centrosomal proteins
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Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5638
Author(s):  
Pavel Dráber ◽  
Eduarda Dráberová

In cells, microtubules typically nucleate from microtubule organizing centers, such as centrosomes. γ-Tubulin, which forms multiprotein complexes, is essential for nucleation. The γ-tubulin ring complex (γ-TuRC) is an efficient microtubule nucleator that requires additional centrosomal proteins for its activation and targeting. Evidence suggests that there is a dysfunction of centrosomal microtubule nucleation in cancer cells. Despite decades of molecular analysis of γ-TuRC and its interacting factors, the mechanisms of microtubule nucleation in normal and cancer cells remains obscure. Here, we review recent work on the high-resolution structure of γ-TuRC, which brings new insight into the mechanism of microtubule nucleation. We discuss the effects of γ-TuRC protein dysregulation on cancer cell behavior and new compounds targeting γ-tubulin. Drugs inhibiting γ-TuRC functions could represent an alternative to microtubule targeting agents in cancer chemotherapy.


Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2384
Author(s):  
Valentin Pitzen ◽  
Sophia Sander ◽  
Otto Baumann ◽  
Ralph Gräf ◽  
Irene Meyer

The Dictyostelium centrosome is a nucleus-associated body with a diameter of approx. 500 nm. It contains no centrioles but consists of a cylindrical layered core structure surrounded by a microtubule-nucleating corona. At the onset of mitosis, the corona disassembles and the core structure duplicates through growth, splitting, and reorganization of the outer core layers. During the last decades our research group has characterized the majority of the 42 known centrosomal proteins. In this work we focus on the conserved, previously uncharacterized Cep192 protein. We use superresolution expansion microscopy (ExM) to show that Cep192 is a component of the outer core layers. Furthermore, ExM with centrosomal marker proteins nicely mirrored all ultrastructurally known centrosomal substructures. Furthermore, we improved the proximity-dependent biotin identification assay (BioID) by adapting the biotinylase BioID2 for expression in Dictyostelium and applying a knock-in strategy for the expression of BioID2-tagged centrosomal fusion proteins. Thus, we were able to identify various centrosomal Cep192 interaction partners, including CDK5RAP2, which was previously allocated to the inner corona structure, and several core components. Studies employing overexpression of GFP-Cep192 as well as depletion of endogenous Cep192 revealed that Cep192 is a key protein for the recruitment of corona components during centrosome biogenesis and is required to maintain a stable corona structure.


2021 ◽  
Author(s):  
Momoe Nakajo ◽  
Hikaru Kano ◽  
Kenji Tsuyama ◽  
Nami Haruta ◽  
Asako Sugimoto

Centrosomes consist of two centrioles and surrounding pericentriolar material (PCM). PCM expands during mitosis in a process called centrosome maturation, in which PCM scaffold proteins play pivotal roles to recruit other centrosomal proteins. In C. elegans, the scaffold protein SPD-5 forms PCM scaffold in a PLK-1 phosphorylation-dependent manner. However, how phosphorylation of SPD-5 promotes PCM scaffold assembly is unclear. Here, we identified three functional domains of SPD-5 through in vivo domain analyses, and propose that sequential domain interactions of SPD-5 are required for mitotic PCM scaffold assembly. Firstly, SPD-5 is targeted to centrioles through direct interaction between its centriole localization (CL) domain and a centriolar protein PCMD-1. Then, intra- and inter-molecular interaction between SPD-5 phospho-regulated multimerization (PReM) domain and the PReM association (PA) domain is triggered by phosphorylation by PLK-1, which leads to PCM scaffold expansion. Our findings suggest that the sequential domain interactions of scaffold proteins mediated by Polo/PLK-1 phosphorylation is an evolutionarily conserved mechanism of PCM scaffold assembly.


2021 ◽  
Vol 220 (7) ◽  
Author(s):  
Franz Meitinger ◽  
Dong Kong ◽  
Midori Ohta ◽  
Arshad Desai ◽  
Karen Oegema ◽  
...  

Centrosomes are composed of a centriolar core surrounded by pericentriolar material that nucleates microtubules. The ubiquitin ligase TRIM37 localizes to centrosomes, but its centrosomal roles are not yet defined. We show that TRIM37 does not control centriole duplication, structure, or the ability of centrioles to form cilia but instead prevents assembly of an ectopic centrobin-scaffolded structured condensate that forms by budding off of centrosomes. In ∼25% of TRIM37-deficient cells, the condensate organizes an ectopic spindle pole, recruiting other centrosomal proteins and acquiring microtubule nucleation capacity during mitotic entry. Ectopic spindle pole–associated transient multipolarity and multipolar segregation in TRIM37-deficient cells are suppressed by removing centrobin, which interacts with and is ubiquitinated by TRIM37. Thus, TRIM37 ensures accurate chromosome segregation by preventing the formation of centrobin-scaffolded condensates that organize ectopic spindle poles. Mutations in TRIM37 cause the disorder mulibrey nanism, and patient-derived cells harbor centrobin condensate-organized ectopic poles, leading us to propose that chromosome missegregation is a pathological mechanism in this disorder.


2021 ◽  
Author(s):  
Farners Amargant ◽  
Aida Pujol ◽  
Anna Ferrer-Vaquer ◽  
Merce Durban ◽  
Meritxell Martinez ◽  
...  

The mechanism of conversion of the human sperm basal body to a centrosome after fertilization, and its role in supporting human early embryogenesis has not been directly addressed so far. Using proteomics and immunofluorescence studies we show here that the human zygote inherits a basal body enriched with centrosomal proteins from the sperm, establishing the first functional centrosome of the new organism. Injection of human sperm tails containing the basal body into human oocytes followed by parthenogenetically activation, showed that the centrosome contributes to the robustness of the early cell divisions, increasing the probability of parthenotes reaching the compaction stage. In the absence of the sperm-derived centrosome, pericentriolar (PCM) components stored in the oocyte can form de novo structures after genome activation, suggesting a tight PCM expression control in zygotes. Our results reveal that the sperm basal body is a complex organelle which converts to a centrosome after fertilization, ensuring the early steps of embryogenesis and successful compaction. However, more experiments are needed to elucidate the exact molecular mechanisms of centrosome inheritance in humans.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Qi Wu ◽  
Xin Yu ◽  
Le Liu ◽  
Shengrong Sun ◽  
Si Sun

AbstractAutophagy is a prominent mechanism to preserve homeostasis and the response to intracellular or extracellular stress. Autophagic degradation can be selectively targeted to dysfunctional subcellular compartments. Centrosome homeostasis is pivotal for healthy proliferating cells, but centrosome aberration is a hallmark of diverse human disorders. Recently, a process called centrosome-phagy has been identified. The process involves a panel of centrosomal proteins and centrosome-related pathways that mediate the specific degradation of centrosomal components via the autophagic machinery. Although autophagy normally mediates centrosome homeostasis, autophagy defects facilitate ageing and multiple human diseases, such as ciliopathies and cancer, which benefit from centrosome aberration. Here, we discuss the molecular systems that trigger centrosome-phagy and its role in human disorders.


2021 ◽  
Author(s):  
Hideki Yokoyama ◽  
Kaoru Takizawa ◽  
Jian Ma ◽  
Daniel Moreno-Andrés ◽  
Wolfram Antonin ◽  
...  

Abstract SART1 is overexpressed in various cancers. However, its physiological function and cancer relevance remains elusive. Here we identify SART1 as a mitotic-specific and Ran-regulated microtubule-associated protein. SART1 downregulation in human cells as well as its depletion from frog egg extracts disrupts spindle assembly. While SART1 is nuclear in interphase, it localizes during mitosis to spindle poles in a microtubule-dependent manner. SART1 accumulates close to centrosomes forming a half circle which we designate as SART1 cap. Immunoprecipitation of SART1 identifies the centrosome scaffold protein Cep192 as an interaction partner. Accordingly, Cep192 downregulation abolishes SART1 localization to spindle poles, and SART1 downregulation displaces centrosomal proteins like Ninein from centrosomes, but does not affect γ-tubulin localization. Furthermore, SART1 downregulation selectively kills cancer cells and prevents normal cells from oncogenic transformation. Our data unravel a novel function of SART1 for centrosome organization and spotlight SRAT1 as a potential target for anticancer therapies.


2020 ◽  
Author(s):  
Suzanna L. Prosser ◽  
Johnny Tkach ◽  
Ladan Gheiratmand ◽  
Ciaran G. Morrison ◽  
Laurence Pelletier

ABSTRACTProtein degradation at the centrosome, the primary microtubule organizing centre of the cell, is critical to a myriad of cellular processes. Perturbation of the ubiquitin proteasome system causes the formation of an inclusion, or aggresome, at the centrosome. By systematic microscopy analysis, we have placed a subset of centrosomal proteins within the aggresome. Centriolar satellites, proteinaceous granules found in the vicinity of centrosomes, also became incorporated into this structure. Through high-resolution quantitative analysis, we have defined aggresome assembly at the centrosome, demonstrating a requirement for satellites in this process. Furthermore, a module consisting of CP110-CEP97-CEP290 was required to recruit aggresome components early in the pathway and senescent cells were defective in aggresome formation due to limiting amounts of CP110. Finally, satellites and the CP110-CEP97-CEP290 module were required for the aggregation of mutant huntingtin. The accumulation of protein aggregates is central to the pathology of a range of human disorders. These data thereby reveal new roles for CP110, its interactors, and centriolar satellites in controlling cellular proteostasis and the aggregation of disease relevant proteins.


2020 ◽  
Author(s):  
Robert Becker ◽  
Silvia Vergarajauregui ◽  
Florian Billing ◽  
Maria Sharkova ◽  
Eleonora Lippolis ◽  
...  

AbstractNon-centrosomal microtubule organizing centers (ncMTOC) are pivotal for the function of multiple cell types, but the processes initiating their formation are unknown. Here, we find that the transcription factor myogenin is required in myoblasts for recruiting centrosomal proteins. Moreover, myogenin is sufficient in fibroblasts for ncMTOC formation and centrosome attenuation. Bioinformatics combined with loss- and gain-of-function experiments identified induction of AKAP6 expression as one central mechanism for myogenin-mediated ncMTOC formation. Promoter studies indicate that myogenin preferentially induces the transcription of muscle- and ncMTOC-specific isoforms of Akap6 and Syne1, which encodes nesprin-1α, the ncMTOC anchor protein in muscle cells. Overexpression of AKAP6β and nesprin-1α was sufficient to recruit endogenous centrosomal proteins to the nuclear envelope of myoblasts in the absence of myogenin. Taken together, our results illuminate how mammals transcriptionally control the switch from a centrosomal MTOC to an ncMTOC and identify AKAP6 as a novel ncMTOC component in muscle cells.


eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Silvia Vergarajauregui ◽  
Robert Becker ◽  
Ulrike Steffen ◽  
Maria Sharkova ◽  
Tilman Esser ◽  
...  

The switch from centrosomal microtubule-organizing centers (MTOCs) to non-centrosomal MTOCs during differentiation is poorly understood. Here, we identify AKAP6 as key component of the nuclear envelope MTOC. In rat cardiomyocytes, AKAP6 anchors centrosomal proteins to the nuclear envelope through its spectrin repeats, acting as an adaptor between nesprin-1α and Pcnt or AKAP9. In addition, AKAP6 and AKAP9 form a protein platform tethering the Golgi to the nucleus. Both Golgi and nuclear envelope exhibit MTOC activity utilizing either AKAP9, or Pcnt-AKAP9, respectively. AKAP6 is also required for formation and activity of the nuclear envelope MTOC in human osteoclasts. Moreover, ectopic expression of AKAP6 in epithelial cells is sufficient to recruit endogenous centrosomal proteins. Finally, AKAP6 is required for cardiomyocyte hypertrophy and osteoclast bone resorption activity. Collectively, we decipher the MTOC at the nuclear envelope as a bi-layered structure generating two pools of microtubules with AKAP6 as a key organizer.


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