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

Informations projet

EXOGENESIS

N° de convention de subvention: 747025

DOI

10.3030/747025

Projet clôturé

Date de signature de la CE 17 Novembre 2017

Date de début 1 Decembre 2018

Date de fin 30 Novembre 2020

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 173 076,00

Contribution de l’UE

€ 173 076,00

Coordonné par

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)

Période du rapport: 2018-12-01 au 2020-11-30

Résumé du contexte et des objectifs généraux du projet

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.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

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

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

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