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.
Highlights
Important human pathogens such as the human immunodeficiency virus (HIV), the Ebola virus, the rabies virus, and the herpes simplex virus 1 (HSV1) all have well-characterized strategies to hijack members of the endosomal sorting complexes required for the transport (ESCRT) pathway [2,3]
Rab27 and Rab35 did not influence the release of Wingless in Drosophila S2 cells [71] and Rab27 did not affect the extracellular levels of flotillin or of anthrax toxin in retinal epithelial cells [70]. The roles of these Rabs in the endocytic pathway allowed for speculation that there might be extracellular vesicles derived from different routes such as recycling and multivesicular bodies (MVBs), but this awaits confirmation [15]
We provide an overview of identified interactions between viruses and endocytic proteins that regulate exosome biogenesis
Summary
Multivesicular bodies (MVBs) or late endosomes are components of the endocytic pathway that range from 250 to 1000 nm in diameter. What is most striking is that evolutionarily unrelated viruses, with dramatically different genomes, have converged in their use of the host machinery for ILV formation to promote their own budding Important human pathogens such as the human immunodeficiency virus (HIV), the Ebola virus, the rabies virus, and the herpes simplex virus 1 (HSV1) all have well-characterized strategies to hijack members of the endosomal sorting complexes required for the transport (ESCRT) pathway [2,3]. Classical examples include the influenza A virus (IAV), the severe acute respiratory syndrome Corona virus, alphaviruses like chikungunya, and pneumoviruses like respiratory syncytial virus (RSV) To add another layer of complexity, regardless of whether ESCRT is involved in viral budding, recent publications have reported roles of exosomes in viral infection far beyond assisting with the assembly of enveloped viruses. A plethora of reports and reviews has explored several functions of exosomes in mediating intercellular communication, immune system functions, development and differentiation, neuronal function, cell signaling, regeneration [1,14,15,16,17,18,19,20,21], and several steps in viral replication, the latter topic explored in this review
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