The human ciliopathy protein RSG1 links the CPLANE complex to transition zone architecture

Introduction

Ciliopathies are a broad class of human diseases that share an etiology of defective cilia structure or function. These diseases span skeletal anomalies, craniofacial defects, cystic kidneys, blindness, obesity and other clinical manifestations, highlighting the wide array of physiological functions that require components of the cilium^{1, 2–3}. Cilia are assembled and maintained by a cohort of multiprotein machines, such as the IFT complexes^4,5, the BBSome⁶, transition zone complexes⁷, and variants in subunits of these complexes are sufficient to cause ciliopathies^2,3. The Ciliogenesis and PLANar polarity Effector (CPLANE) complex is also essential for ciliogenesis in all vertebrates including humans⁸, yet its function remains far less well defined.

Identified initially as a tripartite complex that controls planar cell polarity in Drosophila, the vertebrate CPLANE complex comprises five proteins⁸. Fuz/Cplane3 and Intu/Cplane4 were the first vertebrate orthologues to be described; in Xenopus they are essential for ciliogenesis by dint of their roles in basal body docking and recruitment of IFT-A2 proteins to the base of cilia^{9, 10, 11–12}. More recently, it was shown that Fuz and Intu together form a GEF for Rab23, which in turn is implicated in the docking of basal bodies to the apical surface^{13, 14–15}.

Rsg1/Cplane2 was identified as a Fuz-interacting small GTPase essential for ciliogenesis in Xenopus^12,16. Wdpcp/Cplane5 encodes a beta-propeller protein and was first found to be essential for ciliogenesis in Xenopus¹⁷. Further studies revealed that each of these CPLANE subunits is essential for ciliogenesis in mice^{16,18, 19, 20–21}, with Rsg1 acting at a relatively late step in ciliogenesis²².

Proteomic analysis revealed that Intu, Fuz, Wdpcp, and Rsg1 form a stable and discrete complex that also contains the human ciliopathy protein Jbts17/CPLANE1²³. Recently, the structure of a partial CPLANE complex lacking Jbts17 was solved by CryoEM (Fig. 1A) revealing a similar structure to other hexa-longin domain GEFs such as Mon1-Czz1 and Hps1-Hps4, and that Fuz interacts directly with Rsg1¹⁵. This structure suggests Rsg1 is not a substrate of the Intu/Fuz GEF, but rather an effector¹⁵. Studies in a variety of cell types indicate that the CPLANE complex localizes...