Axoneme polyglutamylation regulated by Joubert syndrome protein ARL13B controls ciliary targeting of signaling molecules.

Tubulin polyglutamylation is a predominant axonemal post-translational modification. However, if and how axoneme polyglutamylation is essential for primary cilia and contribute to ciliopathies are unknown. Here, we report that Joubert syndrome protein ARL13B controls axoneme polyglutamylation, which is marginally required for cilia stability but essential for cilia signaling. ARL13B interacts with RAB11 effector FIP5 to promote cilia import of glutamylase TTLL5 and TTLL6. Hypoglutamylation caused by a deficient ARL13B-RAB11-FIP5 trafficking pathway shows no effect on ciliogenesis, but promotes cilia disassembly and, importantly, impairs cilia signaling by disrupting the proper anchoring of sensory receptors and trafficking of signaling molecules. Remarkably, depletion of deglutamylase CCP5, the predominant cilia deglutamylase, effectively restores hypoglutamylation-induced cilia defects. Our study reveals a paradigm that tubulin polyglutamylation is a major contributor for cilia signaling and suggests a potential therapeutic strategy by targeting polyglutamylation machinery to promote ciliary targeting of signaling machineries and correct signaling defects in ciliopathies.