Protein Phosphatase 1 regulates atypical mitotic and meiotic division in<i>Plasmodium</i>sexual stages

Zeeshan, Mohammad; Pandey, Rajan Kumar; Subudhi, Amit Kumar; Ferguson, David J. P.; Kaur, Gursimran; Rashpa, Ravish; Nugmanova, Raushan; Brady, Declan; Bottrill, Andrew R.; Vaughan, Sue; Brochet, Mathieu; Pain, Arnab; Holder, Anthony A.; Guttery, David S.; Tewari, Rita

doi:10.1101/2021.01.15.426883

Cited by 2 publications

(3 citation statements)

References 84 publications

(111 reference statements)

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“…This phenotype of kinesin-13 depletion is different from that of the Δkinesin-20 , where apical polarity was not affected. A similar phenotype has been observed following knockdown of two P. berghei phosphatases, PPKL and PP1, where apical polarity was lost, affecting ookinete differentiation (49, 68).…”

Section: Discussionsupporting

confidence: 65%

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Genome-wide functional analysis reveals key roles for kinesins in the mammalian and mosquito stages of the malaria parasite life cycle

Zeeshan

Rashpa

Ferguson

et al. 2021

Preprint

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Kinesins are microtubule-based motors important in cell division, motility, polarity, and intracellular transport in many eukaryotes, but poorly studied in eukaryotic pathogens. Plasmodium, the causative agent of malaria, is a divergent eukaryote with atypical aspects of cell division and plasticity of morphology throughout its lifecycle in both mammalian and mosquito hosts. Here we describe a genome-wide screen of all nine Plasmodium kinesins, revealing diverse subcellular locations and functions in spindle assembly, axoneme formation, and cell morphology. Surprisingly, only kinesin-13 has an essential role for growth in the mammalian host while the other eight kinesins are required during the proliferative and invasive stages of parasite transmission through the mosquito vector. In-depth analyses of kinesin-13 and kinesin-20 revealed functions in microtubule (MT) dynamics during apical polarity formation, spindle assembly, and axoneme biogenesis. This comprehensive study will inform the targeting of MT motors for therapeutic intervention in malaria.

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Section: Discussionsupporting

confidence: 65%

“…A similar phenotype has been observed following the knockdown of two P . berghei phosphatases, PPKL and PP1, where apical polarity was lost, affecting ookinete differentiation (Guttery et al, 2012; Zeeshan et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide functional analysis reveals key roles for kinesins in the mammalian and mosquito stages of the malaria parasite life cycle

Zeeshan

Rashpa

Ferguson

et al. 2021

Preprint

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“…Live-cell fluorescence microscopy has also been explored, with a recent study utilising lattice light-sheet microscopy to acquire 3D live time-lapse data of asexual P. falciparum invasion 26 . Other studies have reported the use of live-cell fluorescence imaging of microgametogenesis to define the phenotypes of transgenic P. berghei 27,28 cell lines.…”

Section: Introductionmentioning

confidence: 99%

4D live-cell imaging of microgametogenesis in the human malaria parasite Plasmodium falciparum

Yahiya

Jordan

Smith

et al. 2021

Preprint

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Formation of gametes in the malaria parasite occurs in the midgut of the mosquito and is critical to onward parasite transmission. Transformation of the male gametocyte into microgametes, called microgametogenesis, is an explosive cellular event and one of the fastest eukaryotic DNA replication events known. The transformation of one microgametocyte into eight flagellated microgametes requires reorganisation of the parasite cytoskeleton, replication of the 22.9 Mb genome, axoneme formation and host erythrocyte egress, all of which occur simultaneously in <20 minutes. Whilst high-resolution imaging has been a powerful tool for defining stages of microgametogenesis, it has largely been limited to fixed parasite samples, given the speed of the process and parasite photosensitivity. Here, we have developed a live-cell fluorescence imaging workflow that captures the explosive dynamics of microgametogenesis in full. Using the most virulent human malaria parasite, Plasmodium falciparum, our live-cell approach combines three-dimensional imaging through time (4D imaging) and covers early microgametocyte development through to microgamete release. Combining live-cell stains for DNA, tubulin and the host erythrocyte membrane, 4D imaging enables definition of the positioning of newly replicated and segregated DNA. It also shows the microtubular cytoskeleton, location of newly formed basal bodies and elongation of axonemes, as well as behaviour of the erythrocyte membrane, including its specific perforation prior to microgamete egress. 4D imaging was additionally undertaken in the presence of known transmission-blocking inhibitors and the untested proteasomal inhibitor bortezomib. Here, for the first time we find that bortezomib inhibition results in a clear block of DNA replication, full axoneme nucleation and elongation. These data not only define a framework for understanding microgametogenesis in general but also suggest that the process is critically dependent on proteasomal activity, helping to identify potentially novel targets for transmission-blocking antimalarial drug development.

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Protein Phosphatase 1 regulates atypical mitotic and meiotic division inPlasmodiumsexual stages

Cited by 2 publications

References 84 publications

Genome-wide functional analysis reveals key roles for kinesins in the mammalian and mosquito stages of the malaria parasite life cycle

Genome-wide functional analysis reveals key roles for kinesins in the mammalian and mosquito stages of the malaria parasite life cycle

4D live-cell imaging of microgametogenesis in the human malaria parasite Plasmodium falciparum

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