Abstract
Tunneling nanotubes (TNTs) are F-actin rich structures that connect distant cells, allowing the transport of many cellular components, including vesicles, organelles and molecules. Rab GTPases are the major regulators of vesicle trafficking and also participate in actin cytoskeleton remodelling, therefore, we examined their role in TNTs. Rab35 functions with several proteins that are involved in vesicle trafficking such as ACAP2, MICAL-L1, ARF6 and EHD1, which are known to be involved in neurite outgrowth. Here we show that Rab35 promotes TNT formation and TNT-mediated vesicle transfer in a neuronal cell line. Furthermore, our data indicates that Rab35-GTP, ACAP2, ARF6-GDP and EHD1 act in a cascade mechanism to promote TNT formation. Interestingly, MICAL-L1 overexpression, shown to be necessary for the action of Rab35 on neurite outgrowth, showed no effect on TNTs, indicating that TNT formation and neurite outgrowth may be processed through similar but not identical pathways, further supporting the unique identity of these cellular protrusions.
Highlights
Tunneling nanotubes (TNTs) are F-actin rich structures that connect distant cells, allowing the transport of many cellular components, including vesicles, organelles and molecules
We have shown that EHD1 is required for TNT formation and acts downstream of Rab[35], ACAP2 and ARF6-GDP
We propose that Rab[35] and its effector ACAP2 promote TNT formation by inactivating ARF6
Summary
Tunneling nanotubes (TNTs) are F-actin rich structures that connect distant cells, allowing the transport of many cellular components, including vesicles, organelles and molecules. Apart from playing a role in development, as discovered for TNT-like structures present in chick and sea urchin embryos[3,13,14], their implication in various diseases was tackled in many studies. They were shown to be hijacked and utilized as means of transport by different pathogens, such as viruses like H IV15,16, and b acteria[17]. In neuronal CAD cells, the most prevalent mechanism is the actin-driven o ne[26] In these cells an actin bundling and capping protein Eps[8] positively regulated TNTs via its actin bundling a ctivity[30].
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