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Nature Cell Biology
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M-Sec promotes membrane nanotube formation by interacting with Ral and the exocyst complex

Nature Cell Biologyvolume 11, pages1427–1432 (2009)Cite this article

Abstract

Cell–cell communication is essential for the development and homeostasis of multicellular organisms. Recently, a new type of cell–cell communication was discovered that is based on the formation of thin membranous nanotubes between remote cells1,2. These long membrane tethers, termed tunneling nanotubes (TNTs), form an intercellular conduit and have been shown to enable the transport of various cellular components and signals. However, the molecular basis for TNT formation remains to be elucidated. Here we report that a mammalian protein, M-Sec, inducesde novo formation of numerous membrane protrusions extending from the plasma membrane, some of which tether onto adjacent cells and subsequently form TNT-like structures. Depletion of M-Sec by RNA interference (RNAi) greatly reduced endogenous TNT formation as well as intercellular propagation of a calcium flux in a macrophage cell line. Furthermore, blockage of the interaction of M-Sec with Ral and the exocyst complex, which serves as a downstream effector of Ral, attenuated the formation of membrane nanotubes. Our results reveal that M-Sec functions as a key regulator of membrane nanotube formation through interaction with the Ral–exocyst pathway.

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Figure 1: M-Sec is important for endogenous TNT formation by Raw264.7 macrophages.
Figure 2: M-Sec induces F-actin-containing membrane protrusions.
Figure 3: Intercellular calcium signalling between remote cells is observed only in physically connected cell pairs.
Figure 4: Involvement of small GTPases in M-Sec-stimulated TNT formation.
Figure 5: Involvement of the exocyst complex in M-Sec-induced TNT formation.

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References

  1. Rustom, A., Saffrich, R., Markovic, I., Walther, P. & Gerdes, H. H. Nanotubular highways for intercellular organelle transport.Science303, 1007–1010 (2004).

    Article CAS  Google Scholar 

  2. Watkins, S. C. & Salter, R. D. Functional connectivity between immune cells mediated by tunneling nanotubules.Immunity23, 309–318 (2005).

    Article CAS  Google Scholar 

  3. Grakoui, A. et al. The immunological synapse: a molecular machine controlling T cell activation.Science285, 221–227 (1999).

    Article CAS  Google Scholar 

  4. Thery, C., Zitvogel, L. & Amigorena, S. Exosomes: composition, biogenesis and function.Nature Rev. Immunol.2, 569–579 (2002).

    Article CAS  Google Scholar 

  5. 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 

  6. 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 

  7. 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 

  8. 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 

  9. 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 

  10. Xu, W. et al. HIV-1 evades virus-specific IgG2 and IgA responses by targeting systemic and intestinal B cells via long-range intercellular conduits.Nature Immunol.10, 1008–1017 (2009).

    Article CAS  Google Scholar 

  11. Kraehenbuhl, J. P. & Neutra, M. R. Epithelial M cells: differentiation and function.Annu. Rev. Cell Dev. Biol.16, 301–332 (2000).

    Article CAS  Google Scholar 

  12. Hase, K. et al. Uptake via glycoprotein 2 of FimH+ bacteria by M cells initiates mucosal immune response.Nature462, 226–230 (2009).

    Article CAS  Google Scholar 

  13. Hase, K. et al. Distinct gene expression profiles characterize cellular phenotypes of follicle-associated epithelium and M cells.DNA Res.12, 127–137 (2005).

    Article CAS  Google Scholar 

  14. Sarma, V., Wolf, F. W., Marks, R. M., Shows, T. B. & Dixit, V. M. Cloning of a novel tumor necrosis factor-alpha-inducible primary response gene that is differentially expressed in development and capillary tube-like formation in vitro.J. Immunol.148, 3302–3312 (1992).

    CAS PubMed  Google Scholar 

  15. Wolf, F. W. et al. B94, a primary response gene inducible by tumor necrosis factor-alpha, is expressed in developing hematopoietic tissues and the sperm acrosome.J. Biol. Chem.269, 3633–3640 (1994).

    CAS PubMed  Google Scholar 

  16. Hijikata, A. et al. Construction of an open-access database that integrates cross-reference information from the transcriptome and proteome of immune cells.Bioinformatics23, 2934–2941 (2007).

    Article CAS  Google Scholar 

  17. Chinnery, H. R., Pealman, E. & McMenamin, P. G. Membrane nanotubulesin vivo: a feature of MHC class II+ cells in the mouse cornea.J. Immunol.180, 5779–5783 (2008).

    Article CAS  Google Scholar 

  18. Davis, D. M. & Sowinski, S. Membrane nanotubes: dynamic long-distance connections between animal cells.Nature Rev. Mol. Cell Biol.9, 431–436 (2008).

    Article CAS  Google Scholar 

  19. Colicelli, J. Human RAS superfamily proteins and related GTPases.Sci. STKE2004, RE13 (2004).

    Google Scholar 

  20. Burridge, K. & Wennerberg, K. Rho and Rac take center stage.Cell116, 167–179 (2004).

    Article CAS  Google Scholar 

  21. Ohta, Y., Suzuki, N., Nakamura, S., Hartwig, J. H. & Stossel, T. P. The small GTPase RalA targets filamin to induce filopodia.Proc. Natl Acad. Sci. USA96, 2122–2128 (1999).

    Article CAS  Google Scholar 

  22. Sugihara, K. et al. The exocyst complex binds the small GTPase RalA to mediate filopodia formation.Nature Cell Biol.4, 73–78 (2002).

    Article CAS  Google Scholar 

  23. Moskalenko, S. et al. The exocyst is a Ral effector complex.Nature Cell Biol.4, 66–72 (2002).

    Article CAS  Google Scholar 

  24. Jin, R. et al. Exo84 and Sec5 are competitive regulatory Sec6/8 effectors to the RalA GTPase.Embo J.24, 2064–2074 (2005).

    Article CAS  Google Scholar 

  25. Lalli, G. & Hall, A. Ral GTPases regulate neurite branching through GAP-43 and the exocyst complex.J. Cell Biol.171, 857–869 (2005).

    Article CAS  Google Scholar 

  26. van Dam, E. M. & Robinson, P. J. Ral: mediator of membrane trafficking.Int. J. Biochem. Cell Biol.38, 1841–1847 (2006).

    Article CAS  Google Scholar 

  27. Ikeda, M., Ishida, O., Hinoi, T., Kishida, S. & Kikuchi, A. Identification and characterization of a novel protein interacting with Ral-binding protein 1, a putative effector protein of Ral.J. Biol. Chem.273, 814–821 (1998).

    Article CAS  Google Scholar 

  28. Mattila, P. K. & Lappalainen, P. Filopodia: molecular architecture and cellular functions.Nature Rev. Mol. Cell Biol.9, 446–454 (2008).

    Article CAS  Google Scholar 

  29. Hsu, S. C., TerBush, D., Abraham, M. & Guo, W. The exocyst complex in polarized exocytosis.Int. Rev. Cytol.233, 243–265 (2004).

    Article CAS  Google Scholar 

  30. Yeaman, C., Grindstaff, K. K. & Nelson, W. J. Mechanism of recruiting Sec6/8 (exocyst) complex to the apical junctional complex during polarization of epithelial cells.J. Cell Sci.117, 559–570 (2004).

    Article CAS  Google Scholar 

  31. Hase, K. et al. The membrane-bound chemokine CXCL16 expressed on follicle-associated epithelium and M cells mediates lympho-epithelial interaction in GALT.J. Immunol.176, 43–51 (2006).

    Article CAS  Google Scholar 

  32. Chien, Y. et al. RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival.Cell127, 157–170 (2006).

    Article CAS  Google Scholar 

  33. Chen, X. W., Inoue, M., Hsu, S. C. & Saltiel, A. R. RalA-exocyst-dependent recycling endosome trafficking is required for the completion of cytokinesis.J. Biol. Chem.281, 38609–38616 (2006).

    CAS  Google Scholar 

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Acknowledgements

We would like to thank I. Yamashita and Y. Fujimura for technical assistance, and. P. Burrows and C. Blaumueller for critically reviewing the manuscript. This study was supported in part by Grants-in-Aid for Young Scientists (B) (K.H.), Scientific Research (B) (H.O.), Scientific Research in Priority Areas (H.O. and K.H.) and Scientific Research on Innovative Areas (H.O.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and grants from the National Institutes of Health (GM067002; C.Y.) and the Takeda Science Foundation (K.H.).

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Authors and Affiliations

  1. Laboratory for Epithelial Immunobiology, 230-0045, Kanagawa, Japan

    Koji Hase, Shunsuke Kimura, Hiroyuki Takatsu, Masumi Ohmae, Sayaka Kawano & Hiroshi Ohno

  2. Laboratory for Immunogenomics, 230-0045, Kanagawa, Japan

    Hiroshi Kitamura & Masatoshi Ito

  3. Laboratory for Immune regulation, Research Center for Allergy and Immunology, RIKEN, 230-0045, Kanagawa, Japan

    Hiroshi Watarai

  4. Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, 52242, IA, USA

    C. Clayton Hazelett & Charles Yeaman

  5. Department of Supramolecular Biology, Graduate School of Nanobioscience, Yokohama City University, 230-0045, Kanagawa, Japan

    Masatoshi Ito & Hiroshi Ohno

Authors
  1. Koji Hase

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  2. Shunsuke Kimura

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  4. Masumi Ohmae

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  9. C. Clayton Hazelett

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  10. Charles Yeaman

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  11. Hiroshi Ohno

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Contributions

K.H. designed and performed experiments, and wrote the paper. S.Ki. performed experiments and helped with data analysis. H.T., M.O., S.Ka., H.K., M.I. and H.W. helped with the experiments. C.Y. and C.C.H. prepared antibodies and performed experiments. H.O. supervised the project and wrote the paper with K.H.

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Correspondence toHiroshi Ohno.

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The authors declare no competing financial interests.

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Hase, K., Kimura, S., Takatsu, H.et al. M-Sec promotes membrane nanotube formation by interacting with Ral and the exocyst complex.Nat Cell Biol11, 1427–1432 (2009). https://doi.org/10.1038/ncb1990

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