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Syntenin-phosphatidic acid interaction in exosome biogenesis and cell-cell communication: a structure-function based approach

Periodic Reporting for period 1 - EXOGENESIS (Syntenin-phosphatidic acid interaction in exosome biogenesis and cell-cell communication: a structure-function based approach)

Reporting period: 2018-12-01 to 2020-11-30

Exosomes are small extracellular vesicles of endosomal origin that play an important role in cell-cell communication and in the progression of many systemic diseases, including cancer. The aim of this study was to show whether and how phosphatidic acid (PA), a lipid produced by the enzyme phospholipase D2 (PLD2), controls the biogenesis of exosomes. This study aimed to a better mechanistic understanding of the production of exosomes and to help the rational design of new therapeutic chemical inhibitors.
Combining gain- and loss-of-function experiments, proteomics, microscopy and lipid-binding studies with reconstituted liposomes mimicking the late endosomal compartment, we showed for the first time that PLD2, and its PA, is required for the recruitment of a component of the endosomal sorting complex required for transport (ESCRT). ESCRT is a molecular machine responsible for the formation of intraluminal vesicles (ILVs) inside multivesicular bodies (MVBs).
Our study indicates that PLD2 controls a large population of exosomes and the formation of secretory MVBs.

These results were presented at international conferences in 2019 such as the joint meeting of the Belgian Society for Extracellular Vesicles and the Belgian Society for Cell and Developmental Biology (Leuven, Belgium) and the Gordon Research Conference on Molecular Membrane Biology (Andover NH, United States).

These data are included in a manuscript entitled “PLD2-phosphatidic acid recruit ESCRT-I to late endosomes for exosome biogenesis” which is under review in EMBO Reports and a preprint is available bioRxiv 2020.11.25.398396; doi: https://doi.org/10.1101/2020.11.25.398396
Although exosomes were long believed to be cellular debris, their significance for intercellular communication is increasingly appreciated in health and disease. However, molecular mechanisms controlling exosome biogenesis and heterogeneity remain poorly understood precluding rational approaches. This study shows that PLD2 broadly stimulates exosome production by supporting the recruitment of one ESCRT-I member to late endosomes via direct PA interaction, and paves the way for potential new therapeutic avenues.
Recruitment of one ESCRT-I member to late endosomes via direct PA interaction