Mechanisms of the unusual cytokinesis in trypanosomes

布氏锥虫的胞质分裂 疾病，是从新的鞭毛附着区（FAZ）丝的前端开始的。胞质分裂 卵裂沟沿着纵轴由前向后单向进入 在T.布氏 从最后一个真核生物共同祖先中分化出来。T.众所周知，布鲁塞完全不同， 因此是一个很有前途的药物靶点。据信， T. brucei与大多数真核生物不同，T.布氏 涉及新的组件。然而，关于胞质分裂调节途径和细胞周期调控途径知之甚少。 T.布氏杆菌，从而大大阻碍了我们对 这种可怕的人类病原体的胞质分裂目前的建议是建立在最近发现的胞质分裂信号级联，并旨在解决以下问题。（一）.在不同的生活史形式的T。brucei？我们假设，多个监管机构，包括进化上保守的蛋白激酶和动质体特异性监管机构，合作在新FAZ丝的前端，以调节胞质分裂起始和在卵裂沟，以促进卵裂沟内移。我们的重点是机械的 两种新的蛋白质，命名为CIF 3和CIF 4，在胞质分裂中的作用，以及它们如何与已知的 胞质分裂调节剂以实现其在昆虫和血流形式中的生物学功能。（二）、是什么 蛋白质磷酸化和去磷酸化在胞质分裂中的生理作用？的参与 胞质分裂中的两种蛋白激酶TbPLK和TbAUK1提示胞质分裂的广泛磷酸化 两种激酶的调节剂。重要的是，我们鉴定了一种动质体特异性蛋白磷酸酶， KPP 1（动塑性蛋白特异性蛋白磷酸酶1），似乎拮抗TbPLK。我们建议 研究TbPLK和TbAUK1对CIF1和CIF2磷酸化的生理作用， KPP1对胞质分裂的贡献。（三）、是什么驱动了卵裂沟的内移？ 乳沟的边缘吗我们发现了一种新的蛋白质，它含有一个驱动蛋白马达结构域和两个 原肌球蛋白结构域和定位到分裂沟在胞质分裂。因此我们假设T. 布氏杆菌采用一种新的基于原肌球蛋白的收缩机制进行沟内移， 驱动蛋白马达驱动从前细胞端（细胞的负端）的单向沟内移。 微管）朝向后细胞端（加上微管的末端）。 本实验室的长期目标是阐明T细胞胞质分裂的调控途径。并探讨不同生命周期形式中不同细胞周期控制的机制。这些研究将促进我们对胞质分裂的分子基础的基本理解，胞质分裂不同于通常公认的通过肌动球蛋白收缩环作用的细胞分裂机制。这些研究结果不仅具有重要的生物学意义，而且可能为抗锥虫化疗提供新的靶点。

Cytokinesis in Trypanosoma brucei, a parasitic protozoan and the causative agent of human sleeping sickness, is initiated from the anterior tip of the new flagellum attachment zone (FAZ) filament. The cytokinesis cleavage furrow ingresses uni-directionally along the longitudinal axis from the anterior towards the posterior end of the cell, without the involvement of an actomyosin contractile ring, which appeared after T. brucei diverged from the last eukaryotic common ancestor. Cytokinesis in T. brucei is known to be totally different from that in its human host, and therefore is a promising drug target. It is believed that the cytokinesis regulatory pathway in T. brucei is different from most eukaryotes and that the cleavage furrow in T. brucei involves novel components. However, little is known about the cytokinesis regulatory pathway and the cleavage furrow components in T. brucei, thus significantly hindering our understanding of the mechanisms of cytokinesis in this dreadful human pathogen. The current proposal is built upon the recently discovered cytokinesis signaling cascade, and aims to address the following questions. (1). What are the cytokinesis signaling pathways in different life cycle forms of T. brucei? We hypothesize that multiple regulators, including evolutionarily conserved protein kinases and kinetoplstid-specific regulators, cooperate at the anterior tip of the new FAZ filament to regulate cytokinesis initiation and at the cleavage furrow to promote cleavage furrow ingression. Our focus is on the mechanistic roles of two novel proteins, named CIF3 and CIF4, in cytokinesis and how they cooperate with the known cytokinesis regulators to fulfil their biological function in both the insect and bloodstream forms. (2). What are the physiological roles of protein phosphorylation and dephosphorylation in cytokinesis? The involvement of two protein kinases, TbPLK and TbAUK1, in cytokinesis suggests an extensive phosphorylation of cytokinesis regulators by the two kinases. Importantly, we identified a kinetoplastid-specific protein phosphatase, named KPP1 (Kinetoplstid-specific Protein Phosphatase 1), that appears to antagonize TbPLK. We propose to investigate the physiological roles of CIF1 and CIF2 phosphorylation by TbPLK and TbAUK1 and the contribution of KPP1 to cytokinesis. (3). What drives cleavage furrow ingression and what are the components of the cleavage furrow? We identified a novel protein that contains a kinesin motor domain and two tropomyosin domains and localizes to the cleavage furrow during cytokinesis. We thus hypothesize that T. brucei employs a novel tropomyosin-based contractile machinery for furrow ingression and a plus end-directed kinesin motor to drive the uni-directional furrow ingression from the anterior cell end (minus end of the microtubules) toward the posterior cell end (plus ends of the microtubules). The long-term goal of my laboratory is to delineate the regulatory pathway that controls cytokinesis in T. brucei and explore the mechanisms underlying the distinct cell cycle control in different life cycle forms. These studies will facilitate our fundamental understanding of the molecular basis of cytokinesis that is different from the commonly recognized cell division mechanism through the action of an actomyosin contractile ring. The outcomes from these investigations not only will have important biological significance, but also could provide novel targets for anti-trypanosome chemotherapy.