Cilia are versatile, microtubule-based organelles that facilitate cellular signaling, motility, and environmental sensing in eukaryotic cells. These dynamic structures act as hubs for key developmental signaling pathways, while their assembly and disassembly are intricately regulated along cell cycle transitions. Recent findings show that factors regulating ciliogenesis and cilia dynamics often integrate their roles across other cellular processes, including cell cycle regulation, cytoskeletal organization, and intracellular trafficking, ensuring multilevel crosstalk of mechanisms controlling organogenesis. Disruptions in these shared regulators lead to broad defects associated with both ciliopathies and cancer. This review explores the crosstalk of regulatory mechanisms governing cilia assembly, disassembly, and maintenance during ciliary signaling and the cell cycle, along with the broader implications for development, tissue homeostasis, and disease.

• Keywords
• Cancer, Cell cycle regulation, Cilia, Ciliary dynamics, Ciliary signaling, Ciliopathies, Tissue development,
• Publication type
• Journal Article MeSH
• Review MeSH

BACKGROUND: Primary cilia facilitate cellular signalling and play critical roles in development, homeostasis, and disease. Their assembly is under the control of Tau-Tubulin Kinase 2 (TTBK2), a key enzyme mutated in patients with spinocerebellar ataxia. Recent work has implicated TTBK2 in the regulation of cilia maintenance and function, but the underlying molecular mechanisms are not understood. METHODS: To dissect the role of TTBK2 during cilia growth and maintenance in human cells, we examined disease-related TTBK2 truncations. We used biochemical approaches, proteomics, genetic engineering, and advanced microscopy techniques to unveil molecular events triggered by TTBK2. RESULTS: We demonstrate that truncated TTBK2 protein moieties, unable to localize to the mother centriole, create unique semi-permissive conditions for cilia assembly, under which cilia begin to form but fail to elongate. Subsequently, we link the defects in cilia growth to aberrant turnover of a microtubule-depolymerizing kinesin KIF2A, which we find restrained by TTBK2 phosphorylation. CONCLUSIONS: Together, our data imply that the regulation of KIF2A by TTBK2 represents an important mechanism governing cilia elongation and maintenance. Further, the requirement for concentrating TTBK2 activity to the mother centriole to initiate ciliogenesis can be under specific conditions bypassed, revealing TTBK2 recruitment-independent functions of its key partner, CEP164.

• Keywords
• Basal body, Cilia, Ciliogenesis, KIF2A, TTBK2,
• MeSH
• Cilia * metabolism   MeSH
• Phosphorylation MeSH
• Kinesins * metabolism   MeSH
• Humans MeSH
• Microtubules * metabolism   MeSH
• Protein Serine-Threonine Kinases * metabolism   genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• KIF2A protein, human MeSH Browser
• Kinesins * MeSH
• Protein Serine-Threonine Kinases * MeSH
• tau-tubulin kinase MeSH Browser

Bardet-Biedl syndrome (BBS) is a pleiotropic ciliopathy caused by dysfunction of the BBSome, a cargo adaptor essential for export of transmembrane receptors from cilia. Although actin-dependent ectocytosis has been proposed to compensate defective cargo retrieval, its molecular basis remains unclear, especially in relation to BBS pathology. In this study, we investigated how actin polymerization and ectocytosis are regulated within the cilium. Our findings reveal that ciliary CDC42, a RHO-family GTPase triggers in situ actin polymerization, ciliary ectocytosis, and cilia shortening in BBSome-deficient cells. Activation of the Sonic Hedgehog pathway further enhances CDC42 activity specifically in BBSome-deficient cilia. Inhibition of CDC42 in BBSome-deficient cells decreases the frequency and duration of ciliary actin polymerization events, causing buildup of G protein coupled receptor 161 (GPR161) in bulges along the axoneme during Sonic Hedgehog signaling. Overall, our study identifies CDC42 as a key trigger of ciliary ectocytosis. Hyperactive ciliary CDC42 and ectocytosis and the resulting loss of ciliary material might contribute to BBS disease severity.

• Keywords
• Actin, Bardet-Biedl Syndrome, CDC42, Cilium, Ectocytosis,
• MeSH
• Actins * metabolism   MeSH
• Bardet-Biedl Syndrome * metabolism   genetics   pathology   MeSH
• cdc42 GTP-Binding Protein * metabolism   genetics   MeSH
• Cilia * metabolism   MeSH
• Humans MeSH
• Mice MeSH
• Hedgehog Proteins metabolism   MeSH
• Receptors, G-Protein-Coupled metabolism   genetics   MeSH
• Signal Transduction MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Actins * MeSH
• cdc42 GTP-Binding Protein * MeSH
• Hedgehog Proteins MeSH
• Receptors, G-Protein-Coupled MeSH