title: Differential identity of Filopodia and Tunneling Nanotubes revealed by the opposite functions of actin regulatory complexes.
abstract: Tunneling Nanotubes (TNTs) are actin enriched filopodia-like protrusions that play a pivotal role in long-range intercellular communication. Different pathogens use TNT-like structures as "freeways" to propagate across cells. TNTs are also implicated in cancer and neurodegenerative diseases, making them promising therapeutic targets. Understanding the mechanism of their formation, and their relation with filopodia is of fundamental importance to uncover their physiological function, particularly since filopodia, differently from TNTs, are not able to mediate transfer of cargo between distant cells. Here we studied different regulatory complexes of actin, which play a role in the formation of both these structures. We demonstrate that the filopodia-promoting CDC42/IRSp53/VASP network negatively regulates TNT formation and impairs TNT-mediated intercellular vesicle transfer. Conversely, elevation of Eps8, an actin regulatory protein that inhibits the extension of filopodia in neurons, increases TNT formation. Notably, Eps8-mediated TNT induction requires Eps8 bundling but not its capping activity. Thus, despite their structural similarities, filopodia and TNTs form through distinct molecular mechanisms. Our results further suggest that a switch in the molecular composition in common actin regulatory complexes is critical in driving the formation of either type of membrane protrusion.
authors.affiliation: Unité Trafic Membranaire et Pathogenèse, Institut Pasteur, 25-28 Rue du Docteur Roux, 75724 Paris CEDEX 15, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Delage
authors.affiliation: Unité Trafic Membranaire et Pathogenèse, Institut Pasteur, 25-28 Rue du Docteur Roux, 75724 Paris CEDEX 15, France.
authors.forename: Diégo Cordero
authors.initials: DC
authors.lastname: Cervantes
authors.affiliation: Unité Trafic Membranaire et Pathogenèse, Institut Pasteur, 25-28 Rue du Docteur Roux, 75724 Paris CEDEX 15, France.
authors.forename: Esthel
authors.initials: E
authors.lastname: Pénard
authors.affiliation: Ultrapole, Institut Pasteur, 25-28 Rue du Docteur Roux, 75724 Paris CEDEX 15, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Schmitt
authors.affiliation: Unité Trafic Membranaire et Pathogenèse, Institut Pasteur, 25-28 Rue du Docteur Roux, 75724 Paris CEDEX 15, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Syan
authors.affiliation: FIRC Institute of Molecular Oncology, 20139 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Disanza
authors.affiliation: FIRC Institute of Molecular Oncology, 20139 Milan, Italy.|Dipartimento di Scienze della Salute, Università degli Studi di Milano, 20122 Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scita
authors.affiliation: Unité Trafic Membranaire et Pathogenèse, Institut Pasteur, 25-28 Rue du Docteur Roux, 75724 Paris CEDEX 15, France.
authors.forename: Chiara
authors.initials: C
authors.lastname: Zurzolo
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002450:Cell Communication; D002462:Cell Membrane / Q000378:metabolism; D004705:Endocytosis; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D043942:Nanotubes / Q000737:chemistry*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011554:Pseudopodia / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; C539986:Baiap2 protein, mouse; C581598:Cdc42 protein, mouse; D015815:Cell Adhesion Molecules; C083430:Eps8 protein, mouse; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D049452:Green Fluorescent Proteins; D020764:cdc42 GTP-Binding Protein