A complex of distal appendage-associated kinases linked to human disease regulates ciliary trafficking and stability

Abstract

Cilia biogenesis is a complex, multi-step process involving the coordination of multiple cellular trafficking pathways. Despite the importance of ciliogenesis in mediating the cellular response to cues from the microenvironment, we have only a limited understanding of the regulation of cilium assembly. We previously identified a kinase that acts as a key regulator of ciliogenesis, TTBK2. In the course of efforts to identify additional players in the TTBK2 pathway, we identified the CK2 subunit CSNK2A1. Super-resolution microscopy revealed that CSNK2A1 is a centrosomal protein predominantly concentrated at the mother centriole and associated with the distal appendages. CSNK2A1 and TTBK2 interact both physically and functionally: Csnk2a1 knockout in Ttbk2 hypomorphic cells partially corrects defects in cilia formation and length. In addition, Csnk2a1 mutant cilia are longer than those of control cells and exhibit instability, particularly at the tip. Csnk2a1 mutant cilia also abnormally accumulate key cilia assembly and SHH-related proteins including IFT, GLI2, KIF7, and Smoothened (SMO). De novo mutations of Csnk2a1 were recently linked to the human genetic disorder Okur-Chung neurodevelopmental syndrome (OCNDS). Consistent with the role of CSNK2A1 in cilium stability, we find that expression of OCNDS-associated Csnk2a1 variants in wild-type cells caused ciliary structural defects. Our findings provide new insights on mechanisms involved in ciliary length regulation, trafficking, and stability that in turn shed light on the significance and implications of cilia instability in human disease.

The exocyst complex and intracellular vesicles mediate soluble protein trafficking to the primary cilium

“…This suggests that Gli may recruit Rab18 via TRAPPII and COPI to promote ciliary trafficking. Interestingly, all three of the above GTPases: Rab18, Rab14, and Arf4, were recently identified as proximity interactors of the cilium base-localized kinase Ttbk2 78 , strengthening the case for their involvement in the targeting of Gli-laden vesicles to the cilium.…”