Role of purinoreceptors in the release of extracellular vesicles and consequences on immune response and cancer progression

Abstract

Cell-to-cell communication is a major process for accommodating cell functioning to changes in the environments and to preserve tissue and organism homeostasis. It is achieved by different mechanisms characterized by the origin of the message, the molecular nature of the messenger, its speed of action and its reach. Purinergic signalling is a powerful mechanism initiated by extracellular nucleotides, such as ATP, acting on plasma membrane purinoreceptors. Purinergic signalling is tightly controlled in time and space by the action of ectonucleotidases. Recent studies have highlighted the critical role of purinergic signalling in controlling the generation, release and fate of extracellular vesicles and, in this way, mediating long-distance responses. Most of these discoveries have been made in immune and cancer cells. This review is aimed at establishing the current knowledge on the way which purinoreceptors control extracellular vesicle-mediated communications and consequences for recipient cells.

Keywords: Cancer; Exosomes; Extracellular vesicles; Immune response; Purinoreceptors.

Fig. 1

(A) Exosome Biogenesis occurs within the endosomal compartment. ESCRT-dependent pathway-mediated exosome biogenesis begins with the inward budding of the plasma membrane to form early endosomes (EE) which are then maturated into late endosomes (LE). ESCRT sub-complexes 0, I, II and III are recruited to the endosomal membrane and cooperatively orchestrate the sorting of protein cargo into the intraluminal vesicles (ILVs) and the formation of multivesicular bodies (MVBs). MVBs can either fuse to the lysosome for degradation or to the plasma membrane leading to the release of exosomes into the extracellular space. ESCRT-independent pathway occurs via specific lipid raft microdomains enriched with sphingolipids. The enzyme neutral sphingomyelinase 2 (nSMase2) converts sphingomyelin to ceramides which allow lateral phase separation and the abscission of ILVs from the endosomal membrane. (B) Structure and molecular composition of exosomes/Small EVs (C) Delivery of the released exosomes from parental cell to the recipient cell can be performed by three different mechanisms including ligand-receptor interaction, direct fusion of the lipid bilayer of exosome with the plasma membrane, or by endocytosis.

Fig. 2

Small and large EV release from ATP-induced P2X7 stimulation. P2X7 activation and consequent K+ efflux promote NLRP3 inflammasome activation and caspase-1 maturation. Caspase-1 maturates Pro-Interleukin (IL)-1β and pro-IL-18 into IL-1β and Il-18, respectively, and cleaves RILP which participates to exosome release. P2X7 also recruits Src-Kinase, leading to P38 MAPK phosphorylation allowing the translocation of lysosomal A-SMase to the plasma. A-SMase produces ceramide from sphingomyelin which facilitates membrane blebbing and microvesicle release. In parallel, ROCK activation by P2X7 allows the reorganization of F-actin cytoskeleton which is indispensable for microvesicle release.