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

Projektinformationen

EXOGENESIS

ID Finanzhilfevereinbarung: 747025

DOI

10.3030/747025

Projekt abgeschlossen

EK-Unterschriftsdatum 17 November 2017

Startdatum 1 Dezember 2018

Enddatum 30 November 2020

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 173 076,00

EU-Beitrag

€ 173 076,00

Koordiniert durch

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

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

Berichtszeitraum: 2018-12-01 bis 2020-11-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

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

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

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