Trypanin, a component of the flagellar Dynein regulatory complex, is essential in bloodstream form African trypanosomes.
Trypanin, a component of the flagellar Dynein regulatory complex, is essential in bloodstream form African trypanosomes.
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DOI：
10.1371/journal.ppat.0020101
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发表时间：
2006-09
期刊：
影响因子：
6.7
通讯作者：
Hill KL
中科院分区：
文献类型：
--
作者：
Ralston KS;Hill KL
布氏锥虫鞭毛是一种多功能的细胞器，在运动、细胞形态发生和细胞分裂中具有重要作用。虽然运动被认为是重要的整个锥虫的生命周期，大多数研究鞭毛的结构和功能已被限制到前循环的生命周期阶段，我们的知识的血流形式鞭毛是有限的。我们以前已经表明，锥虫蛋白的功能作为鞭毛动力蛋白调节系统的一部分，从中央对装置和径向辐条轴丝动力蛋白传输调节信号。在这里，我们调查的要求，这种动力蛋白调节系统在血流形式锥虫。我们证明，锥虫蛋白是本地化的鞭毛的血流形式锥虫，在一个模式相同，在原细胞中看到的。令人惊讶的是，锥虫RNA干扰在血流形式中是致命的。这些敲除突变体不能启动胞质分裂，但经历多轮细胞器复制，积累多个鞭毛、细胞核、动质体、线粒体和鞭毛附着区结构。这些研究结果表明，正常的鞭毛节拍是必不可少的血液形式锥虫，并强调了新兴的概念，锥虫生命周期阶段之间的二分法的因素，有助于细胞分裂和细胞形态发生。这是第一次，一个明确的动力蛋白调控复合物已被证明是必不可少的，在任何生物体和牵连的动力蛋白调控复合物和鞭毛运动的其他酶调节剂作为候选药物治疗非洲昏睡病的目标。非洲锥虫是原生动物寄生虫，引起非洲昏睡病，这是一种致命的疾病，具有毁灭性的健康和经济后果。这些寄生虫原产于撒哈拉以南非洲900万平方公里的地区，每天有6 000万人生活在感染的危险之中。锥虫除了给人类健康造成巨大负担外，它们对野生动物和家畜的感染也阻碍了大片原本富饶的土地的可持续经济发展。目前用于治疗昏睡病的药物是过时的，有毒的，往往是无效的，因此，迫切需要开发创新的方法进行治疗干预。锥虫是高度能动的，这种能动性需要轴丝动力蛋白的协调调节，轴丝动力蛋白是驱动寄生虫鞭毛跳动的分子马达。在目前的工作中，作者证明了蛋白质锥蛋白，这是一个信号系统的一部分，调节鞭毛动力蛋白电机，是必不可少的血流阶段非洲锥虫。这一令人惊讶的发现提出了一种可能性，即鞭毛运动所必需的许多酶和调节蛋白可能是非洲昏睡病化疗干预的新靶点。
The Trypanosoma brucei flagellum is a multifunctional organelle with critical roles in motility, cellular morphogenesis, and cell division. Although motility is thought to be important throughout the trypanosome lifecycle, most studies of flagellum structure and function have been restricted to the procyclic lifecycle stage, and our knowledge of the bloodstream form flagellum is limited. We have previously shown that trypanin functions as part of a flagellar dynein regulatory system that transmits regulatory signals from the central pair apparatus and radial spokes to axonemal dyneins. Here we investigate the requirement for this dynein regulatory system in bloodstream form trypanosomes. We demonstrate that trypanin is localized to the flagellum of bloodstream form trypanosomes, in a pattern identical to that seen in procyclic cells. Surprisingly, trypanin RNA interference is lethal in the bloodstream form. These knockdown mutants fail to initiate cytokinesis, but undergo multiple rounds of organelle replication, accumulating multiple flagella, nuclei, kinetoplasts, mitochondria, and flagellum attachment zone structures. These findings suggest that normal flagellar beat is essential in bloodstream form trypanosomes and underscore the emerging concept that there is a dichotomy between trypanosome lifecycle stages with respect to factors that contribute to cell division and cell morphogenesis. This is the first time that a defined dynein regulatory complex has been shown to be essential in any organism and implicates the dynein regulatory complex and other enzymatic regulators of flagellar motility as candidate drug targets for the treatment of African sleeping sickness. African trypanosomes are protozoan parasites that cause African sleeping sickness, a fatal disease with devastating health and economic consequences. These parasites are indigenous to a 9 million-km2 area of sub-Saharan Africa where 60 million people live at risk of infection every day. In addition to the tremendous human health burden posed by trypanosomes, their infection of wild and domestic animals presents a barrier to sustained economic development of vast regions of otherwise productive land. Current drugs used for treatment of sleeping sickness are antiquated, toxic, and often ineffective; thus, there is a dire need for the development of innovative approaches for therapeutic intervention. Trypanosomes are highly motile and this motility requires coordinated regulation of axonemal dynein, a molecular motor that drives beating of the parasite's flagellum. In the present work, the authors demonstrate that the protein trypanin, which is part of a signaling system that regulates the flagellar dynein motor, is essential in bloodstream stage African trypanosomes. This surprising finding raises the possibility that numerous enzymes and regulatory proteins that are necessary for flagellar motility may represent novel targets for chemotherapeutic intervention in African sleeping sickness.
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DOI：
10.1083/jcb.200201036
发表时间：
2002-03-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hutchings NR;Donelson JE;Hill KL
通讯作者：
Hill KL
影响因子：
11.4
作者：
Kohl, L;Robinson, D;Bastin, P
通讯作者：
Bastin, P
影响因子：
4.8
作者：
Hammarton, TC;Clark, J;Mottram, JC
通讯作者：
Mottram, JC
影响因子：
--
作者：
Ralston, KS;Lerner, AG;Hill, KL
通讯作者：
Hill, KL
DOI：
10.1073/pnas.95.25.14687
发表时间：
1998-12-08
影响因子：
11.1
作者：
Ngô, H;Tschudi, C;Ullu, E
通讯作者：
Ullu, E