Tubulin polyglutamylation is a posttranslational modification that occurs primarily along the axoneme of cilia. Defective axoneme polyglutamylation impairs cilia function and has been correlated with ciliopathies, including Joubert Syndrome (JBTS). However, the precise mechanisms regulating proper axoneme polyglutamylation remain vague. Here, we show that cyclin-dependent kinase 6 (CDK6), but not its paralog CDK4, localizes to the cilia base and suppresses axoneme polyglutamylation by phosphorylating RAB11 family interacting protein 5 (FIP5) at site S641, a critical regulator of cilia import of glutamylases. S641 phosphorylation disrupts the ciliary recruitment of FIP5 and its association with RAB11, thereby reducing the ciliary import of glutamylases. Encouragingly, the FDA-approved CDK4/6 inhibitor Abemaciclib can effectively restore cilia function in JBTS cells with defective glutamylation. In summary, our study elucidates the regulatory mechanisms governing axoneme polyglutamylation and suggests that developing CDK6-specific inhibitors could be a promising therapeutic strategy to enhance cilia function in ciliopathy patients.

中文翻译：

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非经典 CDK6 活性通过抑制轴丝聚谷氨酰化促进纤毛分解。


微管蛋白多谷氨酰化是一种翻译后修饰，主要沿纤毛轴丝发生。有缺陷的轴丝多谷氨酰化会损害纤毛功能，并与纤毛病相关，包括 Joubert 综合征 （JBTS）。然而，调节适当轴丝多谷氨酰化的确切机制仍然模糊不清。在这里，我们表明细胞周期蛋白依赖性激酶 6 （CDK6） 而不是其旁系同源物 CDK4 定位于纤毛碱基，并通过在 S641 位点磷酸化 RAB11 家族相互作用蛋白 5 （FIP5） 来抑制轴丝多谷氨酰化，S641 位点是纤毛输入谷氨酰酶的关键调节因子。S641 磷酸化破坏了 FIP5 的纤毛募集及其与 RAB11 的结合，从而减少了谷氨酰酶的纤毛输入。令人鼓舞的是，FDA 批准的 CDK4/6 抑制剂 Abemaciclib 可以有效恢复谷氨酰化缺陷的 JBTS 细胞的纤毛功能。总之，我们的研究阐明了控制轴丝多谷氨酰化的调节机制，并表明开发 CDK6 特异性抑制剂可能是一种很有前途的治疗策略，可以增强纤毛病患者的纤毛功能。