Post-translational lipidation in extracellular vesicles: chemical mechanisms, biological functions and applications

Abstract Extracellular vesicles (EVs) are phospholipid bilayer enclosed structures containing specific proteins, nucleic acids, and metabolites, which are naturally released from cells as vehicles of intercellular communication. Post-translational modifications (PTMs) of EV proteins can regulate EVs biogenesis or play diverse roles in their biology, in both homeostatic and pathological conditions. Here, we focus on the mechanism and biological roles of post-translational lipidations of EV proteins, with a particular insight on their involvement in EV biogenesis and functions. We investigate various aspects of PTM by lipidation in depth, ranging from chemistry to technical advances for lipidation detection and recent biotech applications. Among lipidations on EV proteins, palmitoylation is the most widespread mechanism. EVs have been shown to be enriched of palmitoylated proteins, and the profile of EV palmitoyl proteome could contribute to early diagnosis in some kinds of cancer, suggesting that EV protein lipidation can be exploited as potential early tumor biomarker. Thus, the emerging evidence on EV protein lipidations could help us to better understand their physio/pathological function with implications for preclinical and clinical settings.