The Ways of Actin: Why Tunneling Nanotubes Are Unique Cell Protrusions.

Actin remodeling is at the heart of the response of cells to external or internal stimuli, allowing a variety of membrane protrusions to form. Fifteen years ago, tunneling nanotubes (TNTs) were identified, bringing a novel addition to the family of actin-supported cellular protrusions. Their unique property as conduits for cargo transfer between distant cells emphasizes the unique nature of TNTs among other protrusions. While TNTs in different pathological and physiological scenarios have been described, the molecular basis of how TNTs form is not well understood. In this review, we discuss the role of several actin regulators in the formation of TNTs and suggest potential players based on their comparison with other actin-based protrusions. New perspectives for discovering a distinct TNT formation pathway would enable us to target them in treating the increasing number of TNT-involved pathologies. Novel structures, known as tunneling nanotubes (TNTs), are membranous protrusions supported by filamentous actin that mediate continuity between remote cells by remaining open at both ends for cargo transport. The formation of morphologically similar protrusions, such as filopodia, microvilli, and immature dendritic spines, involves the processes of initiation, elongation, and stabilization; this includes many actin and membrane regulators, such as Rho GTPases, I-BAR proteins, actin nucleators, and actin bundlers, which likely participate in TNT formation. The unique length of TNTs implies the involvement of motor proteins able to efficiently transport the required components to the growing end, and likely a specific actin arrangement. Specificity in TNT biogenesis may arise from differences in the ability of common actin-regulating molecules to promote TNTs versus filopodia. [ABSTRACT FROM AUTHOR]