Rab11a-Rab8a cascade regulate the formation of tunneling nanotubes through vesicle recycling

• DOI: 10.1242/jcs.215889
• Publication Date: 2018-09-12T09:46:47Z
• Authors: Seng Zhu; Shaarvari Bhat; Sylvie Syan; Yoshihiko Kuchitsu; Mitsunori Fukuda; Chiara Zurzolo
• Keywords: Vesicle-Associated Membrane Protein 3; Vesicle transfer; Vesicle recycling; Models, Biological; Cell Line; 12. Responsible consumption; Mice; 03 medical and health sciences; Models; Rab GTPase; Tunneling nanotube; Vesicle recycling; Vesicle transfer; Animals; Cell Line; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate; Mice; Models, Biological; Nanotubes; Pseudopodia; Transport Vesicles; Vesicle-Associated Membrane Protein 3; rab GTP-Binding Proteins; Endocytosis; Animals; Guanine Nucleotide Exchange Factors; Pseudopodia; Transport Vesicles; [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology; 0303 health sciences; Nanotubes; Biological; [SDV.MP.MYC] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology; Endocytosis; 3. Good health; rab GTP-Binding Proteins; Guanosine Triphosphate; Rab GTPase; Tunneling nanotube

Tunneling nanotubes (TNTs) are actin-enriched membranous channels enabling cells to communicate over long distances. TNT-like structures form between various cell types and mediate the exchange of different cargos, such as ions, vesicles, organelles, and pathogens. Thus, they may play a role in physiological conditions and diseases (e.g., cancer and infection). TNTs also allow the intercellular passage of protein aggregates related to neurodegenerative diseases, thus propagating protein misfolding. Understanding the mechanism of TNT formation is mandatory to reveal the mechanism of disease propagation and to uncover their physiological function. Vesicular transport controlled by the small GTPases Rab11a and Rab8a can promote the formation of different plasma membrane protrusions (filopodia, cilia, and neurites). Here we report that inhibiting membrane recycling reduces the number of TNT-connected cells, while overexpression of Rab11a and Rab8a increases the number of TNT-connected cells and the propagation of vesicles between cells in co-culture. We demonstrate that these two Rab GTPases act in a cascade where Rab11a activation of Rab8a is independent of Rabin8, and we show that VAMP3 acts downstream of Rab8a to regulate TNT formation.