Comprendre les mécanismes de formation des tunneling nanotubes // Assessing the mechanism of Tunneling nanotube formation

non relevant
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Tunneling nanotubes (TNTs) are actin-based, open-ended structures facilitating intercellular transfer of materials, including soluble molecules, vesicles, and organelles. In vitro studies suggest TNT involvement in neurodegenerative disease progression (via amyloid protein transfer), viral spread (SARS-CoV-2, HIV), and cancer cell resistance to radio- and chemotherapy¹–³. Understanding TNT formation in health and disease could pave the way for TNT-targeted therapies; however, their formation mechanisms remain largely unexplored.
By integrating correlative optical and cryo-electron microscopy (cryo-EM), we demonstrated that TNTs differ from other cellular protrusions. They consist of bundles of open-ended individual TNTs (iTNTs) containing actin, vesicles, and organelles⁴. While TNT rely on actin dynamics, the precise mechanisms driving actin polymerization and TNT elongation (hundreds of microns, unlike filopodia) remain unclear. Additionally, little is known about the membrane fusion process between TNT tips and recipient cell plasma membranes.
Our recent findings highlight the roles of Eps8 and IRSp53 in TNT initiation and elongation, akin to filopodia⁵. Interestingly, ARP2/3 complex inhibition (which impedes branched actin polymerization) enhances TNT formation, shifting Eps8's interactome toward linear actin growth regulators. This suggests TNT formation is governed by a competition between branched and linear actin polymerization pathways⁵.
Furthermore, our proteomic analysis of isolated TNTs revealed both known and novel TNT-specific proteins, including some absent from extracellular vesicles⁶. Among the most enriched proteins in TNTs, the tetraspanins CD9 and CD81 appear crucial—CD9 stabilizes growing TNTs, while CD81 promotes full opening—though their precise mechanisms remain unknown⁶. Additionally, N-cadherin (N-cad) overexpression (OE) increases TNT-mediated vesicle transfer, whereas knockdown (KD) reduces it, suggesting a role in adhesion prior to fusion⁷.
Objectives
This project aims to elucidate the molecular mechanisms underlying TNT formation and fusion through three objectives:
1. Investigate actin polymerization in TNTs, focusing on LIMK and cofilin.
2. Assess the roles of novel TNT-specific (non-EV) factors and tropomyosins in TNT growth and organelle transfer.
3. Unravel the fusion mechanism and N-cadherin's role in TNT formation and transfer.
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Début de la thèse : 01/10/2025

Contrat doctoral

Concours pour un contrat doctoral

Sorbonne Université SIS (Sciences, Ingénierie, Santé)

394 Physiologie, physiopathologie et thérapeutique

pas de candidat pressenti. Nous recherchons de jeunes scientifiques avec une bonne formation en biologie cellulaire et moléculaire, désireux de travailler au sein d'un groupe multidisciplinaire.
We are looking for young scientists with a good background in cell and molecular biology, eager to work in a multidisciplinary group.