Molecular interactions at the surface of extracellular vesicles

Abstract

Extracellular vesicles such as exosomes, microvesicles, apoptotic bodies, and large oncosomes have been shown to participate in a wide variety of biological processes and are currently under intense investigation in many different fields of biomedicine. One of the key features of extracellular vesicles is that they have relatively large surface compared to their volume. Some extracellular vesicle surface molecules are shared with those of the plasma membrane of the releasing cell, while other molecules are characteristic for extracellular vesicular surfaces. Besides proteins, lipids, glycans, and nucleic acids are also players of extracellular vesicle surface interactions. Being secreted and present in high number in biological samples, collectively extracellular vesicles represent a uniquely large interactive surface area which can establish contacts both with cells and with molecules in the extracellular microenvironment. Here, we provide a brief overview of known components of the extracellular vesicle surface interactome and highlight some already established roles of the extracellular vesicle surface interactions in different biological processes in health and disease.

Keywords: Drug delivery; Extracellular matrix; Extracellular vesicle; Interactome; Surface.

Fig. 1

Examples for EV surface interactions with the plasma membrane and components of the extracellular matrix. a One of the best characterized interactions between the plasma membrane and the surface of EVs is mediated by proteins that recognize externalized phosphatidyl serine (PS) on EVs. Direct interactions with PS include those with TIM4, stabilin-2, RAGE, or BAI-1. Indirect interactions include those between the PS-binding MFGE-8 and α_vβ₃ integrin as well as the PS-binder GAS-6 and the MER tyrosine kinase on the cell. b Endocytosis of fibronectin (FN) or C3b complement protein is followed by an association of these molecules with intraluminal vesicles within MVBs followed by secretion of exosomes with surface-associated FN or C3b. c Interaction of EVs with ECM is mediated by integrins or CD44. d FN forms a bridge between HSPGs present on both EV surface and plasma membrane, and mediates EV uptake by cells

Fig. 2

Examples for EV surface-associated molecules. a Antibody binding to EVs has been demonstrated, e.g., in numerous autoimmune diseases. b Both complement factors and complement regulatory proteins have been shown to associate with EV surfaces. c On EVs from blood plasma, different coagulation factors are also identified. d EV-associated cytokines include TNF bound to TNF receptor as well as TGFβ bound to TGFβR3 (betaglycan) on EV surfaces. e Both bacterial and mammalian EVs have been demonstrated to carry surface-associated DNA and DNA-binding proteins. In the case of mammalian EVs, both mitochondrial and nuclear DNA were found on EV surfaces. f A surprisingly large variety of EV surface enzymes were identified that can bind and cleave protein or glycan substrates of the EV microenvironment