Centrosome

The 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. 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, which in turn ensures proper segregation of sister chromatids to each of the daughter cells (Nigg EA et al. (2011)).

In the subcellular resource, 686 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 area at which microtubules originate, proteins have been annotated with the location "centriolar satellites" (Figure 1-2). Functional enrichment analysis of genes encoding centrosomal proteins shows enrichment of genes associated with biological processes related to intracellular organization and transport, organization of microtubules, cell cycle progression and cell division.


CEP131

PCNT - U-251MG

MKKS - U2OS

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.

0%10%20%30%40%50%60%70%80%90%100%% genesNot mappedSecretedOther organellesCentrosome

  • 3% (686 proteins) of all human proteins have been experimentally detected in the centrosome by the Human Protein Atlas.
  • 153 proteins in the centrosome are supported by experimental evidence and out of these 15 proteins are enhanced by the Human Protein Atlas.
  • 610 proteins in the centrosome have multiple locations.
  • 53 proteins in the centrosome show single cell variation.

  • Proteins localizing to the centrosome are mainly involved in intracellular organization and transport, microtubule organization, cell cycle progression and mitosis.

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 centrosome

Substructures

  • Centriolar satellite: 229
  • Centrosome: 478

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 centrosome, 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.

Gene
Description
Substructure
MKKS MKKS centrosomal shuttling protein Basal body
Centrosome
CEP350 Centrosomal protein 350 Basal body
Centrosome
End piece
Nucleoplasm
ODF2 Outer dense fiber of sperm tails 2 Basal body
Calyx
Centrosome
Connecting piece
Microtubules
Mid piece
Primary cilium
Principal piece
Vesicles
KIF5B Kinesin family member 5B Centriolar satellite
Cytosol
End piece
PIBF1 Progesterone immunomodulatory binding factor 1 Basal body
Centriolar satellite
Centrosome

Table 2. Highly expressed centrosome and centriolar satellite marker proteins, in different cell lines.

Gene
Description
Average nTPM
PCLAF PCNA clamp associated factor 162
KLHL21 Kelch like family member 21 24
SLC1A4 Solute carrier family 1 member 4 23
RASSF7 Ras association domain family member 7 21
TUBGCP4 Tubulin gamma complex associated protein 4 16
CCP110 Centriolar coiled-coil protein 110 16
ZNF766 Zinc finger protein 766 14
AUNIP Aurora kinase A and ninein interacting protein 11

See the morphology of centrosomes in human induced stem cells in the Allen Cell Explorer.

The function of the centrosome

The major function of the centrosome is organization of microtubules. Thereby the are important for 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 reveals enrichment of terms describing binding to microtubules and motor proteins, as well as motor activity (Figure 3b).

0246810121416182022242628Fold EnrichmentProtein localization to micr...Ciliary basal body-plasma me...Secretory granule localizationMicrotubule anchoringNuclear migrationProtein localization to cyto...Cytoplasmic microtubule orga...Organelle localization by me...Membrane dockingCentrosome localizationRegulation of G2/M transitio...Microtubule organizing cente...Protein localization to ciliumCilium assemblyRegulation of cell cycle G2/...Cilium organizationPhotoreceptor cell maintenanceNon-motile cilium assemblyMicrotubule-based transportAntigen processing and prese...Positive regulation of plasm...Regulation of plasma membran...Mitotic nuclear divisionCytokinesisPositive regulation of cellu...Golgi vesicle transportShow full plot

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.

0246810121416182022Fold EnrichmentDynein heavy chain bindingDynein light chain bindingDynein light intermediate ch...Dynein intermediate chain bi...Microtubule motor activityATP-dependent microtubule mo...Microtubule binding

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 locations

Approximately 89% (n=610) of the centrosome and centriolar satellite proteins detected in the subcellular resource 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, nucleoplasm and primary cilia. Dual localizations with the primary cilium, a location that includes proteins found in the basal body that stems from the mother centriole, are overrepresented.

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 1.0% 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 tissue

Transcriptome analysis and classification of genes into tissue distribution categories (Figure 8) shows that centrosome and centriolar satellite proteins have a similar distribution over these categories as compared to all genes presented in the subcellular resource.

Detected in singleDetected in someDetected in manyDetected in allNot detected0.0102030405060708090100%CentrosomeAll localized genes

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 resource. 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)
PubMed: 28495876 DOI: 10.1126/science.aal3321

Badano JL et al., The centrosome in human genetic disease. Nat Rev Genet. (2005)
PubMed: 15738963 DOI: 10.1038/nrg1557

Bornens M., Centrosome composition and microtubule anchoring mechanisms. Curr Opin Cell Biol. (2002)
PubMed: 11792541 

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)
PubMed: 26373263 DOI: 10.1038/nrm4062

Doxsey S., Re-evaluating centrosome function. Nat Rev Mol Cell Biol. (2001)
PubMed: 11533726 DOI: 10.1038/35089575

Lüders J et al., Microtubule-organizing centres: a re-evaluation. Nat Rev Mol Cell Biol. (2007)
PubMed: 17245416 DOI: 10.1038/nrm2100

Nigg EA et al., The centrosome cycle: Centriole biogenesis, duplication and inherent asymmetries. Nat Cell Biol. (2011)
PubMed: 21968988 DOI: 10.1038/ncb2345

Rieder CL et al., The centrosome in vertebrates: more than a microtubule-organizing center. Trends Cell Biol. (2001)
PubMed: 11567874