The human EV membranome

Extracellular vesicles (EVs) are membrane bound structures that gained attention over the last decades because they mediate the horizontal transfer of their cargo molecules. Here, we have built the human EV membranome database by the combination of two in silico datasets obtained by: (i) GO term analysis of the human EV proteome and (ii) the extraction of proteins detected in EV preparations from the human membranome database. The EV membranome database contains 1299 frequently identified EV membrane proteins (MPs) and was used for enrichment analysis as well as for data mining of proteins belonging to relevant functional classes. We show that the majority of the EV MPs have plasma membrane origin. However, the presence of MPs of late-endosomal origin and the enrichment of exocytosis related GO term confirms the endosomal route as an alternative way to plasma membrane budding for the secretion of certain EV populations. Enrichment in proteins binding RNA, lipid and carbohydrate highlights the role of EV MPs as signals or ligands in intercellular communication. There are 18 tetraspanins and 40 glycophosphatidylinositol-anchored proteins in the EV membranome that have been frequently identified in EV isolates. Analysis of EV proteome revealed several G-protein-coupled receptor binding proteins (25 proteins) implicated in EV uptake and a high number of transmembrane receptor and tyrosine kinases signaling pathways related surface receptors (80 proteins) involved in cellular communication. These functional classes of EV MPs can represent important pharmaceuticals and clinical targets.