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Vesicles is a collective term for cytoplasmic organelles that are often too small to have distinct features when imaged by light microscopy. The majority of the vesicles are membrane-bound organelles, however, also large protein complexes and cytosolic bodies can fall under this category, as they are difficult to distinguish. Examples of organelles with a vesicle annotation are the members of the endolysosomal pathway, transport vesicles, peroxisomes, and lipid droplets.
In the Cell Atlas, 2149 genes (11% of all protein-coding human genes) have been shown to encode proteins that localize to vesicles (Figure 2). A Gene Ontology (GO)-based functional enrichment analysis of the vesicle proteome shows enrichment of terms related to lipid metabolism, organization of vesicle organelles such as endosomes, vacuoles and peroxisomes, protein transport, endocytosis and exocytosis. About 66% (n=1426) of the vesicle proteins localize to one or more additional compartments, with the nucleoplasm, the cytosol and the Golgi apparatus being the most common ones. Examples of proteins that localize to vesicles can be seen in Figure 1.
Figure 1. Examples of proteins localized to the vesicles. SNX1 is part of the retromer complex that mediates the retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling (detected in HeLa cells). CLTA is a structural element in clathrin-coated vesicles, which are required for the receptor-mediated endocytosis at the plasma membrane (detected in U-251 MG cells). AP2B1 is a component of the adaptor protein complex 2, which is involved in clathrin-dependent endocytosis (detected in U-2 OS cells).
11% (2149 proteins) of all human proteins have been experimentally detected in the vesicles by the Human Protein Atlas.
505 proteins in the vesicles are supported by experimental evidence and out of these 125 proteins are enhanced by the Human Protein Atlas.
1426 proteins in the vesicles have multiple locations.
316 proteins in the vesicles show a cell to cell variation. Of these 299 show a variation in intensity and 18 a spatial variation.
Proteins are mainly involved in lipid metabolism, organization of vesicle organelles such as endosomes, vacuoles and peroxisomes, protein transport, endocytosis and exocytosis.
Figure 2. 11% of all human protein-coding genes encode proteins localized to vesicles. Each bar is clickable and gives a search result of proteins that belong to the selected category.
The general structure of organelles annotated as vesicles is a round membrane-enclosed lumen that is less than 1 μm in diameter. There are a few differences in the appearance and distribution of vesicles that can allow further classification (Figure 3), but the true identity of the organelle is often only revealed by co-staining with specific marker proteins in immunofluorescence images.
Endosomes are membrane-bound compartments that can be further sub-classified into early, recycling, and late endosomes, but there is a continuous transition between these classes. Each of them can be defined by their function, by a distinct set of proteins, and/or by morphological differences. Early endosomes (EE) have a pleomorphic structure, consisting of cisternae from which two distinct subdomains emerge: large vesicular structures (300-400 nm diameter) with internal invaginations and thinner tubular extensions (60 nm diameter) (Gruenberg J. (2001). Tubular extensions give rise to recycling endosomes (RE), which retain a tubular appearance and are typically located close to the microtubule organizing center (MTOC). The large vesicular compartments of early endosomes give rise to multivesicular bodies that mediates transport to, or matures into, late endosomes. Late endosomes (LE) are again highly complex, with cisternal, tubular, and vesicular regions with numerous membrane invaginations and luminal vesicles (Griffiths G et al. (1988)).
Lysosomes were discovered by the Belgian Nobel laureate de Duve in 1955 and are named after the richness in hydrolytic enzymes. Lysosomes have a tubular morphology of about 0.1-1.2 μm in size and a characteristic acidic pH-value of 4.5-5, which is ideal for the enzymes contained in the lysosomal lumen. The membrane of lysosomes is rich in glycoproteins and consists of an unusual lipid composition that provides protection from the digestive enzymes (Schwake M et al. (2013).
Peroxisomes were also discovered by de Duve, but in 1966, and he named them because of their involvement in peroxidase reactions. Peroxisomes originate from the ER, but they are also able to replicate themselves by division. They differ in size from 0.1-1 μm and have a dynamic structure. The shape is usually spherical, but can change and become more elongated prior to peroxisome division or in adaptation to different conditions, which can help to distinguish peroxisomes from other vesicles in IF (Smith JJ et al. (2013)).
Lipid droplets (LDs) have been known for a long time, but were believed to be a rather inert storage for lipids. The discovery of the first LD-associated protein in 1991 by Londos and coworkers (Greenberg AS et al. (1991) changed this view, and today LDs are considered organelles. LDs originate from the ER and have a simple, yet conserved structure: a hydrophobic core containing lipids surrounded by a membrane monolayer (instead of a bilayer found in all other organelles) to which proteins are attached (Walther TC et al. (2012)). The size of LDs ranges from hundreds of nanometers to the single 100 micrometer large LD that fills adipocytes. Under normal conditions, cells have no or only a few small LDs, but if those few LDs are large enough, LD-associated proteins appear in perfectly round rings and the protein location can be annotated more precisely.
A list of proteins that are suitable as markers for vesicles can be found in Table 1. Highly expressed genes encoding proteins that localize to vesicles are listed in Table 2.
Table 1. Selection of proteins suitable as markers for different vesicular organelles.
Figure 3. Examples of the different types of vesicles found in the Cell Atlas. Endosomal protein RAB5C in U-2 OS cells. Lysosomal protein LAMTOR4 in U-2 OS cells. Peroxisomal protein ABCD3 in A-431 cells. LD-associated protein PLIN3 in A-431 cells. Clathrin-coated vesicle protein EPS15L1 in MCF7 cells. Vesicle-front forming protein REX1BD in U-2 OS cells.
Figure 4. 3D-view of peroxisomes in U-2 OS, visualized by immunofluorescent staining of ABCD3. The morphology of Endosomes, Lysosomes, and Peroxisomes in human induced stem cells can be seen in the Allen Cell Explorer.
The function of vesicles
Endocytosis is a process by which cells internalize extracellular solutes, ligands and proteins as well as lipids and proteins located in the plasma membrane (Gruenberg J. (2001)). Endocytic vesicles are typically transported to early endosomes, where efficient sorting takes place. Some lipids and membrane proteins are recycled back to the plasma membrane, either by direct routes or via recycling endosomes (Taguchi T. (2013)). Other cargo molecules enter the retrograde pathway and are delivered to the Golgi apparatus (Bonifacino JS et al. (2006)). Proteins and lipids destined for degradation are instead transported to late endosomes, which then fuse with lysosomes for degradation of the material. Lysosomes contain a large spectra of enzymes, also degrading nucleic acids and carbohydrates. Materials taken up from the cytosol by autophagy are also delivered to this compartment.
Peroxisomes are multifunctional organelles that harbor a variety of enzymes. The main function of peroxisomes is β-oxidation of long- and very long-chain fatty acids. They also contribute to the utilization and production of reactive oxygen species in the cell. In addition, peroxisomes carry out other important anabolic and catabolic reactions. such as phospholipid biosynthesis, chemical detoxification or oxidation of purines, polyamines, and some amino acids (Antonenkov VD et al. (2010)).
Nearly all cells are able to form LDs and use them as the main storage site for cellular neutral lipids. These lipids, which are mainly triacylglycerol and cholesterol, are utilized for generation of energy and serve as building blocks for the synthesis of other lipids. LDs have been linked to a growing number of diseases, but most prominent is their role in obesity and diabetes (Walther TC et al. (2012).
Gene Ontology (GO)-based enrichment analysis of genes encoding proteins that localize to vesicles reveals several functions associated with this group of organelles. The highly enriched terms for the GO domain Biological Process are related mainly to lipid metabolism, structural organization of various vesicles, endosomal and vacuolar transport, antigen presentation and certain cell signalling pathways (Figure 5a). For the GO domain Molecular Function, genes encoding vesicle proteins are enriched for functions related to sterol transport, receptor activities, transporter activity and binding to proteins that are involved in vesicle formation (Figure 5b).
Figure 5a Gene Ontology-based enrichment analysis for the vesicles 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 5b Gene Ontology-based enrichment analysis for the vesicles 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.
Vesicles proteins with multiple locations
Approximately 66% (n=1426) of the proteins that localize to vesicles in the Cell Atlas also localize to other compartments in the cell. The network plot (Figure 6) shows that the additional locations that are overrepresented in combination with vesicles are the nucleoplasm, the ER, the Golgi apparatus, and microtubules. Given the function of vesicles, co-localization of proteins to the ER and Golgi apparatus is in agreement with their role in the secretory pathway. Microtubules, in turn, can serve as cellular highways that guide the transport of vesicles. Examples of multilocalizing proteins within the proteome of vesicles can be seen in Figure 7.
Figure 6. Interactive network plot of vesicle-associated proteins with multiple localizations. The numbers in the connecting nodes show the proteins that are localized to vesicles and to one or more additional locations. Only connecting nodes containing more than one protein and at least 0.5% of proteins in the vesicle 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.
Figure 7. Examples of multilocalizing proteins in the vesicle proteome. The examples show common or overrepresented combinations for multilocalizing proteins in the proteome. VTI1B promotes the fusion of vesicles with the target membrane at the Golgi apparatus (detected in U-2 OS cells). GPRC5A, detected at the plasma membrane and vesicles, is an orphan receptor, which might be involved in the interaction between retinoic acid and G-protein signaling pathways (detected in U-2 OS cells). EPN3 co-localizes with clathrin-coated vesicles and shuttles into the nucleus (detected in HaCaT cells).
Expression levels of vesicles proteins in tissue
Transcriptome analysis and classification of genes into tissue distribution categories (Figure 8) shows that a larger portion of genes that encode proteins localizing to vesicles are detected in some or in many tissues, while a smaller portion are detected in all tissues, compared to all genes presented in the Cell Atlas. This may reflect a variety of tissue-specific functions involving vesicle proteins, particularly in the transport of secretory proteins and other biomolecules to the outside of the cell.
Figure 8. Bar plot showing the percentage of genes in different tissue distribution categories for vesicle-associated protein-coding genes, 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.
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