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

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. 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. 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. family of regulatory molecules that bind phosphorylated serine/threonine motifs to protect phosphorylated residues from phosphatases, block downstream protein binding, and provide a scaffold for promoting direct protein–protein interactions, for example. a serine/threonine-specific enzyme highly expressed in the brain that mediates synaptic structures through binding and bundling of F-actin, and by sequestering G-actin. member of the actin depolymerizing factor (ADF) family that disassembles actin filaments at their pointed end through severing. long (up to 700 μm) actin-based extensions that specifically allow for direct protein–protein interactions involved in growth factor and morphogen signaling over long distances. neuronal protrusions emerging from dendrites that receive excitatory inputs from axons. Immature ‘dendritic filopodia’ adopt the characteristic mushroom shape of the mature spine that is supported by branched actin. an eight-subunit complex involved in vesicle trafficking, where it facilitates the tethering of vesicles to the plasma membrane for exocytosis before membrane fusion. a module originally identified in the four-point one/ezrin/radixin/moesin protein family that mediates plasma membrane binding by interacting with phosphatidylinositol (4,5) bisphosphate lipids. a family of actin-binding proteins that crosslink actin filaments into orthogonal networks. dynamic, closed-ended finger-like protrusions containing parallel bundles of F-actin reaching typical lengths of the order of 1−5 μm. They can be found on the dorsal side of cultured cells, but more commonly they are observed attached to the substrate. also known as Tumor necrosis factor alpha-induced protein 2 (TNFAIP2); acts as a platform that connects RalA (a Ral GTPase subfamily member) and the exocyst complex. epithelial protrusions on the order of 1–2 μm in length that form a dense array known as the ‘brush border.’ Similar to filopodia, they contain a core of bundled actin filaments. motor protein family that bind actin and move along actin filaments. Conventional class II myosins form microfilaments and produce contractile forces, while non-class II myosins comprise notable motors for organelle transport (e.g., Myosin-V and Myosin-X). actin filaments are polarized [i.e., have different ends, referred to as the barbed (i.e., plus) and pointed (i.e., minus) end]. Actin monomers preferentially incorporate at the barbed end, while filament disassembly occurs preferentially at the pointed end. In protrusions, the barbed end is oriented towards the plasma membrane, such that polymerization can help outward growth of the protrusion. an adapter module that mediates the assembly of multiprotein complexes by recognizing short PXXP peptide motifs (P, proline; X, any amino acid) that adopt a polyproline type II helix. membrane protrusions forming networks between cancer cells. TMs are thicker than TNTs and contain microtubules in addition to actin . They are close-ended protrusions with gap junction channels at their ends that permit intercellular transfer of electrical signals and small molecules.