Divide and Thrive: Unravelling the unconventional dynamics and regulation of rapidcell division during Plasmodium male gamete formation

分而治之：揭示疟原虫雄配子形成过程中细胞快速分裂的非常规动力学和调节

• 批准号: EP/X024776/1
• 负责人: Rita Tewari
• 金额: $ 274.29万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX024776%2F1
• 关键词: Divide; Thrive; Unravelling; unconventional; dynamics

Cell division is the central process enabling organisms to proliferate, propagate and survive. Extensive fundamental understanding of cell division mechanisms exist in model eukaryotes like mammalian and yeast systems. Such studies are limited for evolutionarily divergent organisms, such as Plasmodium - the causative agent of malaria - as these species are often more complex or difficult to study. In Plasmodium, male gamete formation occurs by a rapid atypical cell division process within fifteen minutes, compared to many hours in model eukaryotes. Here, genome replication from 1N to 8N takes place with successive spindle formation, chromosome segregation in the nucleus and concomitant axoneme and unusual flagella assembly in the cytoplasm, allowing eight flagellated haploid gametes to be formed in fifteen minutes. This rapidity suggests novel mechanisms control the cell cycle and the microtubule organising centre (MTOC) compared to standard model eukaryotes. Consistent with the unusual nature of this cell division, many canonical regulators like mitotic protein kinases are either missing or highly divergent in Plasmodium. This life cycle stage occurs within the mosquito and is essential for parasite transmission. The proposal aims to unravel how cell division during male gamete formation is governed by the divergent mitotic protein kinases, and dissect the timing of assembly and function of the MTOC, mitotic spindle and axoneme components. We will use real time live cell imaging, genetic modulation of kinase function, phosphoproteomics, protein network analysis and three-dimensional electron microscopy to decipher spatial organisation, function and ultrastructure of the different components. This will deliver a new integrated, holistic view of parasite cell division and broaden our understanding and importance of evolutionarily conserved and divergent mechanisms of cell division. The study will also help to reveal potential targets for intervention of malaria

细胞分裂是使生物可以增殖，繁殖和生存的中心过程。在哺乳动物和酵母系统等真核生物中，对细胞分裂机制的广泛理解存在。这种研究受到进化不同生物的限制，例如疟原虫 - 疟疾的致病药物 - 因为这些物种通常更复杂或难以研究。在疟原虫中，与模型真核生物相比，在十五分钟内，雄性配子的形成是通过15分钟内快速的非典型细胞分裂过程发生的。在这里，从1N到8N的基因组复制发生在连续的纺锤体形成，细胞核中的染色体隔离以及伴随的轴突和不寻常的鞭毛组装中，使八个鞭毛的单倍体配子在十五分钟内形成。这种速度表明，与标准模型真核生物相比，新型机制控制细胞周期和微管组织中心（MTOC）。与该细胞分裂的异常性质一致，许多典型的调节剂（如有丝分裂蛋白激酶）在疟原虫中缺失或高度分歧。这个生命周期阶段发生在蚊子内，对于寄生虫的传播至关重要。该建议旨在揭示雄性配子形成过程中细胞分裂如何受丝分裂蛋白激酶的控制，并剖析MTOC，有丝分裂纺锤体和轴突成分的组装和功能的时机。我们将使用实时活细胞成像，激酶功能的遗传调节，磷光蛋白质组学，蛋白质网络分析和三维电子显微镜，以解读不同成分的空间组织，功能和超微结构。这将提供寄生虫细胞分裂的新综合，整体观点，并扩大我们对细胞分裂的进化保守和不同机制的理解和重要性。该研究还将有助于揭示疟疾干预的潜在目标

项目成果

Atypical flagella assembly and haploid genome coiling during male gamete formation in Plasmodium.

• DOI: 10.1038/s41467-023-43877-w
• 发表时间: 2023-12-13
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Hair, Molly;Moreira-Leite, Flavia;Ferguson, David J. P.;Zeeshan, Mohammad;Tewari, Rita;Vaughan, Sue
• 通讯作者: Vaughan, Sue

Meiosis in Plasmodium: how does it work?

• DOI: 10.1016/j.pt.2023.07.002
• 发表时间: 2023-09-13
• 期刊: TRENDS IN PARASITOLOGY
• 影响因子: 9.6
• 作者: Guttery，David S.;Zeeshan，Mohammad;Tewari，Rita
• 通讯作者: Tewari，Rita

Plasmodium ARK2 and EB1 drive unconventional spindle dynamics, during chromosome segregation in sexual transmission stages.

• DOI: 10.1038/s41467-023-41395-3
• 发表时间: 2023-09-13
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Zeeshan, Mohammad;Rea, Edward;Abel, Steven;Vukusic, Kruno;Markus, Robert;Brady, Declan;Eze, Antonius;Rashpa, Ravish;Balestra, Aurelia C.;Bottrill, Andrew R.;Brochet, Mathieu;Guttery, David S.;Tolic, Iva M.;Holder, Anthony A.;Le Roch, Karine G.;Tromer, Eelco C.;Tewari, Rita
• 通讯作者: Tewari, Rita

Atypical flagella assembly and haploid genome coiling during male gamete formation in Plasmodium

疟原虫雄配子形成过程中的非典型鞭毛组装和单倍体基因组卷曲

• DOI: 10.1101/2023.05.17.540968
• 发表时间: 2023
• 作者: Hair M