Centrobin controls primary ciliogenesis in vertebrates

Ogungbenro, Yetunde Adesanya; Tena, Teresa Casar; Gaboriau, David; Lalor, Pierce; Dockery, Peter; Philipp, Melanie; Morrison, Ciarán

doi:10.1083/jcb.201706095

Cited by 26 publications

(25 citation statements)

References 43 publications

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“…To investigate the potential role of Centrobin in Cenpas formation, we tested whether Centrobin depletion reduces Cenpas numbers in cells depleted of TRIM37. Although Centrobin depletion was reported initially to impair centriole assembly in HeLa cells (Zou et al, 2005), more recent work with Centrobin knock out cells (Centrobin-ko) demonstrates that the protein is dispensable for this process in RPE-1 cells (Ogungbenro et al, 2018). In our hands, siRNAmediated depletion of Centrobin did not impact centriole assembly either in HeLa Kyoto cells, despite near-complete protein depletion ( Fig.…”

Section: Exm Coupled To Sted Super-resolution Microscopy To Analyze Tcontrasting

confidence: 50%

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TRIM37 prevents formation of centriolar protein assemblies by regulating Centrobin stability

Balestra

Wolf

Domínguez-Calvo

et al. 2020

Preprint

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TRIM37 is an E3 ubiquitin ligase mutated in Mulibrey nanism, a disease characterized by impaired organ growth and increased tumorigenesis whose cellular etiology is poorly understood. TRIM37 depletion from tissue culture cells results in supernumerary foci bearing the centriolar protein Centrin. Here, we characterized these centriolar protein assemblies (Cenpas) to uncover the mechanism of action of TRIM37. We established that an atypical de novo assembly pathway is involved in forming Cenpas, which can nevertheless trigger further centriole assembly and act as MTOCs. We found also that Cenpas are present and act similarly in Mulibrey patient cells. Through correlative light electron microscopy, we uncovered that Cenpas correspond to centriole related structures and elongated electron-dense structures with stripes. Importantly, we established that TRIM37 regulates the stability and solubility of the centriolar protein Centrobin. Our findings suggest that elongated Centrobin assemblies are a major constituent of the striped electron dense structures. Furthermore, we established that Cenpas formation upon TRIM37 depletion requires PLK4 activity, as well as two parallel pathways relying respectively on Centrobin and PLK1. Overall, our work uncovers how TRIM37 prevents the formation of Cenpas that would otherwise threaten genome integrity, including in Mulibrey patients.

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Section: Exm Coupled To Sted Super-resolution Microscopy To Analyze Tcontrasting

confidence: 50%

“…5D). To test whether this might have been due to residual Centrobin or TRIM37 in the double siRNA depletion setting, we performed a similar experiment with RPE-1 Centrobin-ko cells (Ogungbenro et al, 2018), reaching similar conclusions (Fig. 5E, 5F, Fig.…”

Section: Exm Coupled To Sted Super-resolution Microscopy To Analyze Tmentioning

confidence: 65%

TRIM37 prevents formation of centriolar protein assemblies by regulating Centrobin stability

Balestra

Wolf

Domínguez-Calvo

et al. 2020

Preprint

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“…Thus, C2B might instead interact with other factors that either synergize with C2A function or regulate additional aspects of centriole assembly. Using a modified BioID procedure, we identified several centrosomal proteins as putative proximity interactors of CEP120 C2B, including CEP350, centrobin, CP110, TALPID3, and KIF24, all of which are involved in ciliogenesis ( Kobayashi et al., 2011 , Kobayashi et al., 2014 , Mojarad et al., 2017 , Ogungbenro et al., 2018 , Spektor et al., 2007 , Yin et al., 2009 ) ( Figure S6 B; Table S4 ). However, it remains to be established whether these factors show a direct interaction with CEP120 C2B and whether such an interaction would be affected by JS and JATD mutations.…”

Section: Discussionmentioning

confidence: 99%

Disease-Associated Mutations in CEP120 Destabilize the Protein and Impair Ciliogenesis

et al. 2018

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SummaryCiliopathies are a group of genetic disorders caused by a failure to form functional cilia. Due to a lack of structural information, it is currently poorly understood how ciliopathic mutations affect protein functionality to give rise to the underlying disease. Using X-ray crystallography, we show that the ciliopathy-associated centriolar protein CEP120 contains three C2 domains. The point mutations V194A and A199P, which cause Joubert syndrome (JS) and Jeune asphyxiating thoracic dystrophy (JATD), respectively, both reduce the thermostability of the second C2 domain by targeting residues that point toward its hydrophobic core. Genome-engineered cells homozygous for these mutations have largely normal centriole numbers but show reduced CEP120 levels, compromised recruitment of distal centriole markers, and deficient cilia formation. Our results provide insight into the disease mechanism of two ciliopathic mutations in CEP120, identify putative binding partners of CEP120 C2B, and suggest a complex genotype-phenotype relation of the CEP120 ciliopathy alleles.

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“…A key regulator of appropriate TTBK2 localization is the distal appendage protein CEP164 (Cajanek and Nigg, 2014;Oda et al, 2014). We used STORM microscopy to visualize CEP164 structures in centrin 2-deficient cells and in cells that lacked centrobin, another centriolar component whose absence negatively affects CP110 removal and primary ciliogenesis (Betzig et al, 2006;Heilemann et al, 2008;Rust et al, 2006;Yang et al, 2018;Ogungbenro et al, 2018). As shown in Fig.…”

Section: Requirement For the Ef-hands Of Centrin 2 In Primary Ciliogementioning

confidence: 99%

Differential requirements for the EF-hand domains of human centrin 2 in primary ciliogenesis and nucleotide excision repair

Khouj

Prosser

Tada

et al. 2019

Journal of Cell Science

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Centrin 2 is a small conserved calcium-binding protein that localizes to the centriolar distal lumen in human cells. It is required for efficient primary ciliogenesis and nucleotide excision repair (NER). Centrin 2 forms part of the xeroderma pigmentosum group C protein complex. To explore how centrin 2 contributes to these distinct processes, we mutated the four calcium-binding EF-hand domains of human centrin 2. Centrin 2 in which all four EF-hands had been mutated to ablate calcium binding (4DA mutant) was capable of supporting in vitro NER and was as effective as the wild-type protein in rescuing the UV sensitivity of centrin 2-null cells. However, we found that mutation of any of the EF-hand domains impaired primary ciliogenesis in human TERT-RPE1 cells to the same extent as deletion of centrin 2. Phenotypic analysis of the 4DA mutant revealed defects in centrosome localization, centriole satellite assembly, ciliary assembly and function and in interactions with POC5 and SFI1. These observations indicate that centrin 2 requires calcium-binding capacity for its primary ciliogenesis functions, but not for NER, and suggest that these functions require centrin 2 to be capable of forming complexes with partner proteins. This article has an associated First Person interview with the first author of the paper.

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Centrobin controls primary ciliogenesis in vertebrates

Abstract: Ogungbenro et al. use reverse genetics in human hTERT-RPE1 cells and zebrafish to demonstrate novel roles for the centriolar BRCA2 interactor, centrobin, in controlling primary cilium formation through a C-terminal tubulin- and CP110-interacting region.

Cited by 26 publications

References 43 publications

TRIM37 prevents formation of centriolar protein assemblies by regulating Centrobin stability

TRIM37 prevents formation of centriolar protein assemblies by regulating Centrobin stability

Disease-Associated Mutations in CEP120 Destabilize the Protein and Impair Ciliogenesis

Differential requirements for the EF-hand domains of human centrin 2 in primary ciliogenesis and nucleotide excision repair

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