Essential role of Cenexin1, but not Odf2, in ciliogenesis
Essential role of Cenexin1, but not Odf2, in ciliogenesis
复制标题
DOI：
10.4161/cc.23585
复制
发表时间：
2013-02-15
期刊：
影响因子：
4.3
通讯作者：
Lee, Kyung S.
中科院分区：
文献类型：
--
作者：
Chang, Jaerak;Seo, Sang Gwon;Lee, Kyung S.
初生纤毛是细胞表面以微管为基础的孤立性感觉结构，在细胞信号和发育中起着至关重要的作用。睫毛功能异常会导致各种人类遗传性疾病，统称为纤毛疾病。外密纤维蛋白2(ODF2)最初是作为精子尾部纤维的主要成分被分离出来的。随后的研究证明了Odf2的许多剪接变异体的存在，包括Cenexin1(Odf2亚型9)，它带有一个不寻常的C末端延伸。值得注意的是，在培养的哺乳动物细胞中，Odf2定位于初生纤毛的轴丝，而Cenexin1定位于基底。Odf2和Cenexin1是否通过共同或不同的功能参与初级纤毛组装尚不清楚。通过利用odf2(-/-)细胞缺乏内源性Odf2和Cenexin1，但外源表达这两种蛋白中的一种或两种，我们证明了Cenexin1，而不是Odf2，是诱导纤毛发生的必要条件和充分条件。此外，依赖于Cenexin1的初级纤毛组装途径似乎独立于Odf2发挥作用。Cenexin1，而不是Odf2，一直与GTP负载的Rab8a相互作用，定位于基底体的远/亚远侧附属物，并促进CHIBBY的招募，CHIBBY是一种对正常纤毛发生至关重要的中心粒成分。综上所述，我们的结果表明，Cenexin1通过其C-末端延伸在纤毛发生中发挥关键作用，赋予了介导初级纤毛组装的独特能力。多个剪接变异体的存在提示Odf2的功能是多样化的，每个变异体在复杂的细胞和发育过程中都有不同的作用。
Primary cilia are microtubule-based solitary sensing structures on the cell surface that play crucial roles in cell signaling and development. Abnormal ciliary function leads to various human genetic disorders, collectively known as ciliopathies. Outer dense fiber protein 2 (Odf2) was initially isolated as a major component of sperm-tail fibers. Subsequent studies have demonstrated the existence of many splicing variants of Odf2, including Cenexin1 (Odf2 isoform 9), which bears an unusual C-terminal extension. Strikingly, Odf2 localizes along the axoneme of primary cilia, whereas Cenexin1 localizes to basal bodies in cultured mammalian cells. Whether Odf2 and Cenexin1 contribute to primary cilia assembly by carrying out either concerted or distinct functions is unknown. By taking advantage of odf2(-/-) cells lacking endogenous Odf2 and Cenexin1, but exogenously expressing one or both of these proteins, we showed that Cenexin1, but not Odf2, was necessary and sufficient to induce ciliogenesis. Furthermore, the Cenexin1-dependent primary cilia assembly pathway appeared to function independently of Odf2. Consistently, Cenexin1, but not Odf2, interacted with GTP-loaded Rab8a, localized to the distal/subdistal appendages of basal bodies, and facilitated the recruitment of Chibby, a centriolar component that is important for proper ciliogenesis. Taken together, our results suggest that Cenexin1 plays a critical role in ciliogenesis through its C-terminal extension that confers a unique ability to mediate primary cilia assembly. The presence of multiple splicing variants hints that the function of Odf2 is diversified in such a way that each variant has a distinct role in the complex cellular and developmental processes.