Fig. 1.

Schematic representation of EV biogenesis and secretion. The proteins or family of proteins implicated in the formation (in blue) and release (in green) of EVs are shown. Exosomes originate within the endocytic pathway, by invagination of the endosomal membrane, forming intraluminal vesicles (ILVs) in a multivesicular body (MVB). ILV generation relies on the ESCRT machinery, tetraspanins and/or lipid-mediated membrane curvature, and are loaded with proteins and RNAs (miRNA, mRNA…) from the originating cell and/or the endocytic pathway. Then, the RAB proteins mediate the trafficking through microtubules, docking to sub-membrane actin, and the SNARE proteins cause the fusion of MVBs with the plasma membrane, to release exosomes. Alternatively, early endosomes can recycle back to the plasma membrane, and MVBs can end up in the lysosome or autophagosome to degrade and recycle its cargo. Microvesicles are instead shed directly from the plasma membrane. Although a clear mechanism has not been fully defined, the loss of lipid asymmetry is important for the curvature of plasma membrane, while components of the ESCRT and SNARE machineries have been also related to the outward budding of the plasma membrane. Then, cytoskeletal remodelling through cleavage or depolymerization of cytoskeletal proteins (ARF6, RhoA) is needed for microvesicle release. The third type of EVs that can be found, apoptotic bodies, are generated upon apoptotic cell death. They are generally bigger than exosomes and microvesicles and carry “eat-me” and DAMP signals like damaged DNA. ARF6 ADP-ribosylation factor 6, DAMP damage-associated molecular pattern, ESCRT endosomal sorting complex required for transport, ILV intraluminal vesicle, MVB multivesicular body, RAB Ras-related proteins in brain (member of the superfamily of GTPases), SNARE soluble N-ethylmaleimide-sensitive fusion attachment protein (SNAP) receptors, RhoA Ras-homologue family member A GTPase. Original graphical artwork