Exosome Biogenesis, Regulation, and Function in Viral Infection

Abstract

Exosomes are extracellular vesicles released upon fusion of multivesicular bodies (MVBs) with the cellular plasma membrane. They originate as intraluminal vesicles (ILVs) during the process of MVB formation. Exosomes were shown to contain selectively sorted functional proteins, lipids, and RNAs, mediating cell-to-cell communications and hence playing a role in the physiology of the healthy and diseased organism. Challenges in the field include the identification of mechanisms sustaining packaging of membrane-bound and soluble material to these vesicles and the understanding of the underlying processes directing MVBs for degradation or fusion with the plasma membrane. The investigation into the formation and roles of exosomes in viral infection is in its early years. Although still controversial, exosomes can, in principle, incorporate any functional factor, provided they have an appropriate sorting signal, and thus are prone to viral exploitation. This review initially focuses on the composition and biogenesis of exosomes. It then explores the regulatory mechanisms underlying their biogenesis. Exosomes are part of the endocytic system, which is tightly regulated and able to respond to several stimuli that lead to alterations in the composition of its sub-compartments. We discuss the current knowledge of how these changes affect exosomal release. We then summarize how different viruses exploit specific proteins of endocytic sub-compartments and speculate that it could interfere with exosome function, although no direct link between viral usage of the endocytic system and exosome release has yet been reported. Many recent reports have ascribed functions to exosomes released from cells infected with a variety of animal viruses, including viral spread, host immunity, and manipulation of the microenvironment, which are discussed. Given the ever-growing roles and importance of exosomes in viral infections, understanding what regulates their composition and levels, and defining their functions will ultimately provide additional insights into the virulence and persistence of infections.

Exosomes in Viral Disease

“…MVBs contain intraluminal vesicles (ILVs) that range in size from 30 to 100 nm and can be targeted for 2 separate fates: lysosomal degradation or fusion with the plasma membrane, after which release of ILVs to the extracellular environment occurs and at which point they are termed exosomes [4,27]. In a process called Bback fusion^, ILVs deliver plasma membrane invaginations (through clathrin-mediated and clathrin-independent endocytosis) to the endosomal network, making them (and therefore exosomes) capable of carrying both intracellular and extracellular materials [8,28,29]. Indeed, exosomes are seen as an exciting avenue for their capability in giving snapshots of the microenvironment, and serving as a good source of biomarkers.…”

“…For example, oligodendrocytes direct exosome formation via the ceramide pathway [37], while other cell types rely on oligomerization of tetraspanin complexes [8,38,39]. Furthermore, while knockdown of some ESCRT components may abrogate exosome production, it does not completely knock it out [40,41].…”

“…Indeed, Rab GTPases, a known family of conserved proteins that regulate vesicular trafficking and membrane fusion events, are also involved in exosome formation as denoted by their high abundance in isolated exosomes [23,42]. Several are implicated in the release of exosomes, including Rab11, Rab27, Rab5, Rab35, and Rab7, depending on cell type [8,23]. Rab 27a, in particular, regulates the fusion of MVBs at the plasma membrane to release ILVs [8,23,43].…”

“…Several are implicated in the release of exosomes, including Rab11, Rab27, Rab5, Rab35, and Rab7, depending on cell type [8,23]. Rab 27a, in particular, regulates the fusion of MVBs at the plasma membrane to release ILVs [8,23,43]. Knockdown of Rab 27a inhibits exosome secretion from tumor cell lines [4,43].…”

“…For the purposes of this review, we will focus our discussion on exosomes; however, there are several excellent reviews in the literature that address Electronic supplementary material The online version of this article (doi:10.1007/s13311-016-0450-6) contains supplementary material, which is available to authorized users. extracellular vesicles as a whole [6][7][8][9][10][11]. In appearance, exosomes are unilamellar vesicles composed of a lipid bilayer that have a homogenous cup-shaped appearance on scanning electromicroscopy [3,12].…”