The Plasmodium falciparum rhoptry protein RhopH3 plays essential roles in host cell invasion and nutrient uptake

Sherling, Emma S.; Knuepfer, Ellen; Brzostowski, Joseph; Miller, Louis H.; Blackman, Michael J.; Ooij, Christiaan van

doi:10.7554/elife.23239

Cited by 87 publications

(94 citation statements)

References 68 publications

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“…Interestingly cytoadherence-linked asexual genes (CLAG) proteins, are also targets of PfAP2-I. Although the CLAGs are members of the RhopH protein family, they are not involved in invasion but their expression matches that of invasion-related genes (Counihan et al, 2017; Ito et al, 2017; Sherling et al, 2017). …”

Section: Discussionmentioning

confidence: 99%

Red Blood Cell Invasion by the Malaria Parasite Is Coordinated by the PfAP2-I Transcription Factor

Santos

Josling

Ross

et al. 2017

Cell Host & Microbe

126

244

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Summary Obligate intracellular parasites must efficiently invade host cells in order to mature and be transmitted. For the malaria parasite Plasmodium falciparum, invasion of host red blood cells (RBCs) is essential. Here we describe a parasite-specific transcription factor PfAP2-I, belonging to the Apicomplexan AP2 (ApiAP2) family, that is responsible for regulating the expression of genes involved in RBC invasion. Our genome-wide analysis by ChIP-seq shows that PfAP2-I interacts with a specific DNA motif in the promoters of target genes. Although PfAP2-I contains three AP2 DNA-binding domains, only one is required for binding of the target genes during blood stage development. Furthermore, we find that PfAP2-I associates with several chromatin-associated proteins, including the Plasmodium bromodomain protein PfBDP1, and that complex formation is associated with transcriptional regulation. As a key regulator of red blood cell invasion, PfAP2-I represents a potential new antimalarial therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Red Blood Cell Invasion by the Malaria Parasite Is Coordinated by the PfAP2-I Transcription Factor

Santos

Josling

Ross

et al. 2017

Cell Host & Microbe

126

244

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“…Erythrocytes infected with malaria parasites have increased permeability to diverse solutes, including Ca ++ . Uncharged solutes and monovalent ions utilise the PSAC, a nutrient uptake channel linked to the RhopH complex conserved in all examined Plasmodia (Counihan et al, 2017;Ito et al, 2017;Sherling et al, 2017). Divalent ions such as Ca ++ are not permeant through PSAC and therefore require a separate mechanism for their increased uptake.…”

Section: Discussionmentioning

confidence: 99%

Increased Ca⁺⁺uptake by erythrocytes infected with malaria parasites: Evidence for exported proteins and novel inhibitors

Kushwaha

Apolis

Ito

et al. 2018

Cellular Microbiology

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Malaria parasites export many proteins into their host erythrocytes and increase membrane permeability to diverse solutes. Although most solutes use a broad-selectivity channel known as the plasmodial surface anion channel, increased Ca uptake is mediated by a distinct, poorly characterised mechanism that appears to be essential for the intracellular parasite. Here, we examined infected cell Ca uptake with a kinetic fluorescence assay and the virulent human pathogen, Plasmodium falciparum. Cell surface labelling with N-hydroxysulfosuccinimide esters revealed differing effects on transport into infected and uninfected cells, indicating that Ca uptake at the infected cell surface is mediated by new or altered proteins at the host membrane. Conditional knockdown of PTEX, a translocon for export of parasite proteins into the host cell, significantly reduced infected cell Ca permeability, suggesting involvement of parasite-encoded proteins trafficked to the host membrane. A high-throughput chemical screen identified the first Ca transport inhibitors active against Plasmodium-infected cells. These novel chemical scaffolds inhibit both uptake and parasite growth; improved in vitro potency at reduced free [Ca ] is consistent with parasite killing specifically via action on one or more Ca transporters. These inhibitors should provide mechanistic insights into malaria parasite Ca transport and may be starting points for new antimalarial drugs.

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“…To achieve this, we employed the robust conditional DiCre approach in combination with Cas9-induced gene modification. This system provides a rapid and efficient means of generating transgenic parasites as well as enabling complete disruption of the gene of interest [29,30]. Our study demonstrates that DiCre-mediated conditional knockout is a powerful tool to study essential genes in the human malaria parasite.…”

Section: Discussionmentioning

confidence: 91%

Function and essentiality of Plasmodium falciparum plasmepsin V

Boonyalai

Collins

Hackett

et al. 2018

Preprint

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29The malaria parasite replicates within erythrocytes. The pathogenesis of clinical malaria is in large part 30 due to the capacity of the parasite to remodel its host cell. To do this, intraerythrocytic stages of 31 Plasmodium falciparum export more than 300 proteins that dramatically alter the morphology of the 32 infected erythrocyte as well as its mechanical and adhesive properties. P. falciparum plasmepsin V 33 (PfPMV) is an aspartic protease that processes proteins for export into the host erythrocyte and is thought 34 to play a key role in parasite virulence and survival. However, although standard techniques for gene 35 disruption as well as conditional protein knockdown have been previously attempted with the pfpmv gene, 36 complete gene removal or knockdown was not achieved so direct genetic proof that PMV is an essential 37 protein has not yet been established. Here we have used a conditional gene excision approach combining 38 CRISPR-Cas9 gene editing and DiCre-mediated recombination to functionally inactivate the pfpmv gene. 39 The resulting mutant parasites displayed a severe growth defect. Detailed phenotypic analysis showed 40 that development of the mutant parasites was arrested at the ring-to-trophozoite transition in the 41 erythrocytic cycle following gene excision, likely due to a defect in protein export. Our findings are the 42 first to elucidate the effects of PMV gene disruption, showing that it is essential for parasite viability in 43 asexual blood stages. The mutant parasites can now be used as a platform to further dissect the 44 Plasmodium protein export pathway. 45 46

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The Plasmodium falciparum rhoptry protein RhopH3 plays essential roles in host cell invasion and nutrient uptake

Cited by 87 publications

References 68 publications

Red Blood Cell Invasion by the Malaria Parasite Is Coordinated by the PfAP2-I Transcription Factor

Red Blood Cell Invasion by the Malaria Parasite Is Coordinated by the PfAP2-I Transcription Factor

Increased Ca⁺⁺uptake by erythrocytes infected with malaria parasites: Evidence for exported proteins and novel inhibitors

Function and essentiality of Plasmodium falciparum plasmepsin V

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The Plasmodium falciparum rhoptry protein RhopH3 plays essential roles in host cell invasion and nutrient uptake

Cited by 87 publications

References 68 publications

Red Blood Cell Invasion by the Malaria Parasite Is Coordinated by the PfAP2-I Transcription Factor

Red Blood Cell Invasion by the Malaria Parasite Is Coordinated by the PfAP2-I Transcription Factor

Increased Ca++uptake by erythrocytes infected with malaria parasites: Evidence for exported proteins and novel inhibitors

Function and essentiality of Plasmodium falciparum plasmepsin V

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Increased Ca⁺⁺uptake by erythrocytes infected with malaria parasites: Evidence for exported proteins and novel inhibitors