Male infertility‐associated Ccdc108 regulates multiciliogenesis via the intraflagellar transport machinery

• Published in: EMBO reports 2022-04, Vol.23 (4), p.e52775-n/a
• Main Authors: Zhao, Huijie, Sun, Jian, Insinna, Christine, Lu, Quanlong, Wang, Ziqiu, Nagashima, Kunio, Stauffer, Jimmy, Andresson, Thorkell, Specht, Suzanne, Perera, Sumeth, Daar, Ira O, Westlake, Christopher J
• Format: Article
• Language: English
• Subjects: Accumulation; Actin; actin cytoskeleton; Animals; Basal bodies; Basal Bodies - metabolism; Biological activity; Ccdc108; Cell surface; Centrioles; Centrioles - metabolism; Cilia; Cilia - metabolism; ciliogenesis; Cytoskeletal Proteins - metabolism; Cytoskeleton; Docking; EMBO05; EMBO24; Embryos; Fluid dynamics; Fluid flow; Humans; IFT‐B complex; Infertility; Infertility, Male - genetics; Male; Males; Membrane Proteins - genetics; motile cilia; Proteins; Recruitment; RhoA protein; RNA-Binding Proteins - genetics; Xenopus laevis
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202152775

Motile cilia on the cell surface generate movement and directional fluid flow that is crucial for various biological processes. Dysfunction of these cilia causes human diseases such as sinopulmonary disease and infertility. Here, we show that Ccdc108, a protein linked to male infertility, has an evolutionarily conserved requirement in motile multiciliation. Using  Xenopus laevis  embryos, Ccdc108 is shown to be required for the migration and docking of basal bodies to the apical membrane in epidermal multiciliated cells (MCCs). We demonstrate that Ccdc108 interacts with the IFT‐B complex, and the ciliation requirement for Ift74 overlaps with Ccdc108 in MCCs. Both Ccdc108 and IFT‐B proteins localize to migrating centrioles, basal bodies, and cilia in MCCs. Importantly, Ccdc108 governs the centriolar recruitment of IFT while IFT licenses the targeting of Ccdc108 to the cilium. Moreover, Ccdc108 is required for the centriolar recruitment of Drg1 and activated RhoA, factors that help establish the apical actin network in MCCs. Together, our studies indicate that Ccdc108 and IFT‐B complex components cooperate in multiciliogenesis. Synopsis Ccdc108, an axonemal central pair apparatus protein, localizes to centrioles and regulates accumulation of IFT‐B complex proteins and PCP‐associated actin cytoskeletal factors required for migration and docking of centrioles to the cell surface during multiciliogenesis. Ccdc108 is evolutionarily conserved to regulate multiciliogenesis. Ccdc108 interacts with IFT‐B components, which licenses the targeting of Ccdc108 to the cilium. Ccdc108 localizes to migrating centrioles where it governs the centriolar accumulation of IFT‐B components during early multiciliogenesis. Ccdc108 and IFT‐B complex components cooperate in regulating the centriolar recruitment of PCP‐associated cytoskeletal proteins for the establishment of the apical actin network. Graphical Abstract Ccdc108, an axonemal central pair apparatus protein, localizes to centrioles and regulates accumulation of IFT‐B complex proteins and PCP‐associated actin cytoskeletal factors required for migration and docking of centrioles to the cell surface during multiciliogenesis.