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Membrane nanotubes: dynamic long-distance connections between animal cells

Abstract

Membrane nanotubes are transient long-distance connections between cells that can facilitate intercellular communication (for example, by trafficking vesicles or transmitting calcium-mediated signals), but they can also contribute to pathologies (for example, by directing the spread of viruses). Recent data have revealed considerable heterogeneity in their structures, processes of formation and functional properties, in part dependent on the cell types involved. Despite recent progress in this young research field, further research is sorely needed.

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Figure 1: Membrane nanotubes readily form between various cell types.
Figure 2: Two distinct processes can lead to membrane nanotube formation.
Figure 3: Functional consequences of membrane nanotubes.

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References

  1. Chhabra, E. S. & Higgs, H. N. The many faces of actin: matching assembly factors with cellular structures. Nature Cell Biol. 9, 1110–1121 (2007).

    Article  CAS  Google Scholar 

  2. Rustom, A., Saffrich, R., Markovic, I., Walther, P. & Gerdes, H. H. Nanotubular highways for intercellular organelle transport. Science 303, 1007–1010 (2004).

    Article  CAS  Google Scholar 

  3. Onfelt, B., Nedvetzki, S., Yanagi, K. & Davis, D. M. Cutting edge: membrane nanotubes connect immune cells. J. Immunol. 173, 1511–1513 (2004).

    Article  Google Scholar 

  4. Watkins, S. C. & Salter, R. D. Functional connectivity between immune cells mediated by tunneling nanotubules. Immunity 23, 309–318 (2005).

    Article  CAS  Google Scholar 

  5. Onfelt, B. et al. Structurally distinct membrane nanotubes between human macrophages support long-distance vesicular traffic or surfing of bacteria. J. Immunol. 177, 8476–8483 (2006).

    Article  Google Scholar 

  6. Sowinski, S. et al. Membrane nanotubes physically connect T cells over long distances presenting a novel route for HIV-1 transmission. Nature Cell Biol. 10, 211–219 (2008).

    Article  CAS  Google Scholar 

  7. Gerdes, H. H., Bukoreshtliev, N. V. & Barroso, J. F. Tunneling nanotubes: a new route for the exchange of components between animal cells. FEBS Lett. 581, 2194–2201 (2007).

    Article  CAS  Google Scholar 

  8. Stinchcombe, J. C., Bossi, G., Booth, S. & Griffiths, G. M. The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity 15, 751–761 (2001).

    Article  CAS  Google Scholar 

  9. Eriksson, M. et al. Inhibitory receptors alter natural killer cell interactions with target cells yet allow simultaneous killing of susceptible targets. J. Exp. Med. 190, 1005–1012 (1999).

    Article  CAS  Google Scholar 

  10. Roda-Navarro, P. et al. Dynamic redistribution of the activating 2B4/SAP complex at the cytotoxic NK cell immune synapse. J. Immunol. 173, 3640–3646 (2004).

    Article  CAS  Google Scholar 

  11. Pontes, B. et al. Structure and elastic properties of tunneling nanotubes. Eur. Biophys. J. 37, 121–129 (2008).

    Article  CAS  Google Scholar 

  12. Kiesel, M. et al. Swelling-activated pathways in human T-lymphocytes studied by cell volumetry and electrorotation. Biophys. J. 90, 4720–4729 (2006).

    Article  CAS  Google Scholar 

  13. Raucher, D. & Sheetz, M. P. Characteristics of a membrane reservoir buffering membrane tension. Biophys. J. 77, 1992–2002 (1999).

    Article  CAS  Google Scholar 

  14. Schmidtke, D. W. & Diamond, S. L. Direct observation of membrane tethers formed during neutrophil attachment to platelets or P-selectin under physiological flow. J. Cell Biol. 149, 719–730 (2000).

    Article  CAS  Google Scholar 

  15. Williams, G. S. et al. Membranous structures transfer cell surface proteins across NK cell immune synapses. Traffic 8, 1190–1204 (2007).

    Article  CAS  Google Scholar 

  16. Shao, J. Y. & Hochmuth, R. M. Micropipette suction for measuring piconewton forces of adhesion and tether formation from neutrophil membranes. Biophys. J. 71, 2892–2901 (1996).

    Article  CAS  Google Scholar 

  17. Zhang, X., Wojcikiewicz, E. & Moy, V. T. Force spectroscopy of the leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. Biophys. J. 83, 2270–2279 (2002).

    Article  CAS  Google Scholar 

  18. Zhang, X., Wojcikiewicz, E. P. & Moy, V. T. Dynamic adhesion of T lymphocytes to endothelial cells revealed by atomic force microscopy. Exp. Biol. Med. (Maywood) 231, 1306–1312 (2006).

    Article  CAS  Google Scholar 

  19. Dai, J. & Sheetz, M. P. Membrane tether formation from blebbing cells. Biophys. J. 77, 3363–3370 (1999).

    Article  CAS  Google Scholar 

  20. Sheetz, M. P. Cell control by membrane–cytoskeleton adhesion. Nature Rev. Mol. Cell Biol. 2, 392–396 (2001).

    Article  CAS  Google Scholar 

  21. Sheetz, M. P. & Dai, J. Modulation of membrane dynamics and cell motility by membrane tension. Trends Cell Biol. 6, 85–89 (1996).

    Article  CAS  Google Scholar 

  22. Vidulescu, C., Clejan, S. & O'Connor K. C. Vesicle traffic through intercellular bridges in DU 145 human prostate cancer cells. J. Cell. Mol. Med. 8, 388–396 (2004).

    Article  Google Scholar 

  23. Iglic, A., Hagerstrand, H., Bobrowska-Hagerstrand, M., Arrigler, V. & Kraij-Iglic, V. Possible role of phospholipid nanotubes in directed transport of membrane vesicles. Physics Letters A 310, 493–497 (2003).

    Article  CAS  Google Scholar 

  24. Spees, J. L., Olson, S. D., Whitney, M. J. & Prockop, D. J. Mitochondrial transfer between cells can rescue aerobic respiration. Proc. Natl Acad. Sci. USA 103, 1283–1288 (2006).

    Article  CAS  Google Scholar 

  25. Cilia, M. L. & Jackson, D. Plasmodesmata form and function. Curr. Opin. Cell Biol. 16, 500–506 (2004).

    Article  CAS  Google Scholar 

  26. Holdaway-Clarke, T. L., Walker, N. A., Hepler, P. K. & Overall, R. L. Physiological elevations in cytoplasmic free calcium by cold or ion injection result in transient closure of higher plant plasmodesmata. Planta 210, 329–335 (2000).

    Article  CAS  Google Scholar 

  27. Davis, D. M. Intercellular transfer of cell-surface proteins is common and can affect many stages of an immune response. Nature Rev. Immunol. 7, 238–243 (2007).

    Article  CAS  Google Scholar 

  28. Sprent, J. Swapping molecules during cell–cell interactions. Sci. STKE 273, pe8 (2005).

    Google Scholar 

  29. Hudrisier, D. & Bongrand, P. Intercellular transfer of antigen-presenting cell determinants onto T cells: molecular mechanisms and biological significance. FASEB J. 16, 477–486 (2002).

    Article  CAS  Google Scholar 

  30. Roda-Navarro, P. & Reyburn, H. T. Intercellular protein transfer at the NK cell immune synapse: mechanisms and physiological significance. FASEB J. 21, 1636–1646 (2007).

    Article  CAS  Google Scholar 

  31. Huang, J. F. et al. TCR-mediated internalization of peptide-MHC complexes acquired by T cells. Science 286, 952–954 (1999).

    Article  CAS  Google Scholar 

  32. McCann, F. E., Eissmann, P., Onfelt, B., Leung, R. & Davis, D. M. The activating NKG2D ligand MHC class I-related chain A transfers from target cells to NK cells in a manner that allows functional consequences. J. Immunol. 178, 3418–3426 (2007).

    Article  CAS  Google Scholar 

  33. Fevrier, B. & Raposo, G. Exosomes: endosomal-derived vesicles shipping extracellular messages. Curr. Opin. Cell Biol. 16, 415–421 (2004).

    Article  CAS  Google Scholar 

  34. Joly, E. & Hudrisier, D. What is trogocytosis and what is its purpose? Nature Immunol. 4, 815 (2003).

    Article  CAS  Google Scholar 

  35. Rorth, P. Communication by touch: role of cellular extensions in complex animals. Cell 112, 595–598 (2003).

    Article  CAS  Google Scholar 

  36. Johnson, D. C. & Huber, M. T. Directed egress of animal viruses promotes cell-to-cell spread. J. Virol. 76, 1–8 (2002).

    Article  CAS  Google Scholar 

  37. Sourisseau, M., Sol-Foulon, N., Porrot, F., Blanchet, F. & Schwartz, O. Inefficient human immunodeficiency virus replication in mobile lymphocytes. J. Virol. 81, 1000–1012 (2007).

    Article  CAS  Google Scholar 

  38. Marsh, M. & Helenius, A. Virus entry: open sesame. Cell 124, 729–740 (2006).

    Article  CAS  Google Scholar 

  39. Igakura, T. et al. Spread of HTLV-I between lymphocytes by virus-induced polarization of the cytoskeleton. Science 299, 1713–1716 (2003).

    Article  CAS  Google Scholar 

  40. Chen, P., Hubner, W., Spinelli, M. A. & Chen, B. K. Predominant mode of human immunodeficiency virus transfer between T cells is mediated by sustained Env-dependent neutralization-resistant virological synapses. J. Virol. 81, 12582–12595 (2007).

    Article  CAS  Google Scholar 

  41. Jolly, C., Kashefi, K., Hollinshead, M. & Sattentau, Q. J. HIV-1 cell to cell transfer across an Env-induced, actin-dependent synapse. J. Exp. Med. 199, 283–293 (2004).

    Article  CAS  Google Scholar 

  42. Davis, D. M. & Dustin, M. L. What is the importance of the immunological synapse? Trends Immunol. 25, 323–327 (2004).

    Article  CAS  Google Scholar 

  43. La Boissiere, S., Izeta, A., Malcomber, S. & O'Hare, P. Compartmentalization of VP16 in cells infected with recombinant herpes simplex virus expressing VP16-green fluorescent protein fusion proteins. J. Virol. 78, 8002–8014 (2004).

    Article  CAS  Google Scholar 

  44. Smith, G. L., Murphy, B. J. & Law, M. Vaccinia virus motility. Annu. Rev. Microbiol. 57, 323–342 (2003).

    Article  CAS  Google Scholar 

  45. Favoreel, H. W., Van Minnebruggen, G., Adriaensen, D. & Nauwynck, H. J. Cytoskeletal rearrangements and cell extensions induced by the US3 kinase of an aherpesvirus are associated with enhanced spread. Proc. Natl Acad. Sci. USA 102, 8990–8995 (2005).

    Article  CAS  Google Scholar 

  46. Sherer, N. M. et al. Retroviruses can establish filopodial bridges for efficient cell-to-cell transmission. Nature Cell Biol. 9, 310–315 (2007).

    Article  CAS  Google Scholar 

  47. Hope, T. J. Bridging efficient viral infection. Nature Cell Biol. 9, 243–244 (2007).

    Article  CAS  Google Scholar 

  48. Brass, A. L. et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science 319, 921–926 (2008).

    Article  CAS  Google Scholar 

  49. Sjostrom, A. et al. Acquisition of external major histocompatibility complex class I molecules by natural killer cells expressing inhibitory Ly49 receptors. J. Exp. Med. 194, 1519–1530 (2001).

    Article  CAS  Google Scholar 

  50. Smyth, L. A., Herrera, O. B., Golshayan, D., Lombardi, G. & Lechler, R. I. A novel pathway of antigen presentation by dendritic and endothelial cells: implications for allorecognition and infectious diseases. Transplantation 82 (Suppl. 1), S15–S18 (2006).

    Article  Google Scholar 

  51. Hsiung, F., Ramirez-Weber, F. A., Iwaki, D. D. & Kornberg, T. B. Dependence of Drosophila wing imaginal disc cytonemes on Decapentaplegic. Nature 437, 560–563 (2005).

    Article  CAS  Google Scholar 

  52. Chinnery, H. R., Pearlman, E. & McMenamin, P. G. Membrane nanotubes in vivo: a feature of MHC class II+ cells in the mouse cornea. J. Immunol. (in the press).

  53. Miller, J., Fraser, S. E. & McClay, D. Dynamics of thin filopodia during sea urchin gastrulation. Development 121, 2501–2511 (1995).

    CAS  PubMed  Google Scholar 

  54. Salas-Vidal, E. & Lomeli, H. Imaging filopodia dynamics in the mouse blastocyst. Dev. Biol. 265, 75–89 (2004).

    Article  CAS  Google Scholar 

  55. Baluska, F., Volkmann, D. & Barlow, P. W. Cell–cell channels (Landes Bioscience and Springer Science, New York, 2006).

    Book  Google Scholar 

  56. Hodneland, E. et al. Automated detection of tunneling nanotubes in 3D images. Cytometry A 69, 961–972 (2006).

    Article  Google Scholar 

  57. Koster, G., Cacciuto, A., Derenyi, I., Frenkel, D. & Dogterom, M. Force barriers for membrane tube formation. Phys. Rev. Lett. 94, 068101 (2005).

    Article  Google Scholar 

  58. Shibata, Y., Voeltz, G. K. & Rapoport, T. A. Rough sheets and smooth tubules. Cell 126, 435–439 (2006).

    Article  CAS  Google Scholar 

  59. Farsad, K. & De Camilli, P. Mechanisms of membrane deformation. Curr. Opin. Cell Biol. 15, 372–381 (2003).

    Article  CAS  Google Scholar 

  60. McMahon, H. T. & Gallop, J. L. Membrane curvature and mechanisms of dynamic cell membrane remodelling. Nature 438, 590–596 (2005).

    Article  CAS  Google Scholar 

  61. Itoh, T. & De Camilli, P. BAR, F-BAR (EFC) and ENTH/ANTH domains in the regulation of membrane-cytosol interfaces and membrane curvature. Biochim. Biophys. Acta 1761, 897–912 (2006).

    Article  CAS  Google Scholar 

  62. Takei, K., Slepnev, V. I., Haucke, V. & De Camilli, P. Functional partnership between amphiphysin and dynamin in clathrin-mediated endocytosis. Nature Cell Biol. 1, 33–39 (1999).

    Article  CAS  Google Scholar 

  63. Mattila, P. K. et al. Missing-in-metastasis and IRSp53 deform PI(4,5)P2-rich membranes by an inverse BAR domain-like mechanism. J. Cell Biol. 176, 953–964 (2007).

    Article  CAS  Google Scholar 

  64. Roux, A. et al. Role of curvature and phase transition in lipid sorting and fission of membrane tubules. EMBO J. 24, 1537–1545 (2005).

    Article  CAS  Google Scholar 

  65. Roda-Navarro, P., Vales-Gomez, M., Chisholm, S. E. & Reyburn, H. T. Transfer of NKG2D and MICB at the cytotoxic NK cell immune synapse correlates with a reduction in NK cell cytotoxic function. Proc. Natl Acad. Sci. USA 103, 11258–11263 (2006).

    Article  CAS  Google Scholar 

  66. Lehmann, M. J., Sherer, N. M., Marks, C. B., Pypaert, M. & Mothes, W. Actin- and myosin-driven movement of viruses along filopodia precedes their entry into cells. J. Cell Biol. 170, 317–325 (2005).

    Article  CAS  Google Scholar 

  67. Karlsson, M. et al. Biomimetic nanoscale reactors and networks. Annu. Rev. Phys. Chem. 55, 613–649 (2004).

    Article  CAS  Google Scholar 

  68. Bauer, B., Davidson, M. & Orwar, O. Direct reconstitution of plasma membrane lipids and proteins in nanotube-vesicle networks. Langmuir 22, 9329–9332 (2006).

    Article  CAS  Google Scholar 

  69. Tokarz, M., Hakonen, B., Dommersnes, P., Orwar, O. & Akerman, B. Electrophoretic transport of latex particles in lipid nanotubes. Langmuir 23, 7652–7658 (2007).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank H. Chinnery, P. McMenamin, I. Rupp, G. Pradel and A. Chauveau for sharing unpublished observations, B. Önfelt and O. Ces for useful discussions, members of our laboratory for comments on the manuscript and N. Powell for help in preparing the figures. Research in our laboratory is funded by the Medical Research Council, the Biotechnology and Biological Science Research Council, a Lister Research Institute Fellowship and a Royal Society Wolfson Research Merit Award. S. S. is funded by a Wellcome Trust studentship.

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Davis, D., Sowinski, S. Membrane nanotubes: dynamic long-distance connections between animal cells. Nat Rev Mol Cell Biol 9, 431–436 (2008). https://doi.org/10.1038/nrm2399

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