Cep164 triggers ciliogenesis by recruiting Tau tubulin kinase 2 to the mother centriole
Cep164 triggers ciliogenesis by recruiting Tau tubulin kinase 2 to the mother centriole
复制标题
DOI：
10.1073/pnas.1401777111
复制
发表时间：
2014-07-15
影响因子：
11.1
通讯作者：
Nigg, Erich A.
中科院分区：
文献类型：
--
作者：
Cajanek, Lukas;Nigg, Erich A.
初级纤毛在发育和疾病中起关键作用。它们的组装由成熟的中心粒（基体）触发，并需要中心体蛋白164 kDa（Cep 164），远端附属物的组成部分。在这里，我们表明，Cep 164的损失导致纤毛发生的早期缺陷，让人想起TTBK 2（Tau微管蛋白激酶2）突变的表型后果。我们确定Cep 164作为TTBK 2的可能的生理底物，并证明Cep 164和TTBK 2形成复合物。我们绘制的相互作用域，并证明，复杂的形成是至关重要的TTBK 2的招聘基体。值得注意的是，纤毛发生可以恢复Cep 164-耗尽细胞的嵌合蛋白的表达，其中TTBK 2融合到Cep 164的C-末端中心粒靶向结构域。这些发现表明Cep 164在纤毛发生中的主要功能之一是将活性TTBK 2募集到中心粒。一旦定位，TTBK 2然后触发纤毛发生所需的关键事件，包括去除CP 110和招募鞭毛内转运蛋白。此外，我们的数据表明，TTBK 2也作用于Cep 164的上游，有助于远端附件的组装。
Primary cilia play critical roles in development and disease. Their assembly is triggered by mature centrioles (basal bodies) and requires centrosomal protein 164kDa (Cep164), a component of distal appendages. Here we show that loss of Cep164 leads to early defects in ciliogenesis, reminiscent of the phenotypic consequences of mutations in TTBK2 (Tau tubulin kinase 2). We identify Cep164 as a likely physiological substrate of TTBK2 and demonstrate that Cep164 and TTBK2 form a complex. We map the interaction domains and demonstrate that complex formation is crucial for the recruitment of TTBK2 to basal bodies. Remarkably, ciliogenesis can be restored in Cep164-depleted cells by expression of chimeric proteins in which TTBK2 is fused to the C-terminal centriole-targeting domain of Cep164. These findings indicate that one of the major functions of Cep164 in ciliogenesis is to recruit active TTBK2 to centrioles. Once positioned, TTBK2 then triggers key events required for ciliogenesis, including removal of CP110 and recruitment of intraflagellar transport proteins. In addition, our data suggest that TTBK2 also acts upstream of Cep164, contributing to the assembly of distal appendages.