Impact of lysosome status on extracellular vesicle content and release

Abstract

Extracellular vesicles (EVs) are nanoscale size bubble-like membranous structures released from cells. EVs contain RNA, lipids and proteins and are thought to serve various roles including intercellular communication and removal of misfolded proteins. The secretion of misfolded and aggregated proteins in EVs may be a cargo disposal alternative to the autophagy-lysosomal and ubiquitin-proteasome pathways. In this review we will discuss the importance of lysosome functionality for the regulation of EV secretion and content. Exosomes are a subtype of EVs that are released by the fusion of multivesicular bodies (MVB) with the plasma membrane. MVBs can also fuse with lysosomes, and the trafficking pathway of MVBs can therefore determine whether or not exosomes are released from cells. Here we summarize data from studies of the effects of lysosome inhibition on the secretion of EVs and on the possibility that cells compensate for lysosome malfunction by disposal of potentially toxic cargos in EVs. A better understanding of the molecular mechanisms that regulate trafficking of MVBs to lysosomes and the plasma membrane may advance an understanding of diseases in which pathogenic proteins, lipids or infectious agents accumulate within or outside of cells.

Lysosomal Exocytosis, Exosome Release and Secretory Autophagy: The Autophagic- and Endo-Lysosomal Systems Go Extracellular

“…This evidence suggests that EV release could be a compensatory event for lysosomal impairment or overload with unnecessary/damaged molecules. An increase of EV release was observed in Niemann Pick Type C (NPC), an LSD characterized by lysosomal accumulation of cholesterol and sphingolipids due to mutation in the NPC1 gene [63,64]. These studies support the hypothesis that lysosomal dysfunction induced by stored materials drives MVB release into the extracellular space to maintain cellular homeostasis [34].…”

Amyloid precursor protein and endosomal‐lysosomal dysfunction in Alzheimer's disease: inseparable partners in a multifactorial disease

“…Changes in the intralumenal ionic fluxes and surface polypeptide composition in each compartment mediate additional inter‐vesicular interactions ( e.g., vesicle fusion/fission events, exchange of lumenal contents) and other cell signaling cascades, which are activated by pH shifts. Finally, ELN compartments undergo varying forms of exocytosis for the purposes of intercellular communication (6–8), repairing cell membranes (9), or eliminating unwanted material as a back‐up to lysosomal degradation (7, 8). Limited proteolytic processing of certain proteins, including APP, occurs along this pathway, though the complete degradation of unneeded cargos is initiated in late endosomes and is completed in lysosomes (10).…”

Circulating miRNAs and miRNA shuttles as biomarkers: Perspective trajectories of healthy and unhealthy aging

“…Such communication system provides control of cell development, cell fate, and tissue homeostasis, likely protecting the functional state of biological systems and affecting the chance of achieving longevity or developing ARDs. EVs may also mediate the extracellular spread of misfolded/pathogenic or garbage proteins in case of lysosome malfunction (Eitan et al, 2016) as well as viral or bacterial proteins and nucleic acids. EV-shuttled molecular communication undergoes major age-related modifications due to factors such as the increase of senescent cells within tissue and organs (Weilner et al, 2013).…”