The Centrosome, a Multitalented Renaissance Organelle

Vertii, Anastassiia; Hehnly, Heidi; Doxsey, Stephen

doi:10.1101/cshperspect.a025049

Cited by 97 publications

(81 citation statements)

References 129 publications

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“…The classic function of the centrosome is to serve as a major microtubule‐organizing center (MTOC) regulating cell cycle progression in animal cells. In addition, it has been shown that the centrosome is involved in immunological synapse formation between T cells and antigen‐presenting cells (Vertii et al , 2016a). Apart from the role in regulating adaptive immunity, a recent study indicates that the centrosome mediates the secretion of cytokines in response to proinflammatory stimuli which induce atypical interphase centrosome maturation in a manner independent of classic mitotic kinase PLK1(Vertii et al , 2016b).…”

Section: Discussionmentioning

confidence: 99%

PLK 4 deubiquitination by Spata2‐CYLD suppresses NEK7‐mediated NLRP3 inflammasome activation at the centrosome

Yang

Zhang

et al. 2019

The EMBO Journal

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The innate immune sensor NLRP3 assembles an inflammasome complex with NEK7 and ASC to activate caspase-1 and drive the maturation of proinflammatory cytokines IL-1b and IL-18. NLRP3 inflammasome activity must be tightly controlled, as its overactivation is involved in the pathogenesis of inflammatory diseases. Here, we show that NLRP3 inflammasome activation is suppressed by a centrosomal protein Spata2. Spata2 deficiency enhances NLRP3 inflammasome activity both in the macrophages and in an animal model of peritonitis. Mechanistically, Spata2 recruits the deubiquitinase CYLD to the centrosome for deubiquitination of polo-like kinase 4 (PLK4), the master regulator of centrosome duplication. Deubiquitination of PLK4 facilitates its binding to and phosphorylation of NEK7 at Ser204. NEK7 phosphorylation in turn attenuates NEK7 and NLRP3 interaction, which is required for NLRP3 inflammasome activation. Pharmacological or shRNA-mediated inhibition of PLK4, or mutation of the NEK7 Ser204 phosphorylation site, augments NEK7 interaction with NLRP3 and causes increased NLRP3 inflammasome activation. Our study unravels a novel centrosomal regulatory pathway of inflammasome activation and may provide new therapeutic targets for the treatment of NLRP3-associated inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

PLK 4 deubiquitination by Spata2‐CYLD suppresses NEK7‐mediated NLRP3 inflammasome activation at the centrosome

Yang

Zhang

et al. 2019

The EMBO Journal

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“…Accumulating evidence indicates that some of the functions of the centrosome depend on the appendages associated with the MC, such as ciliogenesis, cell‐cycle regulation and maintaining the stability of the centrosomal microtubules (Vertii, Hehnly, & Doxsey, ). Dysfunctions of the DAs and SDAs are known to lead to diseases in humans and mice (Bettencourt‐Dias, Hildebrandt, Pellman, Woods, & Godinho, ; Sánchez & Dynlacht, ).…”

Section: Discussionmentioning

confidence: 99%

Cep128 associates with Odf2 to form the subdistal appendage of the centriole

et al. 2019

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The mother centriole in a cell has two appendages, the distal appendage (DA) and subdistal appendage (SDA), which have roles in generating cilia and organizing the cellular microtubular network, respectively. In the knockout (KO) cells of Odf2, the component of the DA and SDA, both appendages simultaneously disappear. However, the molecular mechanisms by which the DA and SDA form independently but close to each other downstream of Odf2 are unknown. Here, using super‐resolution structured illumination microscopy (SR‐SIM), we found that the signal for GFP‐tagged Odf2 overlapped considerably with that of immunofluorescently labeled Cep128. We further found that Cep128 knockdown (KD) caused the dissociation of other SDA components from the centriole, including centriolin, Ndel1, ninein and Cep170, whereas Odf2 was still associated with the centriole. In contrast, the DA components remained associated with the centriole in Cep128 KD cells. Consistent with this observation, we identified Cep128 as an Odf2‐interacting protein by immunoprecipitation. Taken with the finding that Cep128 deletion decreased the stability of centriolar microtubules, our results indicate that Cep128 associates with Odf2 in the hierarchical assembly of SDA components to elicit the microtubule‐organizing function.

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“…Several hundred proteins are thought to be concentrated in the PCM, and these include proteins involved in nucleating and organizing microtubules (MTs) as well as many important cell-cycle regulators and signaling molecules (Conduit et al., 2015, Vertii et al., 2016). It is unclear, however, how the hundreds of proteins localized within the PCM assemble into a functional organelle.…”

Section: Introductionmentioning

confidence: 99%

Structural Basis for Mitotic Centrosome Assembly in Flies

Feng

Caballe

Wainman

et al. 2017

Cell

114

166

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SummaryIn flies, Centrosomin (Cnn) forms a phosphorylation-dependent scaffold that recruits proteins to the mitotic centrosome, but how Cnn assembles into a scaffold is unclear. We show that scaffold assembly requires conserved leucine zipper (LZ) and Cnn-motif 2 (CM2) domains that co-assemble into a 2:2 complex in vitro. We solve the crystal structure of the LZ:CM2 complex, revealing that both proteins form helical dimers that assemble into an unusual tetramer. A slightly longer version of the LZ can form micron-scale structures with CM2, whose assembly is stimulated by Plk1 phosphorylation in vitro. Mutating individual residues that perturb LZ:CM2 tetramer assembly perturbs the formation of these micron-scale assemblies in vitro and Cnn-scaffold assembly in vivo. Thus, Cnn molecules have an intrinsic ability to form large, LZ:CM2-interaction-dependent assemblies that are critical for mitotic centrosome assembly. These studies provide the first atomic insight into a molecular interaction required for mitotic centrosome assembly.

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The Centrosome, a Multitalented Renaissance Organelle

Cited by 97 publications

References 129 publications

PLK 4 deubiquitination by Spata2‐CYLD suppresses NEK7‐mediated NLRP3 inflammasome activation at the centrosome

PLK 4 deubiquitination by Spata2‐CYLD suppresses NEK7‐mediated NLRP3 inflammasome activation at the centrosome

Cep128 associates with Odf2 to form the subdistal appendage of the centriole

Structural Basis for Mitotic Centrosome Assembly in Flies

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