Tau-tubulin kinase 2 restrains microtubule-depolymerizer KIF2A to support primary cilia growth
Year: 2025
Type: article
Abstract: 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.
Source: Cell Communication and Signaling
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,390
Funders: Univerzita Karlova v Praze, Přírodovědecká Fakulta, Univerzita Karlova, European Commission, Ministerstvo Školství, Mládeže a Tělovýchovy, Grantová Agentura České Republiky, Akademie Věd České Republiky, Central European Institute of Technology, Masarykova Univerzita, European Regional Development Fund
Awards: G1093144819, G12500569, G1478526422, G1761812275, G176604203, G190135293, G1940663492, G208869049, National Infrastructure for Biological and Medical Imaging, Cilia-related Tau tubulin kinase 2 in health and disease: structure and function, G2534379819, G291036901, G308298343, G3490171961, National institute for Neurological Research, G3622461675, G4014226167, G4131035492, G4433258970, G5157879570, G5479454656, G5641063287, G5916014575, G5960638817, National Infrastructure for Biological and Medical Imaging, G6734625656, G7202931751, G7890394945, G803096421, G8227998441, G82516473, G8265045674, Czech Infrastructure for Integrative Structural Biology, G8607029115, G941802975
OpenAlex ID: W4407340603