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Review
. 2018 Aug;59(8):1316-1324.
doi: 10.1194/jlr.E086173. Epub 2018 May 15.

Extracellular Vesicles: Lipids as Key Components of Their Biogenesis and Functions

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Free PMC article
Review

Extracellular Vesicles: Lipids as Key Components of Their Biogenesis and Functions

Michel Record et al. J Lipid Res. .
Free PMC article

Abstract

Intercellular communication has been known for decades to involve either direct contact between cells or to operate via circulating molecules, such as cytokines, growth factors, or lipid mediators. During the last decade, we have begun to appreciate the increasing importance of intercellular communication mediated by extracellular vesicles released by viable cells either from plasma membrane shedding (microvesicles, also named microparticles) or from an intracellular compartment (exosomes). Exosomes and microvesicles circulate in all biological fluids and can trigger biological responses at a distance. Their effects include a large variety of biological processes, such as immune surveillance, modification of tumor microenvironment, or regulation of inflammation. Extracellular vesicles can carry a large array of active molecules, including lipid mediators, such as eicosanoids, proteins, and nucleic acids, able to modify the phenotype of receiving cells. This review will highlight the role of the various lipidic pathways involved in the biogenesis and functions of microvesicles and exosomes.

Keywords: lipid kinases; lipid transporters; lipolytic enzymes; membrane asymmetry; membrane fusion.

Figures

Fig. 1.
Fig. 1.
Lipid-related partners of exosome and microvesicle biogenesis. Exosomes and microvesicles (also called ectosomes or microparticles) are recovered by ultracentrifugation from viable cells. Microvesicles sediment in the 10,000 g pellet and their size ranges between 100 and 1,000 nm. The 10,000 g supernatant is then used to recover exosomes by a 100,000 g centrifugation (82); exosome size ranges from 30 to 150 nm, with an average around 100 nm. Some markers to discriminate between these two types of extracellular vesicles have been reported (21, 40, 83). MVB, multivesicular body; mTOC, microtubule organizing center. Enhanced exosome production involves lipid transporters, such as ABCA3 (84), and requires the activities of PLD2 (11), diglyceride kinase (DGK) (85), and neutral sphingomyelinase (46), but the inhibition of phosphoinositide kinases, such as the PI3 kinase (25, 42) and PIKfyve (86). Translocation on the outer leaflet of the plasma membrane of the acid sphingomyelinase (aSMase) promotes the budding of microvesicles (10). This budding process also involves the small G proteins, such as Arf6 and RhoA (87), which are activators of PLD1 and PLD2, supporting the proposition that, in some situations, the production of both exosomes and microvesicles could be coordinated via PLD activity. Microvesicles can also be produced by modification of plasma membrane asymmetry by the aminophospholipid translocases (12), or by modification of the lateral pressure of phospholipids via PS binding protein on the inner leaflet (17) or sphingomyelin/cholesterol binding protein (16) on the outer leaflet. Calcium loading into cells by means of a calcium ionophore can trigger the production of microvesicles (18) or exosomes (20). MVB and exosomes are circled in red in the figure to represent the BMP content of their membrane, which definitely discriminates between exosomes and microvesicles because BMP intracellular localization is strictly restricted to late endosomes and lysosomes (22, 26).
Fig. 2.
Fig. 2.
Lipid pathways involved in exosome biogenesis processes. Connections with lipid pathways are present within the ESCRT, the first pathway described for ILV biogenesis (38). Indeed, Vps4, a member of the AAA family of proteins (ATPases associated with a variety of activities), interacts with oxysterol binding proteins (Osh6 and Osh7) (6), and Alix interacts with BMP via a specific sequence domain (8). Independent of the ESCRT machinery are lipid pathways involving ceramides (nSMase2) (46) and, to some extent, phosphatidic acid (PHOS.ACID/PLD2) (11). Another neutral lipid, precursor of ether-linked phospholipids, hexadecyl-glycerol, stimulates exosome production (88). The phosphoinositides, PIP3 and PI(3,5)P2, act in a negative way because inhibition of PI3K/Akt (25, 42) and PIKfyve (86) favor exosome production. Because PI3K is involved in macroautophagy (89), this observation indicates that there is a requirement to block macroautophagy to promote the microautophay process involved in exosome biogenesis (90). Indeed, rapamycin, the inhibitor of mammalian target of rapamycin (mTOR)C1 induces macroautophagy (90, 91) and decreases exosome production (84). However an alternative pathway for exosome production via a secretory autophagy process, distinct from the degradative autophagy, has been reported following PIKfyve inhibition (86). Because PIKfyve activity promotes mTORC1 translocation to the plasma membrane (92), the reverse PIKfyve inhibition might retain mTORC1 on the late endosome membrane. mTORC1 is located on the endosome membrane (93) and could have a direct function at this location to generate ILVs. mTORC1 is activated by the endosomal cholesterol (93) and enhanced exosome production was reported when cholesterol was supplied to glial cells either directly or by means of U18666A (94). mTORC1 activation by cholesterol is reversed by NPC1, which effluxes cholesterol from endosomes (93). Consistently, NPC1 inactivation is required to enhance exosome production (94). U18666A displays an opposite effect on lymphoblastoma cells where it inhibits exosome production, which is mediated in these cells by the lipid transporter, ABCA3 (84). It is worth noting that NPC1 and ABCA3-containing endosomes are distinct populations (95). In addition, the effect of U18666A cannot be restricted to cholesterol because U18666A also promotes the accumulation of oxysterols in cells (cholesterol 5,6 epoxides) and cholesterol precursors (zymostenol, desmosterol) (96). In the figure, each pathway leading to a specific vesicle content is a graphical simplification. Combination of the various pathways reported could depend upon cell type and activation conditions or mobilization of distinct late endosome populations, and several pathways can probably be triggered at the same time.
Fig. 3.
Fig. 3.
Exosome and microvesicle-mediated transfer of biologically active material into recipient cells. Importantly, both exosomes (31) and microvesicles (12) carry functional molecules able to modify the phenotype of recipient cells. Exosomes are preferentially endocytosed and may release their contents by fusion with the recipient endosomal membrane by a process called back-fusion (8). This may be mediated by the BMP (highlighted in red) present both on the exosome and endosome membrane, because BMP is fusogenic in an acidic pH environment (23). Even though some microvesicles are internalized by receptor-mediated endocytosis (61), the microvesicle membrane is devoid of BMP, and how microvesicles transfer their contents inside target cells is unclear. Instead, the fusion of large microvesicles with the peripheral cell membrane has been observed (97) and fusion between microvesicles and the cellular plasma membrane might represent the preferential transfer mechanism of material from microvesicles to recipient cells.

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