Centriole triplet microtubules are required for stable centriole formation and inheritance in human cells

Wang, Jennifer T.; Kong, Dong; Hoerner, Christian R.; Lončarek, Jadranka; Stearns, Tim

doi:10.7554/elife.29061

Cited by 47 publications

(60 citation statements)

References 47 publications

(59 reference statements)

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“…Mutations in the Chlamydomonas ortholog of Tubd1 , encoded by the UNI3 gene, cause defects in the assembly of flagella, which are analogous to vertebrate motile cilia ( Dutcher and Trabuco, 1998 ). Centrioles in human cells lacking TUBD1 are unstable and fail to undergo maturation ( Wang et al., 2017 ). GLI1 induction was abolished in Tubd1 −/− NIH/3T3 cells ( Figures 4 B and S3 E) because nearly 100% of these cells lacked primary cilia ( Figure 4 C).…”

Section: Resultsmentioning

confidence: 99%

CRISPR Screens Uncover Genes that Regulate Target Cell Sensitivity to the Morphogen Sonic Hedgehog

et al. 2018

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SummaryTo uncover regulatory mechanisms in Hedgehog (Hh) signaling, we conducted genome-wide screens to identify positive and negative pathway components and validated top hits using multiple signaling and differentiation assays in two different cell types. Most positive regulators identified in our screens, including Rab34, Pdcl, and Tubd1, were involved in ciliary functions, confirming the central role for primary cilia in Hh signaling. Negative regulators identified included Megf8, Mgrn1, and an unannotated gene encoding a tetraspan protein we named Atthog. The function of these negative regulators converged on Smoothened (SMO), an oncoprotein that transduces the Hh signal across the membrane. In the absence of Atthog, SMO was stabilized at the cell surface and concentrated in the ciliary membrane, boosting cell sensitivity to the ligand Sonic Hedgehog (SHH) and consequently altering SHH-guided neural cell-fate decisions. Thus, we uncovered genes that modify the interpretation of morphogen signals by regulating protein-trafficking events in target cells.

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Section: Resultsmentioning

confidence: 99%

CRISPR Screens Uncover Genes that Regulate Target Cell Sensitivity to the Morphogen Sonic Hedgehog

et al. 2018

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“…Of the many characterized isoforms within the tubulin protein superfamily, the delta and epsilon tubulin variants remain incompletely understood. Recent work has suggested that these isoforms exist as an evolutionarily conserved module (Turk et al, 2015) and may be involved in forming triplet microtubules that are critical for centriole assembly (Wang et al, 2017a). …”

Section: Resultsmentioning

confidence: 99%

Interrogation of Mammalian Protein Complex Structure, Function, and Membership Using Genome-Scale Fitness Screens

et al. 2018

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Summary Protein complexes are assemblies of subunits that have co-evolved to execute one or many coordinated functions in the cellular environment. Functional annotation of mammalian protein complexes is critical to understanding biological processes as well as disease mechanisms. Here, we used genetic co-essentiality derived from genome-scale RNAi- and CRISPR-Cas9- based fitness screens performed across hundreds of human cancer cell lines to assign measures of functional similarity. From these measures, we systematically built and characterized functional similarity networks which recapitulate known structural and functional features of well-studied protein complexes and resolve novel functional modules within complexes lacking structural resolution, such as the mammalian SWI/SNF complex. Finally, by integrating functional networks with large protein-protein interaction networks, we discovered novel protein complexes involving recently-evolved genes of unknown function. Taken together, these findings demonstrate the utility of genetic perturbation screens alone and in combination with large-scale biophysical data to enhance our understanding of mammalian protein complexes in normal and disease states.

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“…as the A-and B-microtubule inner junction would be missing. As a consequence, the 421 inner scaffold proteins will not be recruited, as already shown for POC5, leading to the 422 observed futile cycle of centriole formation and disintegration (Wang et al, 2017). It 423 would therefore be interesting to study the presence of WDR90 in these null mutants 424 as well as the other components of the inner scaffold in the future.…”

Section: Wdr90 Depletion Leads To a Loss Of Inner Scaffold Componentsmentioning

confidence: 96%

WDR90 is a centriolar microtubule wall protein important for centriole architecture integrity

Steib

Gambarotto

Laporte

et al. 2020

Preprint

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27Centrioles are characterized by a nine-fold arrangement of long-lived 28 microtubule triplets that are held together by an inner protein scaffold. These 29 structurally robust organelles experience strenuous cellular processes such as cell 30 division or ciliary beating while performing their function. However, the molecular 31 mechanisms underlying the stability of microtubule triplets, as well as centriole 32 architectural integrity remain poorly understood. Here, using ultrastructure expansion 33 microscopy (U-ExM) for nanoscale protein mapping, we reveal that POC16 and its 34 human homolog WDR90 are components of the centriolar microtubule wall along the 35 central core region of the centriole. We further found that WDR90 is an evolutionary 36 microtubule associated protein with a predicted structurally homology with the ciliary 37 inner junction protein FAP20. Finally, we demonstrate that WDR90 depletion impairs 38 the localization of inner scaffold components, leading to centriole structural 39 abnormalities in both human and Chlamydomonas cells. Altogether, this work 40 highlights that POC16/WDR90 is a crucial evolutionary conserved molecular player 41 participating in centriole architecture integrity. 42 43 44 45

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Centriole triplet microtubules are required for stable centriole formation and inheritance in human cells

Cited by 47 publications

References 47 publications

CRISPR Screens Uncover Genes that Regulate Target Cell Sensitivity to the Morphogen Sonic Hedgehog

CRISPR Screens Uncover Genes that Regulate Target Cell Sensitivity to the Morphogen Sonic Hedgehog

Interrogation of Mammalian Protein Complex Structure, Function, and Membership Using Genome-Scale Fitness Screens

WDR90 is a centriolar microtubule wall protein important for centriole architecture integrity

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