Vesicle Induced Receptor Sequestration: Mechanisms behind Extracellular Vesicle‐Based Protein Signaling

Extracellular vesicles (EVs) are fundamental for proper physiological functioning of multicellular organisms. By shuttling nucleic acids and proteins between cells, EVs regulate a plethora of cellular processes, especially those involved in immune signalling. However, the mechanistic understanding concerning the biophysical principles underlying EV‐based communication is still incomplete. Towards holistic understanding, particular mechanisms explaining why and when cells apply EV‐based communication and how protein‐based signalling is promoted by EV surfaces are sought. Here, the authors study vesicle‐induced receptor sequestration (VIRS) as a universal mechanism augmenting the signalling potency of proteins presented on EV‐membranes. By bottom‐up reconstitution of synthetic EVs, the authors show that immobilization of the receptor ligands FasL and RANK on EV‐like vesicles, increases their signalling potential by more than 100‐fold compared to their soluble forms. Moreover, the authors perform diffusion simulations within immunological synapses to compare receptor activation between soluble and EV‐presented proteins. By this the authors propose vesicle‐triggered local clustering of membrane receptors as the principle structural mechanism underlying EV‐based protein presentation. The authors conclude that EVs act as extracellular templates promoting the local aggregation of membrane receptors at the EV contact site, thereby fostering inter‐protein interactions. The results uncover a potentially universal mechanism explaining the unique structural profit of EV‐based intercellular signalling.