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Mechanisms of the Unusual Cytokinesis in Trypanosomes

锥虫异常细胞分裂的机制

基本信息

批准号：
8505659
负责人：
Ziyin Li
金额：
$ 35.72万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-06 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8505659
关键词：
Actomyosin Address African African Trypanosomiasis Anaphase Animals Anterior Antigenic Variation Binding Biochemical Biological Cell Cycle Proteins Cell Cycle Regulation Cell division Cells Chromatin Chromosome Segregation Chromosome Structures Chromosomes Complex Country Cytokinesis Disease Drug Targeting Exhibits Flagella Goals Homologous Gene Homologous Protein Human Immune system Infection Laboratories Link Mediating Mediator of activation protein Metaphase Microtubules Mitosis Molecular Outcome Study Parasites Parasitic Diseases Pathway interactions Pharmaceutical Preparations Phosphorylation Play Positioning Attribute Protein Kinase Proteins Regulation Regulatory Pathway Risk Role Site Structure Structure-Activity Relationship System Testing Trypanosoma Trypanosoma brucei brucei Trypanosomiasis World Health Organization Yeasts aurora kinase base chemical genetics chemotherapy constriction drug development genetic regulatory protein human PLK1 protein novel protein complex public health relevance research study vector yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Cytokinesis in Trypanosoma brucei, a parasitic protozoan and the causative agent of human sleeping sickness, is known to be totally different from that in its human host. The cleavage plane in a dividing trypanosome is not defined by the central spindle like in yeasts and animals, but rather by the position of the new flagellum and the flagellum attachment zone (FAZ). Consequently, cytokinesis in trypanosomes is initiated from the anterior tip of the new FAZ, and the cleavage furrow ingresses unidirectionally along the long axis from the anterior towards the posterior end of the cell. Strikingly, an actomyosin contractile ring is not formed in trypanosomes, indicating that trypanosome cleavage furrow may possess an unusual structure with novel components. Despite these differences, however, both Aurora-like and Polo-like kinases are implicated in cytokinesis initiation in trypanosomes (Hammarton et al., 2007; Li and Wang, 2006; Tu et al., 2006). The Aurora kinase homolog in trypanosomes, TbAUK1, forms a unique chromosomal passenger complex (CPC) that plays essential roles in chromosome segregation and cytokinesis initiation (Li et al., 2008a). The CPC exhibits a dynamic localization during mitosis and cytokinesis by migrating from chromatins to the central spindle during metaphase-anaphase transition and from the central spindle to the anterior tip of the new FAZ during mitosis-cytokinesis transition (Li et al., 2008a; Li et al., 200). The Polo-like kinase homolog in trypanosomes, TbPLK, is also concentrated at the anterior tip of the new FAZ where it promotes cytokinesis initiation (de Graffenried et al., 2008; Kumar and Wang, 2006; Umeyama and Wang, 2008). The downstream factors of the CPC and TbPLK at the anterior tip of the new FAZ are not identified, and trypanosomes appear to lack most of the partner protein homologs of the CPC and Polo-like kinase, suggesting that trypanosomes may have evolved distinct CPC- and PLK-mediated pathways for cytokinesis. The current proposal is built upon the essential roles of TbAUK1 and TbPLK in cytokinesis, and aims to address the following questions. (1). How is cytokinesis initiation regulated by TbAUK1 and TbPLK? We hypothesize that TbAUK1 and TbPLK cooperate to regulate cytokinesis initiation by forming a complex or regulating some common downstream factors at the anterior tip of the new FAZ. Our central hypothesis is that after fulfilling its essential function in mitosis TbAUK1 migrates to th anterior tip of the new FAZ where it cooperates with TbPLK and other novel proteins to initiate cytokinesis. (2). How is TbAUK1 activity and subcellular localization regulated during mitosis-cytokinesis transition and during cytokinesis progression? This is still poorly understood, mainly due to the presence of a novel CPC in trypanosomes and the unique dynamic trans-localization of TbAUK1 during mitosis and cytokinesis. (3). What is the structure-function relationship of the CPC and what are the roles of the two novel CPC components, TbCPC1 and TbCPC2? Our hypothesis is that TbCPC1 and/or TbCPC2 are the mediator(s) of TbAUK1 localization and are also likely the activator(s) of TbAUK1. Through molecular, cell biological, chemical genetic, and biochemical means, our overall goal in this proposal is to understand the mechanistic role of TbAUK1 and TbPLK in cytokinesis initiation, the regulation of TbAUK1 by its novel partners TbCPC1 and TbCPC2. The long-term goal of my laboratory is to delineate the regulatory networks that control mitosis and cytokinesis in T. brucei, which will facilitate our fundamental understanding of the molecular basis of mitosis, mitosis-cytokinesis coordination, and cytokinesis that is different from the commonly recognized cell division through the constriction of an actomyosin contractile ring. The outcome from these studies would not only have important biological significance, but also could provide novel targets for anti-trypanosomiasis chemotherapy.

描述（由申请人提供）：布氏锥虫是一种寄生原生动物，也是人类昏睡病的病原体，已知其细胞分裂与其人类宿主完全不同。分裂锥虫中的分裂平面不像酵母和动物那样由中心纺锤体定义，而是由新鞭毛和鞭毛的位置定义。鞭毛附着区（FAZ）。因此，锥虫中的胞质分裂是从新 FAZ 的前端开始的，并且卵裂沟沿着长轴从细胞的前端向后端单向进入。引人注目的是，锥虫中没有形成肌动球蛋白收缩环，这表明锥虫分裂沟可能具有具有新颖成分的不寻常结构。然而，尽管存在这些差异，Aurora 样激酶和 Polo 样激酶都与锥虫胞质分裂的起始有关（Hammarton 等，2007；Li 和 Wang，2006；Tu 等，2006）。锥虫中的极光激酶同源物 TbAUK1 形成独特的染色体过客复合物 (CPC)，在染色体分离和胞质分裂启动中发挥重要作用 (Li et al., 2008a)。 CPC 在有丝分裂和胞质分裂过程中表现出动态定位，在中期-后期转变期间从染色质迁移到中央纺锤体，并在有丝分裂-细胞分裂转变期间从中央纺锤体迁移到新 FAZ 的前尖（Li 等人，2008a；Li 等人，200）。锥虫中的 Polo 样激酶同源物 TbPLK 也集中在新 FAZ 的前端，促进胞质分裂的启动（de Graffenried 等，2008；Kumar 和 Wang，2006；Umeyama 和 Wang，2008）。新 FAZ 前端的 CPC 和 TbPLK 下游因子尚未确定，并且锥虫似乎缺乏 CPC 和 Polo 样激酶的大部分伙伴蛋白同源物，这表明锥虫可能进化出了不同的 CPC 和 PLK 介导的胞质分裂途径。当前的提案基于 TbAUK1 和 TbPLK 在胞质分裂中的重要作用，旨在解决以下问题。 (1). TbAUK1 和 TbPLK 如何调节胞质分裂的启动？我们假设 TbAUK1 和 TbPLK 通过在新 FAZ 的前尖形成复合物或调节一些常见的下游因子来合作调节胞质分裂的启动。我们的中心假设是，在完成有丝分裂中的基本功能后，TbAUK1 迁移到新 FAZ 的前尖，在那里它与 TbPLK 和其他新蛋白合作启动胞质分裂。（2）。在有丝分裂-细胞分裂过程和胞质分裂过程中，TbAUK1 活性和亚细胞定位是如何受到调节的？这仍然知之甚少，主要是由于锥虫中存在一种新型 CPC 以及 TbAUK1 在有丝分裂和胞质分裂过程中独特的动态反式定位。（3）。 CPC 的结构-功能关系是什么？两个新的 CPC 成分 TbCPC1 和 TbCPC2 的作用是什么？我们的假设是 TbCPC1 和/或 TbCPC2 是 TbAUK1 定位的介体，也可能是 TbAUK1 的激活剂。通过分子、细胞生物学、化学遗传和生化手段，我们在本提案中的总体目标是了解TbAUK1和TbPLK在胞质分裂启动中的机制作用，以及其新伙伴TbCPC1和TbCPC2对TbAUK1的调节。我实验室的长期目标是描绘控制布氏锥虫有丝分裂和胞质分裂的调控网络，这将有助于我们对有丝分裂、有丝分裂-细胞分裂协调和胞质分裂的分子基础的基本理解，这与通常公认的通过肌动球蛋白收缩环收缩进行的细胞分裂不同。这些研究的结果不仅具有重要的生物学意义，而且可以为抗锥虫病化疗提供新的靶点。