Sigg Monika Abedin, Menchen Tabea, Lee Chanjae, Johnson Jeffery, Jungnickel Melissa K, Choksi Semil P, Garcia Galo, Busengdal Henriette, Dougherty Gerard W, Pennekamp Petra, Werner Claudius, Rentzsch Fabian, Florman Harvey M, Krogan Nevan, Wallingford John B, Omran Heymut, Reiter Jeremy F
Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA.
Department of General Pediatrics, University Children's Hospital Muenster, Muenster 48149, Germany.
Dev Cell. 2017 Dec 18;43(6):744-762.e11. doi: 10.1016/j.devcel.2017.11.014.
Cilia are organelles specialized for movement and signaling. To infer when during evolution signaling pathways became associated with cilia, we characterized the proteomes of cilia from sea urchins, sea anemones, and choanoflagellates. We identified 437 high-confidence ciliary candidate proteins conserved in mammals and discovered that Hedgehog and G-protein-coupled receptor pathways were linked to cilia before the origin of bilateria and transient receptor potential (TRP) channels before the origin of animals. We demonstrated that candidates not previously implicated in ciliary biology localized to cilia and further investigated ENKUR, a TRP channel-interacting protein identified in the cilia of all three organisms. ENKUR localizes to motile cilia and is required for patterning the left-right axis in vertebrates. Moreover, mutation of ENKUR causes situs inversus in humans. Thus, proteomic profiling of cilia from diverse eukaryotes defines a conserved ciliary proteome, reveals ancient connections to signaling, and uncovers a ciliary protein that underlies development and human disease.
纤毛是专门用于运动和信号传导的细胞器。为了推断信号通路在进化过程中何时与纤毛相关联，我们对海胆、海葵和领鞭毛虫的纤毛蛋白质组进行了表征。我们鉴定出437种在哺乳动物中保守的高可信度纤毛候选蛋白，并发现刺猬信号通路和G蛋白偶联受体通路在两侧对称动物出现之前就与纤毛相关联，而瞬时受体电位（TRP）通道在动物出现之前就已存在。我们证明了先前未涉及纤毛生物学的候选蛋白定位于纤毛，并进一步研究了ENKUR，一种在所有三种生物体的纤毛中鉴定出的与TRP通道相互作用的蛋白。ENKUR定位于运动性纤毛，是脊椎动物左右轴模式形成所必需的。此外，ENKUR的突变会导致人类内脏反位。因此，对不同真核生物纤毛的蛋白质组分析定义了一个保守的纤毛蛋白质组，揭示了与信号传导的古老联系，并发现了一种与发育和人类疾病相关的纤毛蛋白。
