HEATR2 plays a conserved role in assembly of the ciliary motile apparatus.
HEATR2 plays a conserved role in assembly of the ciliary motile apparatus.
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DOI：
10.1371/journal.pgen.1004577
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发表时间：
2014-09
期刊：
影响因子：
4.5
通讯作者：
Mill P
中科院分区：
文献类型：
--
作者：
Diggle CP;Moore DJ;Mali G;zur Lage P;Ait-Lounis A;Schmidts M;Shoemark A;Garcia Munoz A;Halachev MR;Gautier P;Yeyati PL;Bonthron DT;Carr IM;Hayward B;Markham AF;Hope JE;von Kriegsheim A;Mitchison HM;Jackson IJ;Durand B;Reith W;Sheridan E;Jarman AP;Mill P
纤毛是一种高度保守的微管结构，在发育和成体体内平衡过程中执行各种感觉和运动功能。在人类中，特异性影响运动纤毛的缺陷导致慢性气道感染、不育和遗传异质性疾病原发性纤毛运动障碍（PCD）中的偏侧性缺陷。使用比较简单的果蝇系统，其中mechanosensory神经元具有修改运动纤毛，我们采用了最近阐明的纤毛转录RFX-FOX代码，以确定新的PCD候选基因。在这里，我们报告的CG 31320/HEATR 2，这起着保守的关键作用，在形成所需的纤毛运动在苍蝇和人类的轴丝动力蛋白武器的表征。内臂和外臂动力蛋白不存在CG 31320突变苍蝇的轴丝和PCD个体与一种新的剪接受体HEATR 2突变。HEATR 2直系同源物上游紧密排列的RFX-FOX结合位点的功能保守可能在早期能动纤毛发生期间驱动HEATR 2的更高细胞质表达。免疫沉淀显示HEATR 2与DNAI 2相互作用，但不与HSP 70或HSP 90相互作用，将其与动力蛋白臂组装所需的其他细胞质蛋白（如DNAAF 1 -4）所描述的客户/伴侣功能区分开来。这些数据暗示CG 31320/HEATR 2在一个不断增长的细胞内预组装和运输网络，这是必要的，以提供功能性动力蛋白机械纤毛室整合到运动轴丝。纤毛是从细胞表面延伸出来的小而专门的突起，发挥关键的感觉功能，有时还发挥运动功能，例如产生流体流动以清除气道或男性生育所需的精子推进。遗传性疾病原发性纤毛运动障碍（PCD）的纤毛运动缺陷。虽然基本的纤毛蓝图在进化过程中已经被详细阐述，但许多参与构建或维持功能性纤毛的核心基因已经被保守。我们已经使用了相对简单的果蝇，只有少数的触摸敏感的感觉细胞上有运动的纤毛，以确定参与纤毛运动的基因，因此是导致PCD的候选基因。我们在这里表明，当一个这样的基因（CG 31320/HEATR 2）在苍蝇或人类PCD患者中被破坏时，纤毛形成，但它们不能移动。我们发现这种蛋白质停留在细胞质中，在那里它就像一个灵活的支架，在为纤毛运动提供动力所需的大型多组分纤毛运动复合体的组装过程中稳定和促进相互作用。
Cilia are highly conserved microtubule-based structures that perform a variety of sensory and motility functions during development and adult homeostasis. In humans, defects specifically affecting motile cilia lead to chronic airway infections, infertility and laterality defects in the genetically heterogeneous disorder Primary Ciliary Dyskinesia (PCD). Using the comparatively simple Drosophila system, in which mechanosensory neurons possess modified motile cilia, we employed a recently elucidated cilia transcriptional RFX-FOX code to identify novel PCD candidate genes. Here, we report characterization of CG31320/HEATR2, which plays a conserved critical role in forming the axonemal dynein arms required for ciliary motility in both flies and humans. Inner and outer arm dyneins are absent from axonemes of CG31320 mutant flies and from PCD individuals with a novel splice-acceptor HEATR2 mutation. Functional conservation of closely arranged RFX-FOX binding sites upstream of HEATR2 orthologues may drive higher cytoplasmic expression of HEATR2 during early motile ciliogenesis. Immunoprecipitation reveals HEATR2 interacts with DNAI2, but not HSP70 or HSP90, distinguishing it from the client/chaperone functions described for other cytoplasmic proteins required for dynein arm assembly such as DNAAF1-4. These data implicate CG31320/HEATR2 in a growing intracellular pre-assembly and transport network that is necessary to deliver functional dynein machinery to the ciliary compartment for integration into the motile axoneme. Cilia are small, specialized projections extending from a cell's surface that play key sensory and sometimes motility functions, such as generating fluid flow for clearing airways or sperm propulsion necessary for male fertility. Ciliary motility is defective in the inherited disease, Primary Ciliary Dyskinesia (PCD). Although the basic cilium blueprint has been elaborated on during evolution, many of the core genes involved in building or maintaining functional cilia have been conserved. We have used the comparatively simple fruit fly, which has motile cilia on only a handful of touch-sensitive sensory cells, to identify genes involved in ciliary motility and which are therefore candidate genes for causing PCD. We show here that when one such gene (CG31320/HEATR2) is disrupted in either flies or in human PCD patients, cilia form but they cannot move. We show this protein stays in the cytoplasm, where it is acts like a flexible scaffold stabilizing and facilitating interactions during the assembly of large multi-component ciliary motor complexes needed to power cilia movement.
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DOI：
10.1126/science.1162327
发表时间：
2009-06-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badis G;Berger MF;Philippakis AA;Talukder S;Gehrke AR;Jaeger SA;Chan ET;Metzler G;Vedenko A;Chen X;Kuznetsov H;Wang CF;Coburn D;Newburger DE;Morris Q;Hughes TR;Bulyk ML
通讯作者：
Bulyk ML
影响因子：
9.8
作者：
Austin-Tse, Christina;Halbritter, Jan;Hildebrandt, Friedhelm
通讯作者：
Hildebrandt, Friedhelm
DOI：
10.1083/jcb.201304076
发表时间：
2014-01-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Dong F;Shinohara K;Botilde Y;Nabeshima R;Asai Y;Fukumoto A;Hasegawa T;Matsuo M;Takeda H;Shiratori H;Nakamura T;Hamada H
通讯作者：
Hamada H
影响因子：
7.7
作者：
Chung MI;Kwon T;Tu F;Brooks ER;Gupta R;Meyer M;Baker JC;Marcotte EM;Wallingford JB
通讯作者：
Wallingford JB
影响因子：
5.8
作者：
Carr, I. M.;Robinson, J. I.;Bonthron, D. T.
通讯作者：
Bonthron, D. T.