Plasmodium species: master renovators of their host cells

Koning-Ward, Tania F. de; Dixon, Matthew W. A.; Tilley, Leann; Gilson, Paul R.

doi:10.1038/nrmicro.2016.79

Cited by 163 publications

(160 citation statements)

References 142 publications

(146 reference statements)

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“…Given the extensive repertoire of exported proteins required for efficient Pf EMP1 trafficking12, the specific requirement for PTEX in Pf EMP1 export has remained uncertain. Here, we provide evidence of a close interaction between Pf EMP1 and PTEX, and corroborate suggestions that PEXEL and PEXEL-negative protein trafficking pathways converge in the PV10112241.…”

Section: Discussionmentioning

confidence: 99%

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An exported protein-interacting complex involved in the trafficking of virulence determinants in Plasmodium-infected erythrocytes

et al. 2017

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The malaria parasite, Plasmodium falciparum, displays the P. falciparum erythrocyte membrane protein 1 (PfEMP1) on the surface of infected red blood cells (RBCs). We here examine the physical organization of PfEMP1 trafficking intermediates in infected RBCs and determine interacting partners using an epitope-tagged minimal construct (PfEMP1B). We show that parasitophorous vacuole (PV)-located PfEMP1B interacts with components of the PTEX (Plasmodium Translocon of EXported proteins) as well as a novel protein complex, EPIC (Exported Protein-Interacting Complex). Within the RBC cytoplasm PfEMP1B interacts with components of the Maurer’s clefts and the RBC chaperonin complex. We define the EPIC interactome and, using an inducible knockdown approach, show that depletion of one of its components, the parasitophorous vacuolar protein-1 (PV1), results in altered knob morphology, reduced cell rigidity and decreased binding to CD36. Accordingly, we show that deletion of the Plasmodium berghei homologue of PV1 is associated with attenuation of parasite virulence in vivo.

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Section: Discussionmentioning

confidence: 99%

“…Indeed, conditional knockdown of the PTEX components heat shock protein-101 (HSP101) or PTEX-150 (PTEX150) prevents Pf EMP1 export beyond the PVM1011. However, it remains to be determined whether Pf EMP1 is a direct substrate for PTEX or is dependent on other proteins that are exported via PTEX12.…”

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confidence: 99%

An exported protein-interacting complex involved in the trafficking of virulence determinants in Plasmodium-infected erythrocytes

et al. 2017

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“…Proteins localizing to the micronemes and rhoptry neck are implicated in the irreversible attachment of the parasite to the host cell and are critical for invasion (reviewed in [Harvey et al, 2012; Weiss et al, 2016]). Dense granule proteins are secreted once Plasmodium parasites have invaded their host cell (Riglar et al, 2011), contributing to remodeling of the host cell (de Koning-Ward et al, 2016). However, the role of proteins that localize to the rhoptry bulb is less clear and although they have been implicated in roles ranging from rhoptry biogenesis, erythrocyte invasion, formation of the parasitophorous vacuole (PV) in which the parasite is encased, as well as modification of the host cell (Kats et al, 2006; Counihan et al, 2013), functional data supporting these roles is very limited.…”

Section: Introductionmentioning

confidence: 99%

Plasmodium falciparum parasites deploy RhopH2 into the host erythrocyte to obtain nutrients, grow and replicate

Counihan

Chisholm

Bullen

et al. 2017

eLife

107

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Plasmodium falciparum parasites, the causative agents of malaria, modify their host erythrocyte to render them permeable to supplementary nutrient uptake from the plasma and for removal of toxic waste. Here we investigate the contribution of the rhoptry protein RhopH2, in the formation of new permeability pathways (NPPs) in Plasmodium-infected erythrocytes. We show RhopH2 interacts with RhopH1, RhopH3, the erythrocyte cytoskeleton and exported proteins involved in host cell remodeling. Knockdown of RhopH2 expression in cycle one leads to a depletion of essential vitamins and cofactors and decreased de novo synthesis of pyrimidines in cycle two. There is also a significant impact on parasite growth, replication and transition into cycle three. The uptake of solutes that use NPPs to enter erythrocytes is also reduced upon RhopH2 knockdown. These findings provide direct genetic support for the contribution of the RhopH complex in NPP activity and highlight the importance of NPPs to parasite survival.DOI: http://dx.doi.org/10.7554/eLife.23217.001

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“…Together these alterations create an environment that supports parasite replication, but also contribute to malaria pathogenesis [1]. The changes are attributed to the export of hundreds of proteins by the parasite to the infected RBC (iRBC) [2]. Although protein export is essential for parasite replication [3], the molecular targets and functions of the P. falciparum exported proteins are largely undefined.…”

Section: Introductionmentioning

confidence: 99%

The Plasmodium falciparum exported protein PF3D7_0402000 binds to erythrocyte ankyrin and band 4.1

Shakya

Penn

Nakayasu

et al. 2017

Molecular and Biochemical Parasitology

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Plasmodium falciparum extensively modifies the infected red blood cell (RBC), resulting in changes in deformability, shape and surface properties. These alterations suggest that the RBC cytoskeleton is a major target for modification during infection. However, the molecular mechanisms leading to these changes are largely unknown. To begin to address this question, we screened for exported P. falciparum proteins that bound to the erythrocyte cytoskeleton proteins ankyrin 1 (ANK1) and band 4.1 (4.1R), which form critical interactions with other cytoskeletal proteins that contribute to the deformability and stability of RBCs. Yeast two-hybrid screens with ANK1 and 4.1R identified eight interactions with P. falciparum exported proteins, including an interaction between 4.1R and PF3D7_0402000 (PFD0090c). This interaction was first identified in a large-scale screen (Vignali et al., Malaria J, 7:211, 2008), which also reported an interaction between PF3D7_0402000 and ANK1. We confirmed the interactions of PF3D7_0402000 with 4.1R and ANK1 in pair-wise yeast two-hybrid and co-precipitation assays. In both cases, an intact PHIST domain in PF3D7_0402000 was required for binding. Complex purification followed by mass spectrometry analysis provided additional support for the interaction of PF3D7_0402000 with ANK1 and 4.1R. RBC ghost cells loaded with maltose-binding protein (MBP)-PF3D7_0402000 passed through a metal microsphere column less efficiently than mock- or MBP-loaded controls, consistent with an effect of PF3D7_0402000 on RBC rigidity or membrane stability. This study confirmed the interaction of PF3D7_0402000 with 4.1R in multiple independent assays, provided the first evidence that PF3D7_0402000 also binds to ANK1, and suggested that PF3D7_0402000 affects deformability or membrane stability of uninfected RBC ghosts.

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Plasmodium species: master renovators of their host cells

Cited by 163 publications

References 142 publications

An exported protein-interacting complex involved in the trafficking of virulence determinants in Plasmodium-infected erythrocytes

An exported protein-interacting complex involved in the trafficking of virulence determinants in Plasmodium-infected erythrocytes

Plasmodium falciparum parasites deploy RhopH2 into the host erythrocyte to obtain nutrients, grow and replicate

The Plasmodium falciparum exported protein PF3D7_0402000 binds to erythrocyte ankyrin and band 4.1

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