Plasmodium P-Type Cyclin CYC3 Modulates Endomitotic Growth during Oocyst Development in Mosquitoes

Roques, Magali; Wall, Richard J.; Douglass, Alexander P.; Ramaprasad, Abhinay; Ferguson, David; Kaindama, Mbinda L.; Brusini, Lorenzo; Nimitray, Joshi; Rchiad, Zineb; Brady, Declan; Guttery, David S.; Wheatley, Sally P.; Yamano, Hiroyuki; Holder, Anthony A.; Pain, Arnab; Wickstead, Bill; Tewari, Rita

doi:10.1371/journal.ppat.1005273

Cited by 66 publications

(83 citation statements)

References 97 publications

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“…4a) 17 . Interestingly, homologues of Group I cyclins are not found in the Plasmodium genome, including cyclin E, which is critical for G1 to S transition in other systems 30 . Interventions targeting Pf CRK4 function would be efficacious throughout the extended period of schizogony in the clinically relevant blood-stage, as well as at the transmission stages, which taken together are attractive features for future drug development.…”

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confidence: 99%

Plasmodium falciparum CRK4 directs continuous rounds of DNA replication during schizogony

et al. 2017

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Plasmodium parasites, the causative agents of malaria, have evolved a unique cell division cycle in the clinically relevant asexual blood-stage of infection1. DNA replication commences approximately halfway through the intracellular development following invasion and parasite growth. The schizont stage is associated with multiple rounds of DNA replication and nuclear division without cytokinesis resulting in a multinucleated cell. Nuclei divide asynchronously through schizogony, with only the final round of DNA replication and segregation being synchronous and coordinated with daughter cell assembly2,3. However, the control mechanisms for this divergent mode of replication are unknown. Here we show that the Plasmodium-specific kinase PfCRK4 is a key cell cycle regulator that orchestrates the multiple rounds of DNA replication throughout schizogony in P. falciparum. PfCRK4 depletion led to a complete block in nuclear division and profoundly inhibited DNA replication. Quantitative phosphoproteomic profiling identified a set of PfCRK4-regulated phosphoproteins with greatest functional similarity to CDK2 substrates, particularly proteins involved in origin of replication firing. PfCRK4 was required for the initial and subsequent rounds of DNA replication during schizogony, and in addition was essential for development in the mosquito vector. Our results identified an essential S phase promoting factor of the unconventional P. falciparum cell cycle. PfCRK4 is required for both a prolonged period of the intraerythrocytic blood-stage of malaria infection, as well as for transmission, revealing a broad window for PfCRK4-targeted chemotherapeutics.

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Plasmodium falciparum CRK4 directs continuous rounds of DNA replication during schizogony

et al. 2017

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“…Also, there could be qualitative differences between merozoite maturation in the erythrocyte host cell versus the hepatocyte that require further checkpoints of developmental control. Cyclins are a family of proteins important for cell cycle progression and recently, a Plasmodium P-type cyclin, CYC3 was shown to be critical for normal endomitosis during oocyst development but not necessary for liver stage development (36). Since PlasMei2 also appears to play a role in endomitosis, it is tempting to hypothesize that liver stage-specific expression of a cyclin other than CYC3 could work alongside PlasMei2 to coordinate liver stage development.…”

Section: Discussionmentioning

confidence: 99%

A Plasmodium yoelii Mei2-Like RNA Binding Protein Is Essential for Completion of Liver Stage Schizogony

et al. 2016

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bPlasmodium parasites employ posttranscriptional regulatory mechanisms as their life cycle transitions between host cell invasion and replication within both the mosquito vector and mammalian host. RNA binding proteins (RBPs) provide one mechanism for modulation of RNA function. To explore the role of Plasmodium RBPs during parasite replication, we searched for RBPs that might play a role during liver stage development, the parasite stage that exhibits the most extensive growth and replication. We identified a parasite ortholog of the Mei2 (Meiosis inhibited 2) RBP that is conserved among Plasmodium species (PlasMei2) and exclusively transcribed in liver stage parasites. Epitope-tagged Plasmodium yoelii PlasMei2 was expressed only during liver stage schizogony and showed an apparent granular cytoplasmic location. Knockout of PlasMei2 (plasmei2 ؊ ) in P. yoelii only affected late liver stage development. The P. yoelii plasmei2 ؊ liver stage size increased progressively until late in development, similar to wild-type parasite development. However, P. yoelii plasmei2 ؊ liver stage schizonts exhibited an abnormal DNA segregation phenotype and failed to form exoerythrocytic merozoites. Consequently the cellular integrity of P. yoelii plasmei2 ؊ liver stages became increasingly compromised late in development and the majority of P. yoelii plasmei2 ؊ underwent cell death by the time wild-type liver stages mature and release merozoites. This resulted in a complete block of P. yoelii plasmei2 Malaria is caused by unicellular eukaryotic parasites of the genus Plasmodium. The life cycles of the Plasmodium parasites that cause human disease (including the major human parasite Plasmodium falciparum) and other mammalian parasites such as rodent malaria parasites (including P. berghei and P. yoelii) are similar. The parasites progress through an elaborate life cycle, part within an anopheline mosquito vector and part within the mammalian host. Within the host, the sporozoite stage first infects hepatocytes, within which the parasite then develops as a liver stage (also known as an exoerythrocytic form), an acyclic process that occurs once during a malaria infection. Intrahepatocytic parasite development progresses in a cellular process known as schizogony, an endomitotic process characterized by an enormous increase in cell mass with concomitant DNA replication and organelle replication but without cytokinesis. It is only in the final hours of liver stage schizogony that organelles and DNA completely segregate and are apportioned into tens of thousands of rapidly differentiating exoerythrocytic invasive merozoites. These are released and initiate the infection of erythrocytes. Erythrocytic schizogony is cyclic and generates approximately 20 to 30 new merozoites in each cycle. Parasite schizogony and merozoite formation in both hepatocytes and erythrocytes likely employ shared gene regulatory networks and cell regulatory mechanisms, but it is possible that because exoerythrocytic schizogony exceeds erythrocytic schizogony by m...

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“…For gene deletion parasites, a diagnostic PCR reaction and Southern blot were used to confirm correct integration. These approaches are described previously (Roques et al, 2015).…”

Section: Generation and Genotypic Analysis Of Transgenic Parasitesmentioning

confidence: 99%

Systematic analysis of Plasmodium myosins reveals differential expression, localization and function in invasive and proliferative parasite stages

Wall

Zeeshan

Katris

et al. 2019

Preprint

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should be considered joint senior authors. Running title: Localization and function of myosins in Plasmodium SummaryThe myosin superfamily comprises of actin-dependent eukaryotic molecular motors important in a variety of cellular functions. Although well studied in many systems, knowledge of their functions in Plasmodium, the causative agent of malaria, is restricted.Previously, six myosins were identified in this genus, including three Class XIV myosins found only in Apicomplexa and some Ciliates. The well characterised MyoA, is a class XIV myosin essential for gliding motility and invasion. Here, we characterize all other Plasmodium myosins throughout the parasite life cycle and show that they have very diverse patterns of expression and cellular location. MyoB and MyoE, the other two Class XIV myosins, are expressed in all invasive stages, with apical and basal locations, respectively. Gene deletion revealed that MyoE is involved in sporozoite motility, MyoF and MyoK are likely essential in the asexual blood stages, and MyoJ and MyoB are not essential. Both MyoB and its essential light chain (MCL-B) are localised at the apical end of ookinetes but expressed at completely different time points. This work provides a better understanding of the role of actomyosin motors in Apicomplexan parasites, particularly in the motile and invasive stages of Plasmodium during sexual and asexual development within the mosquito.

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Plasmodium P-Type Cyclin CYC3 Modulates Endomitotic Growth during Oocyst Development in Mosquitoes

Cited by 66 publications

References 97 publications

Plasmodium falciparum CRK4 directs continuous rounds of DNA replication during schizogony

Plasmodium falciparum CRK4 directs continuous rounds of DNA replication during schizogony

A Plasmodium yoelii Mei2-Like RNA Binding Protein Is Essential for Completion of Liver Stage Schizogony

Systematic analysis of Plasmodium myosins reveals differential expression, localization and function in invasive and proliferative parasite stages

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