanine replacements creating A [10][11][12][13][14][15][16][17][18][19][20] and A [16][17][18][19][20][21][22][23][24][25][26] ( Figure 5A). A [10][11][12][13][14][15][16][17][18][19][20] exhibited the same partial phenotype as did A [16][17][18][19][20] ( Figure 5B). In comparison, substituting amino acids 16-26 by alanines ( Figure 5B) completely abrogated trafficking of the corresponding protein to the Maurer's clefts.…”

Section: Dmentioning

confidence: 99%

“…These proteins are all expressed early during intraerythrocytic development and seem to be accessory or structural components of the trafficking machinery. For example, knockout studies have shown that PfSBP1 and MAHRP-1 are necessary for the trafficking of the immunovariant adhesin PfEMP1 to the erythrocyte surface (18)(19)(20). PfREX-1 seems to play a role in Maurer's cleft morphology (21).…”

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confidence: 99%

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Export of PfSBP1 to the Plasmodium falciparum Maurer’s Clefts

Saridaki

Fröhlich

Braun-Breton

et al. 2009

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The human malaria parasite Plasmodium falciparum exports determinants of virulence and pathology to destinations within the host erythrocyte, including the erythrocyte cytoplasm, plasma membrane and membrane profiles of parasite origin termed Maurer's clefts. Most of the exported proteins contain a conserved pentameric motif termed plasmodial export element (PEXEL)/vacuolar transfer signal (VTS) that functions as a cleavable sorting signal permitting export to the host erythrocyte. However, there are some exported proteins, such as the skeleton-binding protein 1 (PfSBP1) that lack the PEXEL/VTS motif and that are not N-terminally processed, suggesting the presence of alternative sorting signals and/or mechanisms. In this study, we have investigated trafficking of PfSBP1 to the Maurer's clefts. Our data show that the transmembrane domain of PfSBP1 functions as an internal signal sequence for entry into the parasite's secretory pathway and for transport to the parasite plasma membrane. Trafficking beyond the parasite's plasma membrane required additional N-terminal domains, which are characterized by a high negative net charge. Biochemical data indicate that these domains affect the solubility and extraction profile, the orientation of the protein within the membrane and the subcellular localization. Our findings suggest new principles of protein export in P. falciparum-infected erythrocytes.

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Section: Dmentioning

confidence: 99%

Section: Dmentioning

confidence: 99%

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confidence: 99%

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Export of PfSBP1 to the Plasmodium falciparum Maurer’s Clefts

Saridaki

Fröhlich

Braun-Breton

et al. 2009

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“…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). Thus, it seems that many ring stage-specific genes code for proteins that 1) show no homologies to proteins in other organisms and 2) are exported into the host cell and therefore may be involved in host cell modifications.…”

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

116

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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“…Gene-deletion technology made it more possible to study the function of specific genes. First, knock out experiments eliminating the Maurer's clefts proteins MAHRP1 or SBP1 surprisingly revealed that PfEMP1 is not exported to the surface of the infected erythrocyte anymore (41,121,122). This finding was the first proof that Maurer's clefts have a function as an intermediate compartment in transport or sorting of proteins, at least for those destined for the erythrocyte membrane.…”

Section: Gene-deletion Studies Indicate Functions Of Maurer's Cleftsmentioning

confidence: 63%

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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A Maurer's cleft–associated protein is essential for expression of the major malaria virulence antigen on the surface of infected red blood cells

Cited by 162 publications

References 40 publications

Export of PfSBP1 to the Plasmodium falciparum Maurer’s Clefts

Export of PfSBP1 to the Plasmodium falciparum Maurer’s Clefts

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

Maurer's clefts, the enigma of Plasmodium falciparum

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