CentrosomeThe centrosome is the main microtubule organizating center (MTOC) in human and animal cells, and has been widely studied ever since Theodor Bovery first described it in 1888 (Bovery, T, 1900). Although the centrosome is a small organelle, its impact on cellular function is of great importance. Located adjacent to the nucleus, the major role of the centrosome is to regulate the intracellular organization of the microtubules, which is important during cell division when the mitotic spindle is formed. The centrosome is the key responsible organelle for the correct orientation of the poles of the mitotic spindle, facilitating the segregation of the chromosomes, and the subsequent distribution to the daughter cells (Nigg EA et al, 2011). Of all proteins detected in the Cell Atlas, 520 proteins (3%) have been experimentally shown to localize to the centrosome or to centriolar satellites. In images where it has been possible to distinguish the centrioles, proteins have been annotated with the location Centrosome. In images where the centrioles have not been detected, but the protein localizes to the center of the microtubules, proteins have been annotated with the location centriolar satellite (Figure 1-2). Functional enrichment analysis of the centrosome proteome shows highly enriched 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. RAB11FIP5 is involved in intracellular transport and has previously not been shown to localize to centrosomes. By using independent antibodies, RAB11FIP5 is localized to centriolar satellites (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 U-2 OS 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 and the centriolar satellites. Each bar is clickable and gives a search result of proteins that belong to the selected category. Structure of the centrosomeSubstructures The centrosome is a small non-membranous MTOC organelle occupying about 1-2 μm3 of the cytoplasmic volume (Doxsey S. 2001). It is composed of two barrel shaped centrioles, each having nine proximal triplets organized into a symmetric structure, which maintain both the stability and functional activity of the centrosome. The centrioles are organized in a matrix of proteins, commonly referred to as the pericentriolar material (PCM). Among the proteins of this matrix are many important cell cycle regulators and other signaling molecules essential for the function of the centrosome. Pericentrin (Figure 1), aurora kinases, ninein and centriolin are some examples (Doxsey S. 2001). One of the most well studied constituents of the PCM is the highly conserved γ-tubulin protein complex, which is organized into an open ring structure with around 25 nm in diameter, responsible for the nucleation of the 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). Centrosomes are closely surrounded by cytoplasmic granules, known as centriolar satellites, that contain a number of centrosomal proteins, and play key roles in centrosome function and regulation (Tollenaere MA et al, 2015). Centriolar satellites were originally considered only as vehicles for protein trafficking towards the centrosome Table 1. Selection of proteins suitable as markers for the centrosome and centriolar satellites.
See the morphology of centrosomes in human induced stem cells in the Allen Cell Explorer. Function of the centrosomeThe major functional role of centrosome is to manage the organization of the microtubules in the cell, thereby controlling cellular shape, polarity, proliferation, mobility and cell division. One of the major roles of the centrosome is in guiding formation of the bipolar microtubule spindle apparatus that mediates chromosome segregation. During S-phase, the centrioles are replicated into daughter centrioles, which are formed adjacent to the parental centrioles in a semiconservative process. As the cell enters mitosis (G2-M phases), the two centrosomes, each containing a parental centriole and a maturing procentriole, start to move apart and direct formation of the spindle poles at opposite ends of the cell. At the same time, the amount of surrounding PCM proteins, including many proteins that facilitate spindle formation, increase. In addition to serving as an MTOC, 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). As a key regulator of the cell cycle, abnormalities in number, size and morphology of the centrosome is commonly observed in cells undergoing tumorigenesis. Centrosomal abnormalities are also observed in several other diseases. Dysfunction in the ubiquitin-proteasome degradation that has implications in several neurodegenerative disorders is one example (Badano JL et al, 2005). Gene Ontology (GO)-based analysis of genes encoding proteins that localize to centrosomes or centriolar satellites shows enrichment for functions that are well in-line with existing literature about centrosome function. The most highly enriched terms for the GO domain Biological Process are related to the organization of the microtubules, cell division and cilium morphogenesis (Figure 3a). Enrichment analysis of the GO domain Molecular Function, also generates expected results showing dynein- and tubulin binding together with motor activity as the most enriched significant terms (Figure 3b). A list of highly expressed centrosome and centriolar satellite proteins are summarized in Table 2.
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. Table 2. Highly expressed centrosome and centriolar satellite marker proteins, in different cell lines.
Centrosome proteins with multiple locationsApproximately 78% (n=403) of the centrosome and centriolar satellite proteins detected in the Cell Atlas 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 cytoplasm, nucleus and vesicles. Dual localizations with nucleoplasm and cytosol are overrespresented, while dual localizations with the Golgi apparatus and 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 0.5% 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 analysisand classification of genes into tissue distribution categories (Figure 8) shows that centrosome and centriolar satellite proteins are not more likely to show any particular type of tissue distribution, compared to all genes presented in the Cell Atlas. 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 Cell Atlas. 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, 2017. A subcellular map of the human proteome. Science. Bovery T. 1900. Zellen-Studien. Verlag von Gustav Fischer. Conduit PT et al, 2015. Centrosome function and assembly in animal cells. Nat Rev Mol Cell Biol. |
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