Molecular mechanisms underlying the role of the centriolar CEP164-TTBK2 complex in ciliopathies

Silva, Ivan Rosa e; Binó, Lucia; Johnson, Christopher M.; Rutherford, Trevor J.; Neuhaus, David; Andreeva, Antonina; Čajánek, Lukáš; Breugel, M. van

doi:10.1016/j.str.2021.08.007

Cited by 11 publications

(5 citation statements)

References 80 publications

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“…Intriguingly, however, our results further suggest that TTBK1 can partially compensate for the absence of TTBK2 in hPSCs-derived neural rosettes. This is quite surprising, as the Proline-rich motif implicated in TTBK2-CEP164 interaction (Oda et al , 2014; Rosa e Silva et al , 2022; Čajánek & Nigg, 2014) and, in turn, the recruitment of the kinase to the mother centriole, is poorly conserved in TTBK1 (Suppl. Fig.…”

Section: Discussionmentioning

confidence: 99%

Tau tubulin kinase 1 and 2 regulate ciliogenesis and human pluripotent stem cells–derived neural rosettes

Binó

Čajánek

2023

Preprint

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Primary cilia are key regulators of embryo development and tissue homeostasis. However, their mechanisms and functions, particularly in the context of human cells, are still unclear. Here, we analyzed the consequences of primary cilia modulation for human pluripotent stem cells (hPSCs) proliferation and differentiation. We show that neither activation of the cilia-associated Hedgehog signaling pathway nor ablation of primary cilia by CRISPR gene editing to knockout Tau Tubulin Kinase 2 (TTBK2), a crucial ciliogenesis regulator, affects the self-renewal of hPSCs. In addition, we demonstrate that TTBK1, a closely related kinase without previous links to ciliogenesis, is upregulated during hPSCs-derived neural rosette differentiation to regulate primary cilia formation together with TTBK2. Finally, we show that TTBK1/2 and primary cilia are implicated in the regulation of the size of hPSCs-derived neural rosettes.

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Section: Discussionmentioning

confidence: 99%

Tau tubulin kinase 1 and 2 regulate ciliogenesis and human pluripotent stem cells–derived neural rosettes

Binó

Čajánek

2023

Preprint

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“…We and others have demonstrated that the C-term region of TTBK2, missing in SCA11-related TTBK2 proteins, is essential for its interaction with CEP164 25,36,41 . Still, we were initially surprised to see the difference in TTBK2 trunc1/2 -induced phosphorylation between CEP164 and DVL3.…”

Section: Discussionmentioning

confidence: 80%

“…This observation raises several intriguing possibilities. First, our expansion microscopy data suggest the MC-associated pool of KIF2A is well within the reach of TTBK2 kinase activity at MC 34,35 , given the flexibility of its long, highly unstructured C-terminal part 36 . Thus, KIF2A seems to be in a suitable position for direct regulation by TTBK2 phosphorylation, analogous to their interactions at microtubule plus ends 22 .…”

Section: Discussionmentioning

confidence: 85%

Tau-Tubulin Kinase 2 restrains microtubule-depolymerizer KIF2A to support primary cilia growth

Vysloužil

Bernatík

Renzova

et al. 2023

Preprint

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The initiation of assembly of primary cilia, organelles with crucial functions in development and disease, is under the control of Tau-Tubulin Kinase 2 (TTBK2). Recent work has implicated TTBK2 also in the regulation of primary cilia maintenance and function. However, the mechanisms underlying individual functions of TTBK2 in primary cilia are not fully understood. Here, to dissect the role of TTBK2 in primary cilia maintenance in human cells, we examined disease related TTBK2 truncations. We demonstrate that these truncated protein moieties show selective activity towards TTBK2 substrates. This creates a semi-permissive condition where partial TTBK2 activity suffices to support the initiation of ciliogenesis but fails to sustain primary cilia length. Subsequently, we show that the defects in primary cilia growth are linked to aberrant turnover of kinesin KIF2A at basal body. Furthermore, we demonstrate that TTBK2 regulates KIF2A by phosphorylation, which in turn restrains its levels at the ciliary base to promote primary cilia elongation and maintenance. Taken together, our data highlight the regulation of KIF2A by TTBK2 as an important mechanism governing primary cilia in human cells.

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“…In contrast, the transfection with constructs reflecting two of the missense mutations showed a proper centrosomal localization of CEP164 in hTERT RPE-1 cells but lead to diminished cilia formation. Interestingly, these constructs also compromised the interaction with TTBK2 through an impaired folding of the N-terminal domain of CEP164 [113]. The impaired S-phase progression upon depletion of CEP164 in IMCD3 cells cannot be rescued through the overexpression of two different disease-associated cDNA-constructs that mimics a nonsense and a missense human mutation.…”

Section: Cep164/nphp15mentioning

confidence: 99%

The Role of Centrosome Distal Appendage Proteins (DAPs) in Nephronophthisis and Ciliogenesis

Mansour

Boivin

Shaheed

et al. 2021

IJMS

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The primary cilium is found in most mammalian cells and plays a functional role in tissue homeostasis and organ development by modulating key signaling pathways. Ciliopathies are a group of genetically heterogeneous disorders resulting from defects in cilia development and function. Patients with ciliopathic disorders exhibit a range of phenotypes that include nephronophthisis (NPHP), a progressive tubulointerstitial kidney disease that commonly results in end-stage renal disease (ESRD). In recent years, distal appendages (DAPs), which radially project from the distal end of the mother centriole, have been shown to play a vital role in primary ciliary vesicle docking and the initiation of ciliogenesis. Mutations in the genes encoding these proteins can result in either a complete loss of the primary cilium, abnormal ciliary formation, or defective ciliary signaling. DAPs deficiency in humans or mice commonly results in NPHP. In this review, we outline recent advances in our understanding of the molecular functions of DAPs and how they participate in nephronophthisis development.

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Molecular mechanisms underlying the role of the centriolar CEP164-TTBK2 complex in ciliopathies

Cited by 11 publications

References 80 publications

Tau tubulin kinase 1 and 2 regulate ciliogenesis and human pluripotent stem cells–derived neural rosettes

Tau tubulin kinase 1 and 2 regulate ciliogenesis and human pluripotent stem cells–derived neural rosettes

Tau-Tubulin Kinase 2 restrains microtubule-depolymerizer KIF2A to support primary cilia growth

The Role of Centrosome Distal Appendage Proteins (DAPs) in Nephronophthisis and Ciliogenesis

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