1887

Abstract

Herpesvirus glycoproteins often form specific heterodimers that can fulfil functions that cannot be carried out by either of the partners acting alone. This study showed that interactions between the Epstein–Barr virus (EBV) multi-spanning transmembrane envelope protein BMRF2 and type II membrane protein BDLF2 influence the way in which these proteins are trafficked in the cell, and hence the subcellular compartment in which they accumulate. When expressed transiently in mammalian cells, BDLF2 accumulated in the endoplasmic reticulum (ER), whereas BMRF2 accumulated in the ER and Golgi apparatus. However, when the two proteins were co-expressed, BDLF2 was transported with BMRF2 to the Golgi apparatus and from there to the plasma membrane, where the proteins co-localized extensively. The distribution of the two proteins at the plasma membrane was reproducibly associated with dramatic changes in cellular morphology, including the formation of enlarged membrane protrusions and cellular processes whose adhesion extremities were organized by the actin cytoskeleton. A dominant-active form of the small GTPase RhoA was epistatic to this morphological phenotype, suggesting that RhoA is a central component of the signalling pathway that reorganizes the cytoskeleton in response to BDLF2–BMRF2. It was concluded that EBV produces a glycoprotein heterodimer that induces changes in cellular morphology through reorganization of the actin cytoskeleton and may facilitate virion spread between cells.

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2009-06-01
2019-11-14
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References

  1. Arthur, W. T. & Burridge, K. ( 2001; ). RhoA inactivation by p190RhoGAP regulates cell spreading and migration by promoting membrane protrusion and polarity. Mol Biol Cell 12, 2711–2720.[CrossRef]
    [Google Scholar]
  2. Arthur, W. T., Petch, L. A. & Burridge, K. ( 2000; ). Integrin engagement suppresses RhoA activity via a c-Src-dependent mechanism. Curr Biol 10, 719–722.
    [Google Scholar]
  3. Bass, M. D., Morgan, M. R., Roach, K. A., Settleman, J., Goryachev, A. B. & Humphries, M. J. ( 2008; ). p190RhoGAP is the convergence point of adhesion signals from α5β1 integrin and syndecan-4. J Cell Biol 181, 1013–1026.[CrossRef]
    [Google Scholar]
  4. Borza, C. M. & Hutt-Fletcher, L. M. ( 2002; ). Alternate replication in B cells and epithelial cells switches tropism of Epstein–Barr virus. Nat Med 8, 594–599.[CrossRef]
    [Google Scholar]
  5. Cho, M. S., Gissmann, L. & Hayward, S. D. ( 1984; ). Epstein–Barr virus (P3HR-1) defective DNA codes for components of both the early antigen and viral capsid antigen complexes. Virology 137, 9–19.[CrossRef]
    [Google Scholar]
  6. Cox, E. A., Sastry, S. K. & Huttenlocher, A. ( 2001; ). Integrin-mediated adhesion regulates cell polarity and membrane protrusion through the Rho family of GTPases. Mol Biol Cell 12, 265–277.[CrossRef]
    [Google Scholar]
  7. Favoreel, H. W., Van Minnebruggen, G., Adriaensen, D. & Nauwynck, H. J. ( 2005; ). Cytoskeletal rearrangements and cell extensions induced by the US3 kinase of an alphaherpesvirus are associated with enhanced spread. Proc Natl Acad Sci U S A 102, 8990–8995.[CrossRef]
    [Google Scholar]
  8. Favoreel, H. W., Enquist, L. W. & Feierbach, B. ( 2007; ). Actin and Rho GTPases in herpesvirus biology. Trends Microbiol 15, 426–433.[CrossRef]
    [Google Scholar]
  9. Gill, M. B., Edgar, R., May, J. S. & Stevenson, P. G. ( 2008; ). A gamma-herpesvirus glycoprotein complex manipulates actin to promote viral spread. PLoS ONE 3, e1808 [CrossRef]
    [Google Scholar]
  10. Gore, M. & Hutt-Fletcher, L. M. ( 2008; ). The BDLF2 protein of Epstein–Barr virus is a type II glycosylated envelope protein whose processing is dependent on coexpression with the BMRF2 protein. Virology 383, 162–167.
    [Google Scholar]
  11. Hayes, D. P., Brink, A. A., Vervoort, M. B., Middeldorp, J. M., Meijer, C. J. & van den Brule, A. J. ( 1999; ). Expression of Epstein–Barr virus (EBV) transcripts encoding homologues to important human proteins in diverse EBV associated diseases. Mol Pathol 52, 97–103.[CrossRef]
    [Google Scholar]
  12. Hutt-Fletcher, L. M. ( 2007; ). Epstein–Barr virus entry. J Virol 81, 7825–7832.[CrossRef]
    [Google Scholar]
  13. Johannsen, E., Luftig, M., Chase, M. R., Weicksel, S., Cahir-McFarland, E., Illanes, D., Sarracino, D. & Kieff, E. ( 2004; ). Proteins of purified Epstein–Barr virus. Proc Natl Acad Sci U S A 101, 16286–16291.[CrossRef]
    [Google Scholar]
  14. La Boissière, S., Izeta, A., Malcomber, S. & O'Hare, P. ( 2004; ). Compartmentalization of VP16 in cells infected with recombinant herpes simplex virus expressing VP16–green fluorescent protein fusion proteins. J Virol 78, 8002–8014.[CrossRef]
    [Google Scholar]
  15. Majerciak, V., Yamanegi, K. & Zheng, Z. M. ( 2006; ). Gene structure and expression of Kaposi's sarcoma-associated herpesvirus ORF56, ORF57, ORF58, and ORF59. J Virol 80, 11968–11981.[CrossRef]
    [Google Scholar]
  16. May, J. S., de Lima, B. D., Colaco, S. & Stevenson, P. G. ( 2005a; ). Intercellular gamma-herpesvirus dissemination involves co-ordinated intracellular membrane protein transport. Traffic 6, 780–793.[CrossRef]
    [Google Scholar]
  17. May, J. S., Walker, J., Colaco, S. & Stevenson, P. G. ( 2005b; ). The murine gammaherpesvirus 68 ORF27 gene product contributes to intercellular viral spread. J Virol 79, 5059–5068.[CrossRef]
    [Google Scholar]
  18. Modrow, S., Höflacher, B. & Wolf, H. ( 1992; ). Identification of a protein encoded in the EB-viral open reading frame BMRF2. Arch Virol 127, 379–386.[CrossRef]
    [Google Scholar]
  19. Nobes, C. D. & Hall, A. ( 1995; ). Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81, 53–62.[CrossRef]
    [Google Scholar]
  20. Sanderson, C. M., Way, M. & Smith, G. L. ( 1998; ). Virus-induced cell motility. J Virol 72, 1235–1243.
    [Google Scholar]
  21. Subauste, M. C., Von Herrath, M., Benard, V., Chamberlain, C. E., Chuang, T. H., Chu, K., Bokoch, G. M. & Hahn, K. M. ( 2000; ). Rho family proteins modulate rapid apoptosis induced by cytotoxic T lymphocytes and Fas. J Biol Chem 275, 9725–9733.[CrossRef]
    [Google Scholar]
  22. Tugizov, S. M., Berline, J. W. & Palefsky, J. M. ( 2003; ). Epstein–Barr virus infection of polarized tongue and nasopharyngeal epithelial cells. Nat Med 9, 307–314.[CrossRef]
    [Google Scholar]
  23. Valderrama, F., Cordeiro, J. V., Schleich, S., Frischknecht, F. & Way, M. ( 2006; ). Vaccinia virus-induced cell motility requires F11L-mediated inhibition of RhoA signaling. Science 311, 377–381.[CrossRef]
    [Google Scholar]
  24. van Leeuwen, H., Elliott, G. & O'Hare, P. ( 2002; ). Evidence of a role for nonmuscle myosin II in herpes simplex virus type 1 egress. J Virol 76, 3471–3481.[CrossRef]
    [Google Scholar]
  25. Worthylake, R. A. & Burridge, K. ( 2003; ). RhoA and ROCK promote migration by limiting membrane protrusions. J Biol Chem 278, 13578–13584.[CrossRef]
    [Google Scholar]
  26. Worthylake, R. A., Lemoine, S., Watson, J. M. & Burridge, K. ( 2001; ). RhoA is required for monocyte tail retraction during transendothelial migration. J Cell Biol 154, 147–160.[CrossRef]
    [Google Scholar]
  27. Xiao, J., Palefsky, J. M., Herrera, R., Berline, J. & Tugizov, S. M. ( 2007a; ). The Epstein–Barr virus BMRF-2 protein facilitates virus attachment to oral epithelial cells. Virology 370, 430–442.
    [Google Scholar]
  28. Xiao, J., Palefsky, J. M., Herrera, R. & Tugizov, S. M. ( 2007b; ). Characterization of the Epstein–Barr virus glycoprotein BMRF-2. Virology 359, 382–396.[CrossRef]
    [Google Scholar]
  29. Young, L. S. & Rickinson, A. B. ( 2004; ). Epstein–Barr virus: 40 years on. Nat Rev Cancer 4, 757–768.[CrossRef]
    [Google Scholar]
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