An essential role for DYF-11/MIP-T3 in assembling functional intraflagellar transport complexes.
An essential role for DYF-11/MIP-T3 in assembling functional intraflagellar transport complexes.
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DOI：
10.1371/journal.pgen.1000044
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发表时间：
2008-03-28
期刊：
影响因子：
4.5
通讯作者：
Leroux, Michel R.
中科院分区：
文献类型：
--
作者：
Li, Chunmei;Inglis, Peter N.;Leitch, Carmen C.;Efimenko, Evgeni;Zaghloul, Norann A.;Mok, Calvin A.;Davis, Erica E.;Bialas, Nathan J.;Healey, Michael P.;Heon, Elise;Zhen, Mei;Swoboda, Peter;Katsanis, Nicholas;Leroux, Michel R.
MIP-T3 是一种人类蛋白，之前发现与微管和驱动蛋白相互作用的神经元蛋白 DISC1（精神分裂症中断 1）相关，但其细胞功能仍不清楚。在这里，我们证明线虫 MIP-T3 直向同源物 DYF-11 是一种鞭毛内转运 (IFT) 蛋白，在组装功能性驱动蛋白运动-IFT 颗粒复合物中发挥着关键作用。我们克隆了功能缺失的 dyf-11 突变体，其中 IFT 机制的几个关键组件，包括驱动蛋白-II 以及 IFT 亚复合物 A 和 B 蛋白，无法进入纤毛轴丝和/或错误定位，导致纤毛结构和感觉功能受损，以及异常的脂质积累。对不同突变背景的分析进一步表明，DYF-11 是 IFT 亚复合体 B 的新组成部分。与进化上保守的纤毛相关作用一致，哺乳动物 MIP-T3 定位于基体和纤毛，斑马鱼 mipt3 与 Bardet-Biedl 综合征蛋白 Bbs4 协同作用，以确保适当的原肠胚形成，这是纤毛和基底的关键 身体依赖性发育过程。因此，我们的研究结果表明 MIP-T3 在纤毛生物发生中发挥着以前未知但关键的作用，并进一步强调了这种细胞器在脊椎动物发育中的新兴作用。蛋白质复合物和相关货物沿着微管轨道的运输代表了负责多种细胞功能的重要真核过程，包括细胞分裂、囊泡向膜的运动以及沿着树突、轴突和纤毛的运输。后者的细胞器是毛发状的细胞附属物，涉及细胞和液体的运动、感知和转换来自环境的信息以及发育。它们的生物发生和维持取决于驱动蛋白和动力蛋白介导的运动过程，称为鞭毛内运输（IFT）。除了包含这些专门的分子马达之外，IFT 机械还由大型多亚基复合体组成，其确切的组成和组织尚未完全确定。在这里，我们鉴定了一种蛋白质 DYF-11/MIP-T3，它在所有纤毛生物中都是保守的，并且与线虫中的 IFT 相关。线虫 DYF-11 的破坏会导致纤毛结构受损，这可能是由于 IFT 电机和亚基错误组装造成的。缺乏 DYF-11 的动物表现出化学感觉异常，这与该蛋白在纤毛相关感觉过程中的作用一致。在斑马鱼中，MIP-T3 对于发育过程中的原肠胚形成运动至关重要，类似于在其他纤毛成分（包括 Bardet-Biedl 综合征蛋白）中观察到的情况。总之，我们已经确定了一种新型 IFT 机械组件，它对于脊椎动物的发育也至关重要。
MIP-T3 is a human protein found previously to associate with microtubules and the kinesin-interacting neuronal protein DISC1 (Disrupted-in-Schizophrenia 1), but whose cellular function(s) remains unknown. Here we demonstrate that the C. elegans MIP-T3 ortholog DYF-11 is an intraflagellar transport (IFT) protein that plays a critical role in assembling functional kinesin motor-IFT particle complexes. We have cloned a loss of function dyf-11 mutant in which several key components of the IFT machinery, including Kinesin-II, as well as IFT subcomplex A and B proteins, fail to enter ciliary axonemes and/or mislocalize, resulting in compromised ciliary structures and sensory functions, and abnormal lipid accumulation. Analyses in different mutant backgrounds further suggest that DYF-11 functions as a novel component of IFT subcomplex B. Consistent with an evolutionarily conserved cilia-associated role, mammalian MIP-T3 localizes to basal bodies and cilia, and zebrafish mipt3 functions synergistically with the Bardet-Biedl syndrome protein Bbs4 to ensure proper gastrulation, a key cilium- and basal body-dependent developmental process. Our findings therefore implicate MIP-T3 in a previously unknown but critical role in cilium biogenesis and further highlight the emerging role of this organelle in vertebrate development. The transport of protein complexes and associated cargo along microtubule tracks represents an essential eukaryotic process responsible for a multitude of cellular functions, including cell division, vesicle movement to membranes, and trafficking along dendrites, axons, and cilia. The latter organelles are hair-like cellular appendages implicated in cell and fluid motility, sensing and transducing information from their environment, and development. Their biogenesis and maintenance depends on a kinesin- and dynein-mediated motility process termed intraflagellar transport (IFT). In addition to comprising these specialized molecular motors, the IFT machinery consists of large multisubunit complexes whose exact composition and organization has not been fully defined. Here we identify a protein, DYF-11/MIP-T3, that is conserved in all ciliated organisms and is associated with IFT in C. elegans. Disruption of C. elegans DYF-11 results in structurally compromised cilia, likely as a result of IFT motor and subunit misassembly. Animals lacking DYF-11 display chemosensory anomalies, consistent with a role for the protein in cilia-associated sensory processes. In zebrafish, MIP-T3 is essential for gastrulation movements during development, similar to that observed for other ciliary components, including Bardet-Biedl syndrome proteins. In conclusion, we have identified a novel IFT machinery component that is also essential for development in vertebrates.
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影响因子：
3.3
作者：
Efimenko, Evgeni;Blacque, Oliver E.;Swoboda, Peter
通讯作者：
Swoboda, Peter
影响因子：
30.8
作者：
Gerdes, Jantje M.;Liu, Yangfan;Katsanis, Nicholas
通讯作者：
Katsanis, Nicholas
DOI：
10.1083/jcb.141.4.993
发表时间：
1998-05-18
期刊：
The Journal of cell biology
影响因子：
--
作者：
Cole DG;Diener DR;Himelblau AL;Beech PL;Fuster JC;Rosenbaum JL
通讯作者：
Rosenbaum JL
影响因子：
9.2
作者：
Deane, JA;Cole, DG;Rosenbaum, JL
通讯作者：
Rosenbaum, JL
影响因子：
9.2
作者：
Blacque, OE;Perens, EA;Leroux, MR
通讯作者：
Leroux, MR