Critical Steps in Protein Export of Plasmodium falciparum Blood Stages

Spielmann, Tobias; Gilberger, Tim‐Wolf

doi:10.1016/j.pt.2015.06.010

Cited by 35 publications

(28 citation statements)

References 102 publications

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“…As mentioned above, it had been speculated that PTEX may insert nonexported transmembrane (TM) proteins into the PVM (Haase & de Koning‐Ward, ; Elsworth et al, ; Spielmann & Gilberger, ). To investigate whether Exp1 is trafficked in this manner, we studied insertion of Exp1 into the PVM in cell lines in which levels of the essential PTEX component PTEX150 can be downregulated using a glmS riboswitch system (Elsworth et al, ).…”

Section: Resultsmentioning

confidence: 99%

Trafficking of PfExp1 to the parasitophorous vacuolar membrane ofPlasmodium falciparumis independent of protein folding and the PTEX translocon

Tribensky

Graf

Diehl

et al. 2017

Cellular Microbiology

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Having entered the mature human erythrocyte, the malaria parasite survives and propagates within a parasitophorous vacuole, a membrane-bound compartment separating the parasite from the host cell cytosol. The bounding membrane of this vacuole, referred to as the parasitophorous vacuolar membrane (PVM), contains parasite-encoded proteins, but how these membrane proteins are trafficked to the PVM remains unknown. Here, we have studied the trafficking of PfExp1 to the PVM. We find that trafficking of PfExp1 to the PVM is independent of the folding state of the protein and also continues unabated upon inactivation of the PVM translocon Plasmodium Translocon of Exported proteins (PTEX). Our data strongly suggest that the trafficking of membrane proteins to the PVM occurs by as yet unknown mechanism, potentially unique to Plasmodium.

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Section: Resultsmentioning

confidence: 99%

Trafficking of PfExp1 to the parasitophorous vacuolar membrane ofPlasmodium falciparumis independent of protein folding and the PTEX translocon

Tribensky

Graf

Diehl

et al. 2017

Cellular Microbiology

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“…Although some of its components are clearly essential for protein export, PTEX is still a translocon in concept, as translocation activity has so far not been shown and a function upstream of membrane translocation would also satisfy the findings so far [ 3 , 17 ]. It is also puzzling that it promotes trafficking of both TM and soluble proteins.…”

Section: Introductionmentioning

confidence: 84%

Stable Translocation Intermediates Jam Global Protein Export in Plasmodium falciparum Parasites and Link the PTEX Component EXP2 with Translocation Activity

et al. 2016

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Protein export is central for the survival and virulence of intracellular P. falciparum blood stage parasites. To reach the host cell, exported proteins cross the parasite plasma membrane (PPM) and the parasite-enclosing parasitophorous vacuole membrane (PVM), a process that requires unfolding, suggestive of protein translocation. Components of a proposed translocon at the PVM termed PTEX are essential in this phase of export but translocation activity has not been shown for the complex and questions have been raised about its proposed membrane pore component EXP2 for which no functional data is available in P. falciparum. It is also unclear how PTEX mediates trafficking of both, soluble as well as transmembrane proteins. Taking advantage of conditionally foldable domains, we here dissected the translocation events in the parasite periphery, showing that two successive translocation steps are needed for the export of transmembrane proteins, one at the PPM and one at the PVM. Our data provide evidence that, depending on the length of the C-terminus of the exported substrate, these steps occur by transient interaction of the PPM and PVM translocon, similar to the situation for protein transport across the mitochondrial membranes. Remarkably, we obtained constructs of exported proteins that remained arrested in the process of being translocated across the PVM. This clogged the translocation pore, prevented the export of all types of exported proteins and, as a result, inhibited parasite growth. The substrates stuck in translocation were found in a complex with the proposed PTEX membrane pore component EXP2, suggesting a role of this protein in translocation. These data for the first time provide evidence for EXP2 to be part of a translocating entity, suggesting that PTEX has translocation activity and provide a mechanistic framework for the transport of soluble as well as transmembrane proteins from the parasite boundary into the host cell.

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“…Most of the symptoms and sequalae of malaria result from parasite growth and replication within circulating erythrocytes in the animal host. The virulent human parasite, P. falciparum, significantly remodels its host cell by exporting hundreds of effector proteins into erythrocyte cytosol [5,6]. These proteins establish membranous structures in the host cell [7], alter erythrocyte deformability [8], mediate cytoadherence and immune evasion [9,10], and facilitate uptake of nutrients and essential ions [11].…”

Section: Introductionmentioning

confidence: 99%

Complex nutrient channel phenotypes despite Mendelian inheritance in a Plasmodium falciparum genetic cross

et al. 2020

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Malaria parasites activate a broad-selectivity ion channel on their host erythrocyte membrane to obtain essential nutrients from the bloodstream. This conserved channel, known as the plasmodial surface anion channel (PSAC), has been linked to parasite clag3 genes in P. falciparum, but epigenetic switching between the two copies of this gene hinders clear understanding of how the encoded protein determines PSAC activity. Here, we used linkage analysis in a P. falciparum cross where one parent carries a single clag3 gene to overcome the effects of switching and confirm a primary role of the clag3 product with high confidence. Despite Mendelian inheritance, CLAG3 conditional knockdown revealed remarkably preserved nutrient and solute uptake. Even more surprisingly, transport remained sensitive to a CLAG3 isoform-specific inhibitor despite quantitative knockdown, indicating that low doses of the CLAG3 transgene are sufficient to confer block. We then produced a complete CLAG3 knockout line and found it exhibits an incomplete loss of transport activity, in contrast to rhoph2 and rhoph3, two PSAC-associated genes that cannot be disrupted because nutrient uptake is abolished in their absence. Although the CLAG3 knockout did not incur a fitness cost under standard nutrient-rich culture conditions, this parasite could not be propagated in a modified medium that more closely resembles human plasma. These studies implicate oligomerization of CLAG paralogs encoded by various chromosomes in channel formation. They also reveal that CLAG3 is dispensable under standard in vitro conditions but required for propagation under physiological conditions.

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Critical Steps in Protein Export of Plasmodium falciparum Blood Stages

Cited by 35 publications

References 102 publications

Trafficking of PfExp1 to the parasitophorous vacuolar membrane ofPlasmodium falciparumis independent of protein folding and the PTEX translocon

Trafficking of PfExp1 to the parasitophorous vacuolar membrane ofPlasmodium falciparumis independent of protein folding and the PTEX translocon

Stable Translocation Intermediates Jam Global Protein Export in Plasmodium falciparum Parasites and Link the PTEX Component EXP2 with Translocation Activity

Complex nutrient channel phenotypes despite Mendelian inheritance in a Plasmodium falciparum genetic cross

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