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

Abstract

Actin remodeling is at the heart of the cell' response 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. This review addresses several actin regulators in the formation of TNTs and suggests 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 processes generate a diverse array of cell protrusionsActin, one of the key cytoskeletal polymers of the cell, forms helix-shaped polar filaments (see Glossary) that are further assembled into highly-organized actin networks, such as branched and linear.[1] The spatial and temporal control of these actin networks is crucial in maintaining the integrity of the cell, contributing to its mechanical properties, and driving cell shape changes that c ' to various processes.[1] Cell protrusions appear as the most prominent changes in cell shape, whose growth and characteristics mainly rely on actin cytoskeleton structure.[1] Filamentous actin (F-actin) is formed through the polymerization of globular actin (G-actin) monomers, a process governed by a broad pool of actin regulators and/or actin-binding proteins. In order for a cell protrusion to form into a mature structure, actin remodeling processes-that comprise the steps of initiation, actin polymerization and stabilization of the actin filaments-need to take place in the cell in a tightly controlled manner. Among these protrusions, filopodia, microvilli and dendritic filopodia/spines (see Glossary) comprise a family of morphologically similar structures (see Figure 1). An addition to the family of cell protrusions, tunneling nanotubes (TNTs), were first documented in 2004 by Rustom and colleagues.[2] They described TNTs as membranous tubular extensions connecting two remote cells, thus providing cytoplasmic continuity between them. Similar to canonical protrusions, they are thin (up to 700 nm)[3] and comprised of F-actin, but in contrast, they are non-surface adherent, and have an ability to reach extraordinarily long distances (up to 100 m).[4] First evidence of being actinsupported was shown by phalloidin staining in rat pheochromocytoma (PC-12) cells.[2] More recently, an ultrastructural study employing correlative cryogenic electron microscopy (cryoEM), shed light on the actin organization within TNTs in two different neuronal cell lines.[3] This work uniquely showed straight and continuous, hexagonally packed actin bundles that appear to run parallel along the entire length of th...

Opportunities and Challenges in Tunneling Nanotubes Research: How Far from Clinical Application?

“…The characterization of TNTs in vitro indicated that TNTs are uniformly F-actinpositive [30], which separates them from other cellular protrusions such as tethers and nanopodia [5]. Surprisingly, F-actin may not be simply arranged in TNTs, as we thought until Anna Sartori-Rupp et al demonstrated highly organized parallel actin bundles within TNTs [3].…”

“…Paradoxically, TNTs were also observed in M-sec or p53-deficient cells [42,47]. Such inconsistent results imply that the biogenesis of TNTs may not have a universal molecular regulation mechanism, probably due to their heterogeneity [30].…”

“…On the cellular level, two models of TNT formation based on cell-cell interactions in different cell types have long been recognized [48]: (i) the cell dislodgement model, proposing that two adjacent cells retain thin membrane tubes when they move apart [49,50], and (ii) the filopodia interplay model, meaning that TNTs are generated from active cellular protrusions that make direct contact with neighboring cells [30,34,51,52]. Since mechanical forces are required in both models to pull out the tube structure after membrane binding, adequate cell-cell contact is a prerequisite for the generation of TNTs.…”

Role of Tunneling Nanotubes in Viral Infection, Neurodegenerative Disease, and Cancer

“…Membrane depolarization at the leading edge of wounds has been shown to connect adjacent cells via TNTs activation of PI3 kinase signaling suggesting a supportive role of TNTs in wound healing, which involves F-actin remodeling (118). Similarly, TNT formation and induction have also been observed following injury, trauma or chronic tissue stresses (38).…”

Two routes of direct intercellular communication in brain cancer

“…The discovery 16 years ago that thin and very long membrane tubes can interconnect individual cells has broadened our understanding of how normal and malignant tissues function [1][2][3][4]. In effect, these protrusions allow cells to convene to a communicating syncytial network that is capable of exchange of information, molecules, and partially even cell organelles in a complex and multitude manner [3,5].…”