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

Kai He, Xiaoyu Ma, Tao Xu, Yan Li, Allen Hodge, Qing Zhang, Julia Torline, Yan Huang, Jian Zhao, Kun Ling and Jinghua Hu ()
Additional contact information
Kai He: Mayo Clinic
Xiaoyu Ma: Mayo Clinic
Tao Xu: Mayo Clinic
Yan Li: Mayo Clinic
Allen Hodge: Mayo Clinic
Qing Zhang: Mayo Clinic
Julia Torline: Mayo Clinic
Yan Huang: Mayo Clinic
Jian Zhao: Tongji University
Kun Ling: Mayo Clinic
Jinghua Hu: Mayo Clinic

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-05867-1

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