Sorting it out: regulation of exosome loading

Abstract

Extracellular vesicles (EVs), a term that includes both exosomes of endocytic origin and vesicles derived from plasma membranes, are continuously secreted by cells to the extracellular environment, and represent a novel vehicle for cell-cell communication. Exosomes contain specific repertoires of proteins and RNAs, indicating the existence of mechanisms that control the sorting of molecules into them. Although the molecular mechanisms that regulate the loading of proteins into exosomes have been studied for years, the sorting of RNA has been elusive until recently. Here we review the molecular mechanisms that control the sorting of molecules into exosomes, with special attention to the sorting of RNA. We also discuss how the cellular context affects the composition of exosomes, and thus the outcome of the communication between the exosome-producer and recipient cells, with particular focus on the communication between tumor cells and with cells of the tumor microenvironment.

Keywords: Exosomes; Extracellular vesicles; MicroRNAs; Stress; hnRNPs.

Figure 1. Exosomes contain specific repertoires of proteins, RNAs and lipids

(A) The molecular composition of exosomes is not a reflection of the cell. Exosomes are enriched in specific proteins, lipids and RNAs, whereas others are absent, indicating the existence of specialized mechanisms that control the sorting of molecules into exosomes. (B) The stress-induced changes in exosomal RNA and protein composition can influence the response of distant cells to stress by providing protective signals (surveillance, drug resistance, etc.).

Figure 2. Mechanisms that control the sorting of cargo into exosomes

(A) Endosomal Sorting Complexes Required for Transport (ESCRT) 0, I and III, and Alix accessory protein control the sorting of ubiquitinated proteins into the intraluminal vesicles of multivesicular bodies (MVBs). Syntenin and the Small integral membrane protein of the lysosome/late endosome (SIMPLE) are also involved in exosome secretion through their interaction with specific components of the ESCRT complex. (B) Tetraspanins (CD81, CD9, CD63) play a key role in the composition of ESCRT-independent exosomes. Different lipids and lipid-related enzimes control the secretion of these exosomes. nSMase2: neutral sphingomyelinase 2; S1P: sphingosine-1-phosphate; SphK2: sphingosine kinase 2; DAG: diacylglycerol; SMS2: sphingomyelin synthase 2; PA: phosphatidic acid; PC: phosphatidyl choline; PLD: phospholipase D; LBPA: lysophosphatidic acid. (C) Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific short motifs (EXOmotif).