Cytosol

The cytosol is a semi-fluid substance filling the interior of the cell and embedding the other organelles and subcellular compartments (Clegg JS. (1984)). The cytosol itself is enclosed by the cell membrane and the membranes of different organelles, thus making up a separate cellular compartment. Together, the cytosol and all organelles, except for the nucleus, make up the cytoplasm. Example images of proteins localized to the cytosol can be seen in Figure 1.

In the subcellular section, 4957 genes (25% of all protein-coding human genes) have been shown to encode proteins that localize to the cytosol and its substructures (Figure 2). A Gene Ontology (GO)-based functional enrichment analysis of genes encoding cytosolic proteins shows enrichment of genes associated with bological processes related to protein modifications, mRNA degradation, metabolic processes, signal transduction, and cell death. About 79% (n=3937) of the cytosolic proteins localize to other cellular compartments in addition to the cytosol. The most common additional locations are the nucleus and the plasma membrane.

G3BP1 - U-251MG
QARS1 - U2OS
MTHFS - U2OS

Figure 1. Examples of proteins localized to the cytosol. G3BP1 is an enzyme localized in the cytosol and plays a role in signal transduction (detected in U-251 MG cells). QARS1 catalyzes the aminoacylation of tRNA by their associated amino acid (detected in U2OS cells). MTHFS is an enzyme involved in metabolic processes (detected in U2OS cells).

Figure 2. 25% of all human protein-coding genes encode proteins localized to the cytosol. Each bar is clickable and gives a search result of proteins that belong to the selected category.

Composition of the cytosol

Substructures

• Aggresome: 19
• Cytosol: 4883
• Cytoplasmic bodies: 73
• Rods & Rings: 20

The cytosol makes up about 70% of the total volume of human cells, and is highly crowded and complex (Luby-Phelps K. (2013)). The cytosol is mainly composed of water (approximately 70% of the volume) and proteins (20-30% of the volume) (Luby-Phelps K. (2000); Ellis RJ. (2001)). Rather than a liquid, it is often described as a hydrophilic jelly-like matrix that allows for free movement of ions, hydrophilic molecules and proteins, but also larger structures such as protein complexes and vesicles, across the cell. Ions such as potassium, sodium, bicarbonate, chloride, calcium, magnesium and amino acids are also important constitues of the cytosol. The differences in concentration of these ions between the cytosol and the extracellular fluid or cytoplamic organelles are essential for many cellular functions, for example to enable cell-to-cell communication at the synapses of nerve cells. The cytosolic pH of human cells ranges between 7.0 - 7.4 and is usually higher if the cell is growing (Bright GR et al. (1987)).

Example images of the protein coded by MTHFD1 stained in 3 different cell lines can be seen in Figure 3.

MTHFD1 - A-431
MTHFD1 - U-251MG
MTHFD1 - U2OS

Figure 3. Examples of the morphology of the cytosol in different cell lines, represented by immunofluorescent staining of protein MTHFD1 in A-431, U-251 MG and U2OS cells.

The cytosol also contains different non-membrane bound structures, including cytoplasmic inclusions, such as glycogen-, pigment- and crystalline inclusions, and cytoplasmic bodies, such as P-bodies and stress granules. Aggresomes are large inclusion bodies formed upon active retrograde transport of misfolded proteins along microtubules (Kopito RR. (2000)). This sequestration of aggregated proteins that fail to be cleared by proteosomal degradation has a cytoprotective function. P-bodies are non-membrane bound foci of mRNA and proteins that function in RNA turnover, translational repression, RNA-mediated silencing, and RNA storage (Aizer A et al. (2008)). A rare, and rather recently discovered structure that can appear in the cytosol are Rods and Rings (RRs). These are filament-like structures containing proteins involved in the biosynthesis of nucleotides, originally discovered by the use of human autoantibodies, but little is known about their biological function (Carcamo WC et al. (2014)).

A selection of proteins suitable to be used as markers for the cytosol is listed in Table 1.

Table 1. Selection of proteins suitable as markers for the cytosol.

Gene	Description	Substructure
ADSL	Adenylosuccinate lyase	Cytosol
ATXN2	Ataxin 2	Cytosol
G3BP2	G3BP stress granule assembly factor 2	Cytosol
AIMP1	Aminoacyl tRNA synthetase complex interacting multifunctional protein 1	Cytosol
SERBP1	SERPINE1 mRNA binding protein 1	Cytosol
CCDC43	Coiled-coil domain containing 43	Cytosol
ATXN2L	Ataxin 2 like	Cytosol
AMPD2	Adenosine monophosphate deaminase 2	Cytosol
RABGAP1	RAB GTPase activating protein 1	Cytosol

Function of the cytosol

The cytosol has an important role in providing structural support for other organelles and in allowing transport of molecules across the cell. For example, metabolites often need to be transported across the cytosol from the area of their production to the site where they are needed, and various signals need to be transduced from the cell membrane to target compartments. Moreover, many important cellular processes and reactions, especially of metabolic character, occur in the cytosol. These processes include protein synthesis through translation, the first stage of cellular respiration through glycolysis, and cell division through mitosis and meiosis. The cytosol also plays a pivotal role in maintaining gradients across the membranes, which is important for cell signaling, osmosis and cellular excitability (Lang F. (2007)).

A list of highly expressed cytosolic proteins is summarized in Table 2. Gene Ontology (GO)-based analysis of the cytosolic proteome shows enrichment of terms that are well in-line with the known functions of the cytosol. The most highly enriched terms for the GO domain Biological Process are related to translation, post-translational modifications, metabolic pathways, signaling pathways, and apoptosis (Figure 4a). Enrichment analysis of the GO domain Molecular Function also shows significant enrichment for terms related to translation, protein metabolism and protein interactions (Figure 4b).

Figure 4a. Gene Ontology-based enrichment analysis for the cytosol 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 4b. Gene Ontology-based enrichment analysis for the cytosol 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 single localizing cytosolic proteins across different cell lines.

Gene	Description	Average nTPM
RPS18	Ribosomal protein S18	5997
TPT1	Tumor protein, translationally-controlled 1	3949
RPL23	Ribosomal protein L23	2658
LGALS1	Galectin 1	2035
PKM	Pyruvate kinase M1/2	1703
HSP90AB1	Heat shock protein 90 alpha family class B member 1	1534
LDHB	Lactate dehydrogenase B	1389
HSP90AA1	Heat shock protein 90 alpha family class A member 1	1260
BTF3	Basic transcription factor 3	1062
RPL36	Ribosomal protein L36	1060

Cytosolic proteins with multiple locations

Approximately 79% (n=3937) of the cytosolic proteins detected in the subcellular section also localize to other cellular compartments (Figure 5). The network plot shows that the most common compartments sharing proteins with the cytosol are the nucleus and the plasma membrane, and that these dual localizations are overrepresented. Indeed, there are many proteins known to be transported, or to continuously shuttle, between the cytosol and these compartments, including transcription factors, ribosomal proteins and signaling molecules. Examples of multilocalizing proteins within the cytosolic proteome can be seen in Figure 6.

Figure 5. Interactive network plot of the cytosol proteins with multiple localizations. The numbers in the connecting nodes show the proteins that are localized to the cytosol and to one or more additional locations. Only connecting nodes containing more than one protein and at least 0.7% of proteins in the cytosolic 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.

RPL10A - U2OS
STAT5A - A-431
DDX55 - A-431

Figure 6. Examples of multilocalizing proteins in the cytosolic proteome. RPL10A is a known ribosomal protein, which is required for formation of the 60S ribosomal subunits. It has been shown to localize both to the nucleoli and the cytosol (detected in U2OS cells). STAT5A belongs to the family of STAT transcription factors. It translocates from the cytosol into the nucleus in response to phosphorylation (detected in A-431 cells). DDX55 is a member of DEAD box protein family implicated in several cellular processes involving alteration of RNA secondary structure. It has been shown to localize to the nucleus, nucleoli and cytosol (detected in A-431 cells).

Expression levels of cytosol proteins in tissue

Transcriptome analysis and classification of genes into tissue distribution categories (Figure 8) shows that genes encoding proteins localizing to the cytosol and its substructures have a similar distribution as all genes in the subcellular section, but with a slightly larger fraction of genes expressed in all tissues, and a slightly smaller fraction of genes expressed in many or some tissues.

Figure 7. Bar plot showing the percentage of genes in different tissue distribution categories for cytosol-associated protein-coding genes 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.

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