The regulation of cilium assembly and disassembly in development and disease

Wang, Lei; Dynlacht, Brian David

doi:10.1242/dev.151407

Cited by 167 publications

(213 citation statements)

References 166 publications

(220 reference statements)

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“…To test this, we used quantitative immunofluorescence to determine the centrosomal levels of proteins that are components of distal appendages, transition zone proteins, IFT machinery as well as activators and suppressors of ciliogenesis in asynchronous and serum-starved control cells, IMCD3 PCM1 KO cells, and the LAP-PCM1 rescue clone. Distal appendages function in docking of the mother centriole to the membrane during ciliogenesis, and transition zone regulates the entry and exit of ciliary cargo [43,44]. The defects in ciliogenesis were not because of mislocalization of distal appendage or the transition zone proteins since Cep164 and Cep290 localized correctly to the centrosomes in both control and IMCD3 PCM1 KO cells ( Figs 4A and B, and EV3A and B).…”

Section: Satellites Have Variable Effects On Regulating Centrosomal Amentioning

confidence: 87%

Centriolar satellites are required for efficient ciliogenesis and ciliary content regulation

et al. 2019

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Centriolar satellites are ubiquitous in vertebrate cells. They have recently emerged as key regulators of centrosome/cilium biogenesis, and their mutations are linked to ciliopathies. However, their precise functions and mechanisms of action remain poorly understood. Here, we generated a kidney epithelial cell line ( IMCD 3) lacking satellites by CRISPR /Cas9‐mediated PCM 1 deletion and investigated the cellular and molecular consequences of satellite loss. Cells lacking satellites still formed full‐length cilia but at significantly lower numbers, with changes in the centrosomal and cellular levels of key ciliogenesis factors. Using these cells, we identified new ciliary functions of satellites such as regulation of ciliary content, Hedgehog signaling, and epithelial cell organization in three‐dimensional cultures. However, other functions of satellites, namely proliferation, cell cycle progression, and centriole duplication, were unaffected in these cells. Quantitative transcriptomic and proteomic profiling revealed that loss of satellites affects transcription scarcely, but significantly alters the proteome. Importantly, the centrosome proteome mostly remains unaltered in the cells lacking satellites. Together, our findings identify centriolar satellites as regulators of efficient cilium assembly and function and provide insight into disease mechanisms of ciliopathies.

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Section: Satellites Have Variable Effects On Regulating Centrosomal Amentioning

confidence: 87%

Centriolar satellites are required for efficient ciliogenesis and ciliary content regulation

et al. 2019

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“…In addition, cilia abnormalities have been recently related to cancer (3)(4)(5), further affirming the importance of correctly functioning PC for tissue homeostasis.…”

Section: Introductionmentioning

confidence: 90%

Phosphorylation of multiple proteins involved in ciliogenesis by Tau Tubulin kinase 2

Bernatík

Pejšková

Vysloužil

et al. 2019

Preprint

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Primary cilia (PC) are organelles necessary for proper implementation of developmental and homeostasis processes. To initiate their assembly, coordinated actions of multiple proteins are needed. Tau tubulin kinase 2 (TTBK2) is a key player in the cilium assembly pathway, controlling final step of cilia initiation. The function of TTBK2 in ciliogenesisis is critically dependent on its kinase activity, however, precise mechanism of TTBK2 action is so far incompletely understood, due to very limited information about its relevant substrates. In this study we identify CEP83, CEP89, CCDC92, Rabin8 and DVL3 as substrates of TTBK2 kinase activity. Further, we characterise a set of phosphosites of the newly identified substrates and CEP164, induced by TTBK2 in vitro and in vivo. Intriguingly, we further show that identified TTBK2 phosphosites and consensus sequence delineated from those are distinct from motifs previously assigned to TTBK2. Finally, we address functional relevance of selected phosphorylations of CEP164 and provide evidence that the examined TTBK2-induced phosphorylations of CEP164 are relevant for the process of cilia formation. In summary, our work provides important insight into substrates-TTBK2 kinase relationship and suggests that phosphorylation of substrates on multiple sites by TTBK2 is probably involved in the control of ciliogenesis in human cells.

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“…Conversion of the mother centriole into a basal body underscores cilium assembly; distal and subdistal appendages facilitate recruitment of Golgi-derived vesicles onto the distal end of the mother centriole, which enable fusion with the plasma membrane and subsequent axoneme extension (Vertii et al, 2016). Consistent with the role of primary cilia in coordinating several signal transduction pathways including Hedgehog and PDGFR, cilia defects manifest as multisystemic genetic disorders and diseases (Spasic & Jacobs, 2017;Wang & Dynlacht, 2018).…”

Section: Introductionmentioning

confidence: 97%

Centriolar satellites are acentriolar assemblies of centrosomal proteins

et al. 2019

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Centrioles are core structural elements of both centrosomes and cilia. Although cytoplasmic granules called centriolar satellites have been observed around these structures, lack of a comprehensive inventory of satellite proteins impedes our understanding of their ancestry. To address this, we performed mass spectrometry (MS)‐based proteome profiling of centriolar satellites obtained by affinity purification of their key constituent, PCM1, from sucrose gradient fractions. We defined an interactome consisting of 223 proteins, which showed striking enrichment in centrosome components. The proteome also contained new structural and regulatory factors with roles in ciliogenesis. Quantitative MS on whole‐cell and centriolar satellite proteomes of acentriolar cells was performed to reveal dependencies of satellite composition on intact centrosomes. Although most components remained associated with PCM1 in acentriolar cells, reduced cytoplasmic and satellite levels were observed for a subset of centrosomal proteins. These results demonstrate that centriolar satellites and centrosomes form independently but share a substantial fraction of their proteomes. Dynamic exchange of proteins between these organelles could facilitate their adaptation to changing cellular environments during development, stress response and tissue homeostasis.

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The regulation of cilium assembly and disassembly in development and disease

Cited by 167 publications

References 166 publications

Centriolar satellites are required for efficient ciliogenesis and ciliary content regulation

Centriolar satellites are required for efficient ciliogenesis and ciliary content regulation

Phosphorylation of multiple proteins involved in ciliogenesis by Tau Tubulin kinase 2

Centriolar satellites are acentriolar assemblies of centrosomal proteins

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