Ccdc113/Ccdc96 complex, a novel regulator of ciliary beating that connects radial spoke 3 to dynein g and the nexin link

摘要

Ciliary beating requires the coordinated activity of numerous axonemal complexes. The protein composition and role of radial spokes (RS), nexin links (N-DRC) and dyneins (ODAs and IDAs) is well established. However, how information is transmitted from the central apparatus to the RS and across other ciliary structures remains unclear. Here, we identify a complex comprising the evolutionarily conserved proteins Ccdc96 and Ccdc113, positioned parallel to N-DRC and forming a connection between RS3, dynein g, and N-DRC. Although Ccdc96 and Ccdc113 can be transported to cilia independently, their stable docking and function requires the presence of both proteins. Deletion of either CCDC113 or CCDC96 alters cilia beating frequency, amplitude and waveform. We propose that the Ccdc113/Ccdc96 complex transmits signals from RS3 and N-DRC to dynein g and thus regulates its activity and the ciliary beat pattern. Author summary Motile cilia and flagella are evolutionarily conserved microtubule-based cell protrusions with the ability to actively beat. Their coordinated movement propels unicellular organisms, sperm cells and zoospores, or drives a flow of the extracellular fluids in multicellular organisms including humans. Lack or dysfunction of motile cilia cause respiratory diseases that can be accompanied by infertility and laterality defects. The emergence of cilia movement requires coordinated activity of the ciliary complexes, including inner and outer dynein arms and radial spokes. The nexin-dynein regulatory complex (N-DRC) is a main node that coordinates the activity of these ciliary complexes and mediates a transduction of the regulatory signals from radial spokes to axonemal dynein motors. Here we described the identification of a new ciliary complex composed of the two proteins, Ccdc96 and Ccdc113 that extends parallel to the N-DRC and connects radial spoke 3 with N-DRC and dynein g. Knockout of the gene encoding either of these two proteins results in altered pattern of cilia motion. Our data suggest that the Ccdc113/Ccdc96 complex transmits signals from radial spoke 3 and N-DRC to dynein g, and thus further contribute to the understanding of the molecular mechanism(s) behind the regulation of the ciliary beat.