The miR-669a-5p/G3BP/HDAC6/AKAP12 Axis Regulates Primary Cilia Length

Primary cilia are conserved organelles in most mammalian cells, acting as "antennae" to sense external signals. Maintaining a physiological cilium length is required for cilium function. MicroRNAs (miRNAs) are potent gene expression regulators, and aberrant miRNA expression is closely associated with ciliopathies. However, how miRNAs modulate cilium length remains elusive. Here, using the calcium-shock method and small RNA sequencing, a miRNA is identified, namely, miR-669a-5p, that is highly expressed in the cilia-enriched noncellular fraction. It is shown that miR-669a-5p promotes cilium elongation but not cilium formation in cultured cells. Mechanistically, it is demonstrated that miR-669a-5p represses ras-GTPase-activating protein SH3-domain-binding protein (G3BP) expression to inhibit histone deacetylase 6 (HDAC6) expression, which further upregulates A-kinase anchor protein 12 (AKAP12) expression. This effect ultimately blocks cilia disassembly and leads to greater cilium length, which can be restored to wild-type lengths by either upregulating HDAC6 or downregulating AKAP12. Collectively, these results elucidate a previously unidentified miR-669a-5p/G3BP/HDAC6/AKAP12 signaling pathway that regulates cilium length, providing potential pharmaceutical targets for treating ciliopathies. Primary cilia transduce extracellular stimuli into cellular responses. This study identifies a microRNA, namely, miR-669a-5p as a potent regulator of cilium elongation rather than cilium formation. Mechanically, miR-669a-5p targets G3BPs to inhibit HDAC6 expression, which further upregulates AKAP12 expression. Collectively, it is proposed that the miR-669a-5p/G3BP/HDAC6/AKAP12 axis is a promising pharmaceutical target for treating ciliopathies.image