MAHRP-1, a Novel Plasmodium falciparum Histidine-rich Protein, Binds Ferriprotoporphyrin IX and Localizes to the Maurer's Clefts

Spycher, Cornelia; Klonis, Nectarios; Spielmann, Tobias; Kump, Erwin; Steiger, Sylvia; Tilley, Leann; Beck, Hans‐Peter

doi:10.1074/jbc.m305851200

Cited by 97 publications

(107 citation statements)

References 51 publications

(90 reference statements)

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“…However, there are exceptions to the rule that a PEXEL/VTS motif is needed to cross the PVM, because some PEXELnegative exported proteins have been documented (Blisnick et al, 2000;Spycher et al, 2003). Our analysis of the cluster of ring stage-specific genes on chromosome 9 revealed that only two of the 4 exported proteins possess an obvious PEXEL.…”

Section: Discussionmentioning

confidence: 97%

“…The remaining five genes code for PEXEL-negative proteins. The locations of three of these (now called SBP1, MAHRP1, and REX2) have since been determined, and they are all exported to the Maurer's clefts (Blisnick et al, 2000;Spycher et al, 2003;this study). Hence, apart from the ETRAMPs (which are exported but do not need a PEXEL, because they remain in the PVM), Ͼ50% of the identified proteins do not have a PEXEL, and all three tested so far are exported.…”

Section: Discussionmentioning

confidence: 99%

“…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

Self Cite

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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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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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116

162

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“…Only one gene was up-regulated by at least threefold in all five selections: PF14_0472, a member of the Plasmodium helical interspersed subtelomeric (PHISTa) family (37). Six other up-regulated genes encode proteins predicted or proven to be exported: P. falciparum erythrocyte membrane protein 3 (PfEMP3) (38), ring-IE surface antigen (RESA-1) (39), membrane associated histine-rich protein 1 (MAHRP-1) (40), and three others with a Pexel motif: PF14_0740, PF11_0035, and PFF0055w (37). These six genes and PF14_0472 are up-regulated at time point 3 (16-24 h postinvasion) in almost all selections, indicating that they could be translated in time for cytoadherence at the pigmented trophozoite stage.…”

Section: Some Exported Proteins Show Increased Transcription In Hbec-mentioning

confidence: 99%

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

Claessens

Adams

Ghumra

et al. 2012

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

197

230

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Cerebral malaria is the most deadly manifestation of infection with Plasmodium falciparum. The pathology of cerebral malaria is characterized by the accumulation of infected erythrocytes (IEs) in the microvasculature of the brain caused by parasite adhesins on the surface of IEs binding to human receptors on microvascular endothelial cells. The parasite and host molecules involved in this interaction are unknown. We selected three P. falciparum strains (HB3, 3D7, and IT/FCR3) for binding to a human brain endothelial cell line (HBEC-5i). The whole transcriptome of isogenic pairs of selected and unselected parasites was analyzed using a variant surface antigen-supplemented microarray chip. After selection, the most highly and consistently up-regulated genes were a subset of group A-like var genes (HB3var3, 3D7_PFD0020c, ITvar7, and ITvar19) that showed 11-to >100-fold increased transcription levels. These var genes encode P. falciparum erythrocyte membrane protein (PfEMP)1 variants with distinct N-terminal domain types (domain cassette 8 or domain cassette 13). Antibodies to HB3var3 and PFD0020c recognized the surface of live IEs and blocked binding to HBEC-5i, thereby confirming the adhesive function of these variants. The clinical in vivo relevance of the HBEC-selected parasites was supported by significantly higher surface recognition of HBEC-selected parasites compared with unselected parasites by antibodies from young African children suffering cerebral malaria (Mann-Whitney test, P = 0.029) but not by antibodies from controls with uncomplicated malaria (Mann-Whitney test, P = 0.58). This work describes a binding phenotype for virulence-associated group A P. falciparum erythrocyte membrane protein 1 variants and identifies targets for interventions to treat or prevent cerebral malaria.adherence | pathogenesis | sequestration

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“…The HRPs (histidine-rich proteins) of P. falciparum (PfHRP II, III, IV and membraneassociated histidine-rich protein-1 etc. ), which readily bind multiple haem monomers [10][11][12], have been suggested to play a crucial role in the haem detoxification process. These HRPs may also be involved in the neutralization of toxic haem in the parasite cytoplasm and infected red blood cells by removing haem that is membrane bound [13].…”

Section: Introductionmentioning

confidence: 99%

Reaction of artemisinin with haemoglobin: implications for antimalarial activity

Kannan

Kumar

Sahal

et al. 2005

Biochemical Journal

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Elucidation of the principal targets of the action of the antimalarial drug artemisinin is an ongoing pursuit that is important for understanding the action of this drug and for the development of more potent analogues. We have examined the chemical reaction of Hb with artemisinin. The protein-bound haem in Hb has been found to react with artemisinin much faster than is the case with free haem. It appears that the uptake of Hb and the accumulation of artemisinin into the food vacuole, together with the preferred reactivity of artemisinin with haem in Hb, may make Hb the primary target of artemisinin's antimalarial action. Both monoalkylated (HA) and dialkylated (HAA) haem derivatives of artemisinin have been isolated. These 'haemarts' bind to PfHRP II (Plasmodium falciparum histidine-rich protein II), inhibiting haemozoin formation, and possess a significantly decreased ability to oxidize ascorbic acid. The accelerated formation of HAA from Hb is expected to decrease the ratio of haem to its alkylated derivatives. The haemarts that are generated from 'haemartoglobins' may bring about the death of malaria parasite by a two-pronged effect of stalling the formation of haemozoin by the competitive inhibition of haem binding to its templates and creating a more reducing environment that is not conducive to the formation of haemozoin.

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MAHRP-1, a Novel Plasmodium falciparum Histidine-rich Protein, Binds Ferriprotoporphyrin IX and Localizes to the Maurer's Clefts

Cited by 97 publications

References 51 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

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

Reaction of artemisinin with haemoglobin: implications for antimalarial activity

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