The secretion of extracellular vesicles was initially described as a means of selective elimination of proteins, lipids and RNA from cells. Now, extracellular vesicles are also considered a new mode of intercellular communication.
In any given setting, the population of extracellular vesicles comprises diverse subpopulations that can differ in size, morphology, composition or biogenic mechanisms. Complementary methods of analysis are required to distinguish between these subpopulations.
Several machineries, prominently including components of the endocytic sorting machineries, act concomitantly for the generation of extracellular vesicles. As a result, extracellular vesicles can vary widely in terms of their composition and may carry specific sets of proteins, lipids or RNA species that then determine their fate and functions.
Generation of extracellular vesicles requires the fine-tuning of various intracellular trafficking processes, which define the composition of nascent vesicles and affect their generation and, in the case of exosomes, their secretion from an intracellular compartment.
Interactions of extracellular vesicles with recipient cells can have various effects on the target cell, from stimulating signalling pathways to providing trophic support, depending on the mode of interaction and on the intracellular fate of the vesicles in case of their uptake.
Studies of the cell biology of extracellular vesicles is not only essential for addressing cell biological questions but also critical to open new avenues for their clinical use as biomarkers, as cargo vehicles for the targeted delivery of compounds or as specific modulators of cell behaviours.
Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising exosomes and microvesicles, which originate from the endosomal system or which are shed from the plasma membrane, respectively. They are present in biological fluids and are involved in multiple physiological and pathological processes. Extracellular vesicles are now considered as an additional mechanism for intercellular communication, allowing cells to exchange proteins, lipids and genetic material. Knowledge of the cellular processes that govern extracellular vesicle biology is essential to shed light on the physiological and pathological functions of these vesicles as well as on clinical applications involving their use and/or analysis. However, in this expanding field, much remains unknown regarding the origin, biogenesis, secretion, targeting and fate of these vesicles.
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The authors are grateful to P. Stahl for fruitful insights and reading the manuscript and to members of their team for stimulating discussions. The authors thank the Fondation pour la Recherche Médicale (FRM), Institut Curie and the Centre National de la Recherche Scientifique (CNRS) for support.
The authors declare no competing financial interests.
Precursors of red blood cells (erythrocytes).
- Sorting machineries
Protein complexes mediating cargo sorting in endosomes.
- Major histocompatibility complex
(MHC). A group of genes that code for cell surface glycoproteins that help the immune system to determine self and non-self.
An intracellular adaptor protein linking syndecan-mediated signalling to the cytoskeleton.
A single-transmembrane-domain heparan sulfate proteoglycan that binds a large variety of ligands, such as growth factors and fibronectin.
A lipid molecule composed of sphingosine and a fatty acid linked through an amide bond; in fact, many chemically diverse ceramides have been described, showing that ceramide is not a single molecular species but rather a family of related molecules.
A type of sphingolipid found in animal cell membranes.
- Tetraspanin family
A family of proteins with four transmembrane domains that allow association with other members of the family and with other proteins to generate dynamic membrane domains.
- Glycosylphosphatidylinositol (GPI)-anchored proteins
Proteins with a post-translational modification comprising a phosphoethanolamine linker, a glycan core and a phospholipid tail. This modification anchors the protein to the outer leaflet of the cell membrane.
- Lipid rafts
Specialized membrane microdomains enriched in cholesterol and glycosphingolipid that serve as organizing centres for the assembly of signalling molecules.
- KRAS–MEK signalling pathway
The interaction between the proto-oncogene KRAS, which encodes a small GTPase, and its downstream effector, the canonical RAF proto-oncogene serine/threonine-protein kinase (RAF)–MEK–ERK signalling pathway. Both pathways have roles in cell division, cell differentiation and apoptosis.
- Major vault protein
The main component of ribonucleoparticles termed vaults, which also contain two additional proteins, the vault poly(ADP-ribose) polymerase (vPARP) and telomerase-associated protein 1 (TEP1), and several short, untranslated vault RNAs (vRNAs). It has been implicated in the regulation of several cellular processes, including transport mechanisms, signal transmission and immune responses.
- Y-Box-binding protein 1
A transcription factor shown to have a role in oncogenic cell transformation, multidrug resistance and the dissemination of tumours.
- Aminophospholipid translocases
Enzymes that transport phosphatidylserine and phosphatidylethanolamine from one side of a bilayer to the other.
Proteins responsible for the translocation of phospholipids between the inner and outer leaflets of a cell membrane.
A calcium-dependent protein expressed ubiquitously in mammals and many other organisms.
- RHO family of small GTPases
A family of small signalling G proteins implicated in the regulation of many aspects of actin dynamics.
- Brush border
The microvillus-covered surface of epithelial cells found in enterocytes in the intestine.
- Warburg effect
An aerobic process whereby cancer cells produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol rather than by oxidation of pyruvate in the mitochondria.
- Zipcode RNA sequence motifs
cis-Acting regulatory sequences (25 nucleotides) in the 3′-untranslated region (3′ UTR) of mRNA transcripts that mediate binding of a ribonuclear protein complex to the mRNA, thereby temporarily blocking mRNA translation, and that mediate movement of mRNA via the cytoskeleton to a cellular location where mRNA is released from protein binding and translation initiates.
- Immunological synapses
Specialized cell–cell junctions between a thymus-derived lymphocyte (T cell) and an antigen-presenting cell.
An essential signalling molecule, termed a morphogen, required for numerous processes during animal development.
A ubiquitin-like modification that controls exosome release by decreasing the number of multivesicular endosomes.
The principal component of caveolae, which are involved in receptor (clathrin)-independent endocytosis, mechanotransduction and lipid homeostasis.
- SNARE proteins
Proteins named from SNAP (soluble NSF attachment protein) receptor; their primary role is to mediate the fusion of intracellular vesicles with their target membrane-bound compartments.
- Synaptotagmin family
A family of membrane-trafficking proteins that has been implicated in calcium-dependent neurotransmitter release.
- Protein kinase C
A serine/threonine kinase that plays important roles in several signal transduction cascades by controlling the function of other proteins through their phosphorylation.
- P2X7 receptors
Trimeric ATP-gated cation channels found predominantly, but not exclusively, on immune cells; these receptors have been implicated in various inflammatory, immune, neurological and musculoskeletal disorders.
- Follicular dendritic cells
Cells of the immune system found in primary and secondary lymph follicles of the B cell areas of the lymphoid tissue.
Carbohydrate-binding proteins that are highly specific for sugar moieties.
Heavily glycosylated proteins consisting of a 'core protein' with one or more covalently attached glycosaminoglycan (GAG) chains.
- Intercellular adhesion molecules
(ICAMs). Members of the immunoglobulin superfamily that are involved in inflammation, immune responses and intracellular signalling events.
A form of regulated endocytosis that involves the nonspecific uptake of extracellular material (such as small soluble molecules, nutrients or antigens) by invagination of the plasma membrane, which is then pinched, resulting in small vesicles in the cytoplasm.
Cells that form the outer layer of a blastocyst, provide nutrients to the embryo and give rise to a large part of the placenta.
Brain glial cells that act as the first and main endogenous immune defence in the central nervous system.
Star-shaped glial cells in the brain involved in nutrient supply, maintenance of extracellular ion balance and tissue repair following brain injuries.
Highly dynamic actin-rich cell surface protrusions used by cells to sense their external environment.
- Suicide mRNAs/proteins
Non-mammalian enzymes or their encoding mRNAs that are able to convert an inactive drug into highly toxic metabolites, which subsequently inhibit the synthesis of nucleic acids and cause cells to initiate apoptosis.
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van Niel, G., D'Angelo, G. & Raposo, G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol 19, 213–228 (2018). https://doi.org/10.1038/nrm.2017.125
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