Trends in Cell Biology
ReviewCytonemes and tunneling nanotubules in cell–cell communication and viral pathogenesis
Introduction
Life depends on the ability of cells to communicate with each other. Much of this crosstalk occurs at cell–cell contacts and is regulated by complex structural interfaces. Neurological or immunological synapses transmit cell–cell signals through the extracellular space, relying on mechanisms of ligand-receptor signaling across tight cell–cell junctions. By contrast, gap junctions in animal cells and plasmodesmata in plants provide portals for the direct exchange of cytoplasmic contents and can efficiently propagate an intracellular signal from cell to cell (Figure 1). In addition to these well-established examples of cell–cell communication, advances in fluorescence-based imaging have recently illuminated thin, fragile and elongated intercellular membrane bridges 1, 2, 3. These membrane bridges probably represent different biological structures that are formed, maintained and disassembled by different mechanisms. Given the diversity of these mechanisms, we review this emerging field in the context of well-characterized cell–cell contacts such as synapses and gap junctions (Figure 1).
Section snippets
Cytonemes and tunneling nanotubules
In a broad sense, two distinct types of thin membrane bridges have been described, which are distinguished by the ability of cytosolic content to traffic within the interior of the filament from cell to cell (tubular) versus contacts in which no cytoplasmic connection is made (non-tubular) (Figure 1). For the non-tubular bridges, two membranes are tightly juxtaposed at the site of cell–cell contact. Signals must be transduced using molecules resident at the outer surface of the membrane. By
Biogenesis of membrane bridges
The biogenesis of membrane bridges can probably proceed by either of two general mechanisms 1, 2, 3, 14. In the first, linkages form after a cell extends a de novo filopodial process that is then bound and tightly anchored to a neighboring cell (Figure 3a,b). Filopodia are dynamic exploratory and sensory organelles that can redirect cell migration towards specific sources, including nearby cells. These structures can be maintained to form a long-lived stable filopodial bridge or, alternatively,
Filopodial intermediates in cell adhesion and synaptogenesis
Increasing evidence in various cell–cell adhesion systems points to an important role for filopodia in the establishment of cell–cell contacts. Our system, which uses virally infected cells expressing the viral Env glycoprotein as an adhesion protein, has demonstrated that ‘fingertip’ filopodial contacts between cells can lead to anchorage of filopodia from the uninfected target cell at the infected cell surface [4]. Maintenance of anchored bridges is dependent on the continued pulling of
Downregulation of tight cell–cell contacts
In contrast to the formation of filopodial bridges by de novo outgrowth, membrane bridges or nanotubes can also form when tight cell–cell contacts are downregulated (Figure 3). Time-lapse microscopy has monitored the formation of nanotubes and filopodial bridges during the separation of both macrophages and T cells 10, 13. Importantly, the formation of T-cell nanotubes requires a prolonged period of T-cell interaction, indicating a kinetic requirement for the accumulation of adhesion factors
Nanotubes and cytonemes in vivo
Because cell–cell adhesion profiles are vital to intercellular signaling, it follows that in vitro investigations, in which cells are cultured in the absence of their natural tissue context, can be misleading. The limitations of ‘suspension immunology’ and importance of intravital imaging have been widely recognized [27]. For instance, in vivo, dendritic cells are maintained in a wide interconnected web [28]. When cultured in vitro, they clump together, a feature that depends on the expression
Bridging the void: viral exploitation of membrane bridges
In culture, viral infection is thought to be several orders of magnitude more efficient under conditions of physical cell–cell contact between infected and uninfected cells 32, 33, 34. In vivo, it is likely that direct cell–cell spread predominates in the dense and dynamic environment of an animal tissue. Viral spread is probably enhanced at cell–cell contacts because the mechanisms of viral egress and entry can be directly coupled in space and time 35, 36. However, only recently has live
Concluding remarks and future perspectives
Cells communicate with each other using a variety of distinct structures. As is the case for classical, well-characterized interfaces such as synapses and gap junctions, it is clear that mechanisms of contact and communication by membrane bridges are diverse and multi-faceted. In this review, we have emphasized cytoplasmic connectivity as a defining criterion and summarized testable models for the biogenesis and downregulation of membrane bridges. Thorough studies assessing the ability of
Acknowledgements
We thank Jolynne Roorda for art work and Thomas Biederer and Jing Jin for critical reading of the manuscript. The work was supported by EMBO long-term fellowship (ALTF 176–2007) to N.S. and a NIH grant (CA098727) to W.M.
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