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CentrosomeThe centrosome is the main microtubule organizing center (MTOC) in human cells, and has been widely studied ever since Theodor Boveri first described it in 1888. Although the centrosome is a small organelle, it is of great importance for fundamental cellular functions. Located adjacent to the nucleus, the main role of the centrosome is to regulate the intracellular organization of microtubules. This is of great importance for cell shape, cell polarity, cell migration, intracellular organization and intracellular transport. During cell division, the centrosome is the key responsible organelle for the correct formation and orientation of the mitotic spindle, ensuring proper segregation of sister chromatids to each of the daughter cells (Nigg EA et al. (2011)). In the subcellular section, 579 genes (3% of all protein-coding human genes) have been shown to encode proteins that localize to the centrosome or the centriolar satellites. In images where it has been possible to distinguish one or two clear dots, proteins have been annotated with the location "centrosome", while in images where the protein localizes more diffusely to the are at which microtubules originate, proteins have been annotated with the location "centriolar satellite" (Figure 1-2). Functional enrichment analysis of the centrosome proteome shows enrichment of terms for biological processes related to intracellular organization and transport, organization of microtubules, cell cycle progression and cell division.
Figure 1. Examples for proteins localized to the centrosome and centriolar satellites. CEP131 localizes to centriolar satellites and has an important role in the formation and function of cilia (detected in A-431 cells). PCNT is a well-characterized protein component of the filamentous matrix of the centrosome with important roles in both mitosis and meiosis (detected in U-251 cells). MKKS is a centrosome-shuttling protein that localizes to a tube-like structure around the centrioles in the pericentriolar material (PCM) and is important for cell division (detected in U2OS cells). Normally, MKKS shuttles between the centrosome and the cytosol throughout the cell cycle but when mutated, it fails to localize to the centrosome, leading to the McKusick Kaufman syndrome, a disease that manifests with impaired development, especially of hands and feet, as well as heart and genital defects.
Figure 2. 3% of all human protein-coding genes encode proteins localized to the centrosome or the centriolar satellites. Each bar is clickable and gives a search result of proteins that belong to the selected category. The structure of the centrosomeSubstructures The centrosome is a small non-membrane bound organelle in the cytoplasm (Doxsey S. (2001)). It is composed of two barrel shaped centrioles, each composed of nine microtubule triplets, held together at a perpendicular angle by interconnecting fibers. The centrioles are surrounded by an amorphous matrix of proteins, commonly referred to as the pericentriolar material (PCM), which contains proteins involved in nucleation and anchoring of microtubules, as well as important cell cycle regulators and other signaling molecules. Pericentrin (Figure 1), γ-tubulin, ninein, centriolin and aurora kinases are some examples (Doxsey S. (2001)).The γ-tubulin protein complex is a highly conserved complex that forms an open ring structure, around 25 nm in diameter, and plays a key role in nucleation of microtubules. As a key regulator of mitosis, the structure and composition of the centrosome is highly dynamic and undergoes dramatic organizational changes throughout the cell cycle (Bornens M. (2002); Conduit PT et al. (2015)). The centrosomes, as well as the basal body of cilia, is closely surrounded by cytoplasmic granules, known as centriolar satellites (Tollenaere MA et al. (2015); Prosser SL et al. (2020)). Centriolar satellites travel along microtubules by association with motor proteins and are known to contain a number of proteins that are also found in centrosomes and cilia. Centriolar satellites can be observed in most cell types, but their composition, size, number and location varies. Centriolar satellites disassemble upon entry into mitosis, bur reappear upon completion of cytokinesis. A selection of proteins suitable as markers for the centrosome and the centriolar satellites can be found in Table 1. A list of highly expressed proteins that localize to centrosomes and centriolar satellites are summarized in Table 2. Table 1. Selection of proteins suitable as markers for the centrosome and centriolar satellites.
Table 2. Highly expressed centrosome and centriolar satellite marker proteins, in different cell lines.
See the morphology of centrosomes in human induced stem cells in the Allen Cell Explorer. The function of the centrosomeThe major function of the centrosome is organization of microtubules, thereby controlling cell shape, polarity, mignation, and division, as well as intracellular trasport and organization. During S-phase, the centrosome is replicated in a semi-conservative manner, resulting in formation of one daughter centriole next to each of the parental centrioles. As the cell approaches mitosis, the two centrosomes, each containing a parental centriole and a maturing procentriole, move to opposite ends of the cell. At the same time, the amount of surrounding PCM proteins increase, enabling nucleation of more microtubules. When the nuclear membrane breaks down, microtubules originating from each of the centrosomes can interact with kinetochores on the replicated sister chromatids, forming the characteristic mitotic spindle. The spindle apparatus mediates separation of sister chromatids to opposite ends of the cell, and upon cytokinesis each of the daughter cells is provided with one set of chromosomes and one centrosome. The parental centriole, i.e. the older of the two in the centriole pair, also has a central role in formation of cilia and flagella. Moreover, increasing evidence suggest a more versatile function of the centrosome, especially pointing to its ability to coordinate a myriad of cellular functions by serving as a compact hub where cytoplasmic proteins can interact at high concentrations (Doxsey S. (2001); Rieder CL et al. (2001)). Centriolar satellites have long been considered as vehicles for protein trafficking to and from the centrosome and cilia, thus playing a role in dynamic regulation of protein composition in these organelles (Tollenaere MA et al. (2015); Prosser SL et al. (2020)). Indeed, several proteins that localize to centriolar satellites have been implicated in centrosome replication, maturation and separation. However, in recent studies, centriolar satellites have also emerged as regulators of multiple other cellular processes, such as protein degradation and autophagy, some of which are independent of centrosomes and cilia. Similarly, centrosomes and cilia are not fully dependent on centriolar satellites. As key regulators of chromosome segregation and cell cycle progression, abnormalities in number, size and morphology of the centrosome, and mutations in genes encoding protein that localize to centrosomes, is commonly observed in cells undergoing tumorigenesis, but also in some other diseases (Badano JL et al. (2005)). Gene Ontology (GO)-based analysis of genes encoding proteins that localize to centrosomes or centriolar satellites shows enrichment of terms that are well in line with their known functions. The most highly enriched terms for the GO domain Biological Process are related to organization of the microtubule cytoskeleton, ciliogenesis, cell cycle progression, and organization of organelles (Figure 3a). Enrichment analysis of the GO domain Molecular Function reveal enrichment of terms describing binding to microtubules and motor proteins, as well as motor activity (Figure 3b).
Figure 3a. Gene Ontology-based enrichment analysis for the centrosome proteome showing the significantly enriched terms for the GO domain Biological Process. Each bar is clickable and gives a search result of proteins that belong to the selected category.
Figure 3b. Gene Ontology-based enrichment analysis for the centrosome proteome showing the significantly enriched terms for the GO domain Molecular Function. Each bar is clickable and gives a search result of proteins that belong to the selected category. Centrosome proteins with multiple locationsApproximately 80% (n=465) of the centrosome and centriolar satellite proteins detected in the Subcellular Section also localize to other cellular compartments (Figure 4). The network plot shows that the most common locations shared with the centrosome and centriolar satellites are the cytosol and nucleoplasm. Dual localizations with the cytosol are overrepresented, while dual localizations with nucleoli are underrepresented.
Figure 4. Interactive network plot of microtubule proteins with multiple localizations. The numbers in the connecting nodes show the proteins that are localized to the centrosome and to one or more additional locations. Only connecting nodes containing more than one protein and at least 0.7% of proteins in the centrosome proteome are shown. The circle sizes are related to the number of proteins. The cyan colored nodes show combinations that are significantly overrepresented, while magenta colored nodes show combinations that are significantly underrepresented as compared to the probability of observing that combination based on the frequency of each annotation and a hypergeometric test (p≤0.05). Note that this calculation is only done for proteins with dual localizations. Each node is clickable and results in a list of all proteins that are found in the connected organelles. Expression levels of centrosome proteins in tissueTranscriptome analysis and classification of genes into tissue distribution categories (Figure 8) shows that centrosome and centriolar satellite proteins are more likely to be detecten in a single tissue, but less likely to be ubiquotously expressed compared to all genes presented in the subcellular section. Figure 5. Bar plot showing the percentage of genes in different tissue distribution categories for genes encoding proteins that localize to the centrosome or centriolar satellites, compared to all genes in the Subcellular Section. Asterisk marks a statistically significant deviation (p≤0.05) in the number of genes in a category based on a binomial statistical test. Each bar is clickable and gives a search result of proteins that belong to the selected category. Relevant links and publications Thul PJ et al., A subcellular map of the human proteome. Science. (2017) Bovery T. 1900. Zellen-Studien. Verlag von Gustav Fischer. Conduit PT et al., Centrosome function and assembly in animal cells. Nat Rev Mol Cell Biol. (2015) |
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