Entry of Rhabdoviruses Into Animal Cells

  • Andrew D. Regan
  • Gary R. WhittakerEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 790)


Entry is the first step in the infectious life cycle of a virus. In the case of rhabdoviruses, entry is facilitated exclusively by the envelope glycoprotein G and its interactions with the host cell. For vesicular stomatitis virus (VSV), attachment to the cell surface was thought to be facilitated by interactions with the lipid phosphatidylserine, however recent work suggests that it is in fact initiated by recognition of proteinaeous receptors. Clathrin-mediated endocytosis delivers the virions into endosomes where they have been proposed to traffic to multi-vesicular bodies. There, the viral envelope fuses with internal vesicles in a process mediated by glycoprotein G in a pH- and phosphatidylserine-dependent manner. A clear mechanistic understanding of glycoprotein G mediated fusion has yet to be obtained, however current data suggests that it is likely facilitated by events distinct from Class I or Class II fusion proteins of other viruses. Rhabdoviruses are also notable in that their fusion protein exists in a reversible pH-dependent equilibrium, which prevents irreversible preactivation during assembly, and may prove to be relevant in the mediation of cell-to-cell fusion - an alternate form of viral spread.


Membrane Fusion Rabies Virus Vesicular Stomatitis Virus Venezuelan Equine Encephalitis Virus Viral Haemorrhagic Septicaemia Virus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Fauquet CM, Mayo MA, Maniloff J et al, eds. Virus Taxonomy. San Diego: Elsevier Academic Press, 2005.Google Scholar
  2. 2.
    Bearzotti M, Delmas B, Lamoureux A et al. Fish rhabdovirus cell entry is mediated by fibronectin. J Virol 1999; 73(9):7703–7709.PubMedGoogle Scholar
  3. 3.
    Lafon M. Rabies virus receptors. J Neurovirol 2005; 11(1):82–87.PubMedCrossRefGoogle Scholar
  4. 4.
    Wunner WH, Reagan KJ, Koprowski H. Characterization of saturable binding sites for rabies virus. J Virol 1984; 50(3):691–697.PubMedGoogle Scholar
  5. 5.
    Altstiel LD, Landsberger FR. Lipid-protein interactions between the surface glycoprotein of vesicular stomatitis virus and the lipid bilayer. Virology 1981; 115(1): 1–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Gaudin Y, Ruigrok RW, Knossow M et al. Low-pH conformational changes of rabies virus glycoprotein and their role in membrane fusion. J Virol 1993; 67(3): 1365–1372.PubMedGoogle Scholar
  7. 7.
    Konieczko EM, Whitaker-Dowling PA, Widnell CC. Membrane fusion as a determinant of the infectibility of cells by vesicular stomatitis virus. Virology 1994; 199(1):200–211.PubMedCrossRefGoogle Scholar
  8. 8.
    Lecocq-Xhonneux F, Thiry M, Dheur I et al. A recombinant viral haemorrhagic septicaemia virus glycoprotein expressed in insect cells induces protective immunity in rainbow trout. J Gen Virol 1994; 75(Pt 7): 1579–1587.PubMedCrossRefGoogle Scholar
  9. 9.
    Coll JM. The glycoprotein G of rhabdoviruses. Arch Virol 1995; 140(5):827–851.PubMedCrossRefGoogle Scholar
  10. 10.
    Balch WE, Elliott MM, Keller DS. ATP-coupled transport of vesicular stomatitis virus G protein between the endoplasmic reticulum and the Golgi. J Biol Chem 1986; 261(31):14681–14689.PubMedGoogle Scholar
  11. 11.
    Doms RW, Keller DS, Helenius A et al. Role for adenosine triphosphate in regulating the assembly and transport of vesicular stomatitis virus G protein trimers. J Cell Biol 1987; 105(5): 1957–1969.PubMedCrossRefGoogle Scholar
  12. 12.
    Gaudin Y, Ruigrok RW, Tuffereau C et al. Rabies virus glycoprotein is a trimer. Virology 1992; 187(2):627–632.PubMedCrossRefGoogle Scholar
  13. 13.
    Kreis TE, Lodish HF. Oligomerization is essential for transport of vesicular stomatitis viral glycoprotein to the cell surface. Cell 1986; 46(6):929–937.PubMedCrossRefGoogle Scholar
  14. 14.
    Lyles DS, Varela VA, Parce JW. Dynamic nature of the quaternary structure of the vesicular stomatitis virus envelope glycoprotein. Biochemistry 1990; 29(10):2442–2449.PubMedCrossRefGoogle Scholar
  15. 15.
    Whitt MA, Buonocore L, Prehaud C et al. Membrane fusion activity, oligomerization, and assembly of the rabies virus glycoprotein. Virology 1991; 185(2):681–688.PubMedCrossRefGoogle Scholar
  16. 16.
    Wilcox MD, McKenzie MO, Parce JW et al. Subunit interactions of vesicular stomatitis virus envelope glycoprotein influenced by detergent micelles and lipid bilayers. Biochemistry 1992; 31(43): 10458–10464.PubMedCrossRefGoogle Scholar
  17. 17.
    Zagouras P, Ruusala A, Rose JK. Dissociation and reassociation of oligomeric viral glycoprotein subunits in the endoplasmic reticulum. J Virol 1991; 65(4): 1976–1984.PubMedGoogle Scholar
  18. 18.
    Schlegel R, Willingham MC, Pastan IH. Saturable binding sites for vesicular stomatitis virus on the surface of Vero cells. J Virol 1982; 43(3):871–875.PubMedGoogle Scholar
  19. 19.
    Conti C, Hauttecoeur B, Morelec MJ et al. Inhibition of rabies virus infection by a soluble membrane fraction from the rat central nervous system. Arch Virol 1988; 98(1–2):73–86.PubMedCrossRefGoogle Scholar
  20. 20.
    Conti C, Mastromarino P, Ciuffarella MG et al. Characterization of rat brain cellular membrane components acting as receptors for vesicular stomatitis virus. Brief report. Arch Virol 1988; 99(3–4):261–269.PubMedCrossRefGoogle Scholar
  21. 21.
    Mastromarino P, Conti C, Goldoni P et al. Characterization of membrane components of the erythrocyte involved in vesicular stomatitis virus attachment and fusion at acidic pH. J Gen Virol 1987; 68(Pt 9):2359–2369.PubMedCrossRefGoogle Scholar
  22. 22.
    Schlegel R, Tralka TS, Willingham MC et al. Inhibition of VSVbinding and infectivity by phosphatidylserine: Is phosphatidylserine a VSV-binding site? Cell 1983; 32(2):639–646.PubMedCrossRefGoogle Scholar
  23. 23.
    Coll JM. Heptad-repeat sequences in the glycoprotein of rhabdoviruses. Virus Genes 1995; 10(2):107–114.PubMedCrossRefGoogle Scholar
  24. 24.
    Coll JM. Synthetic peptides from the heptad repeats of the glycoproteins of rabies, vesicular stomatitis and fish rhabdoviruses bind phosphatidylserine. Arch Virol 1997; 142(10):2089–2097.PubMedCrossRefGoogle Scholar
  25. 25.
    Hall MP, Burson KK, Huestis WH. Interactions of a vesicular stomatitis virus G protein fragment with phosphatidylserine: NMR and fluorescence studies. Biochim Biophys Acta 1998; 1415(1): 101–113.PubMedCrossRefGoogle Scholar
  26. 26.
    Morrot G, Herve P, Zachowski A et al. Aminophospholipid translocase of human erythrocytes: Phospholipid substrate specificity and effect of cholesterol. Biochemistry 1989; 28(8):3456–3462.PubMedCrossRefGoogle Scholar
  27. 27.
    Zachowski A, Favre E, Cribier S et al. Outside-inside translocation of aminophospholipids in the human erythrocyte membrane is mediated by a specific enzyme. Biochemistry 1986; 25(9):2585–2590.PubMedCrossRefGoogle Scholar
  28. 28.
    Coil DA, Miller AD. Phosphatidylserine is not the cell surface receptor for vesicular stomatitis virus. J Virol 2004; 78(20): 10920–10926.PubMedCrossRefGoogle Scholar
  29. 29.
    Carneiro FA, Lapido-Loureiro PA, Cordo SM et al. Probing the interaction between vesicular stomatitis virus and phosphatidylserine. Eur Biophys 2006; 35(2): 145–154.CrossRefGoogle Scholar
  30. 30.
    Burrage TG, Tignor GH, Smith AL. Rabies virus binding at neuromuscular junctions. Virus Res 1985; 2(3):273–289.PubMedCrossRefGoogle Scholar
  31. 31.
    Castellanos JE, Castaneda DR, Velandia AE et al. Partial inhibition of the in vitro infection of adult mouse dorsal root ganglion neurons by rabies virus using nicotinic antagonists. Neurosci Lett 1997; 229(3): 198–200.PubMedCrossRefGoogle Scholar
  32. 32.
    Gastka M, Horvath J, Lentz TL. Rabies virus binding to the nicotinic acetylcholine receptor alpha subunit demonstrated by virus overlay protein binding assay. J Gen Virol 1996; 77(Pt 10):2437–2440.PubMedCrossRefGoogle Scholar
  33. 33.
    Lentz TL, Benson RJ, Klimowicz D et al. Binding of rabies virus to purified Torpedo acetylcholine receptor. Brain Res 1986; 387(3):211–219.PubMedGoogle Scholar
  34. 34.
    Lentz TL, Burrage TG, Smith AL et al. Is the acetylcholine receptor a rabies virus receptor? Science 1982; 215(4529):182–184.PubMedCrossRefGoogle Scholar
  35. 35.
    Lewis P, Fu Y, Lentz T. Rabies virus entry at the neuromuscular junction in nerve-muscle cocultures. Muscle Nerve 2000; 23(5):720–730.PubMedCrossRefGoogle Scholar
  36. 36.
    Superti F, Seganti L, Ruggeri FM et al. Entry pathway of vesicular stomatitis virus into different host cells. J Gen Virol 1987; 68(Pt 2):387–399.PubMedCrossRefGoogle Scholar
  37. 37.
    Matlin KS, Reggio H, Helenius A et al. Pathway of vesicular stomatitis virus leading to infection. J Mol Biol 1982; 156:609–631.PubMedCrossRefGoogle Scholar
  38. 38.
    Cernescu C, Constantinescu SN, Popescu LM. Electron microscopic observations of vesicular stomatitis virus particles penetration in human fibroblasts. Rev Roum Virol 1990; 41:93–96.PubMedGoogle Scholar
  39. 39.
    Sun X, Yau VK, Briggs BJ et al. Role of clathrin-mediated endocytosis during vesicular stomatitis virus entry into host cells. Virology 2005; 338(1):53–60.PubMedCrossRefGoogle Scholar
  40. 40.
    Kolokoltsov AA, Fleming EH, Davey RA. Venezuelan equine encephalitis virus entry mechanism requires late endosome formation and resists cellmembrane cholesterol depletion. Virology 2006; 347(2):333–342.PubMedCrossRefGoogle Scholar
  41. 41.
    Daro E, Sheff D, Gomez M et al. Inhibition of endosome function in CHO cells bearing atemperature-sensitive defect in the coatomer (COPI) component epsilon-COP. J Cell Biol 1997; 139(7): 1747–1759.PubMedCrossRefGoogle Scholar
  42. 42.
    Pelkmans L, Fava E, Grabner H et al. Genome-wide analysis of human kinases in clathrin-and caveolae/ raft-mediated endocytosis. Nature 2005; 436(7047):78–86.PubMedCrossRefGoogle Scholar
  43. 43.
    Fuller S, von Bonsdorff CH, Simons K. Vesicular stomatitis virus infects and matures only through the basolateral surface of the polarized epithelial cell line, MDCK. Cell 1984; 38(l):65–77.PubMedCrossRefGoogle Scholar
  44. 44.
    Gottlieb TA, Ivanov IE, Adesnik M et al. Actin microfilaments play a critical role in endocytosis at the apical but not the basolateral surface of polarized epithelial cells. J Cell Biol 1993; 120(3):695–710.PubMedCrossRefGoogle Scholar
  45. 45.
    Blumenthal R, Bali-Puri A, Walter A et al. pH-dependent fusion of vesicular stomatitis virus with Vero cells. Measurement by dequenching of octadecyl rhodamine fluorescence. J Biol Chem 1987; 262(28):13614–13619.PubMedGoogle Scholar
  46. 46.
    Florkiewicz RZ, Rose JK. A cell line expressing vesicular stomatitis virus glycoprotein fuses at low pH. Science 1984; 225(4663):721–723.PubMedCrossRefGoogle Scholar
  47. 47.
    Hernandez LD, Hoffman LR, Wolfsberg TG et al. Virus-cell and cell-cell fusion. Annu Rev Cell Dev Biol 1996; 12:627–661.PubMedCrossRefGoogle Scholar
  48. 48.
    Matlin KS, Reggio H, Helenius A et al. Pathway of vesicular stomatitis virus entry leading to infection. J Mol Biol 1982; 156(3):609–631.PubMedCrossRefGoogle Scholar
  49. 49.
    White J, Matlin K, Helenius A. Cell fusion by Semliki Forest, influenza, and vesicular stomatitis viruses. J Cell Biol 1981; 89(3):674–679.PubMedCrossRefGoogle Scholar
  50. 50.
    Carneiro FA, Ferradosa AS, Da Poian AT. Low pH-induced conformational changes in vesicular stomatitis virus glycoprotein involve dramatic structure reorganization. J Biol Chem 2001; 276(l):62–67.PubMedGoogle Scholar
  51. 51.
    Pak CC, Puri A, Blumenthal R. Conformational changes and fusion activity of vesicular stomatitis virus glycoprotein: [125I]iodonaphthyl azide photolabeling studies in biological membranes. Biochemistry 1997; 36(29):8890–8896.PubMedCrossRefGoogle Scholar
  52. 52.
    Gaudin Y, Tuffereau C, Durrer P et al. Biological function of the low-pH, fusion-inactive conformation of rabies virus glycoprotein (G): G is transported in a fusion-inactive state-like conformation. J Virol 1995;69(9):5528–5534.PubMedGoogle Scholar
  53. 53.
    Gaudin Y. Reversibility in fusion protein conformational changes. The intriguing case of rhabdo virus-induced membrane fusion. Subcell Biochem 2000; 34:379–408.PubMedCrossRefGoogle Scholar
  54. 54.
    Colman PM, Lawrence MC. The structural biology of type I viral membrane fusion. Nat Rev Mol Cell Biol 2003; 4(4):309–319.PubMedCrossRefGoogle Scholar
  55. 55.
    Le Blanc I, Luyet PP, Pons V et al. Endosome-to-cytosol transport of viral nucleocapsids. Nat Cell Biol 2005; 7(7):653–664.PubMedCrossRefGoogle Scholar
  56. 56.
    Matsuo H, Chevallier J, Mayran N et al. Role of LBPA and Alix in multivesicular liposome formation and endosome organization. Science 2004; 303(5657):531–534.PubMedCrossRefGoogle Scholar
  57. 57.
    Uchil P, Mothes W. Viral entry: A detour through multivesicular bodies. Nat Cell Biol 2005; 7(7):641–642.PubMedCrossRefGoogle Scholar
  58. 58.
    Earp LJ, Delos SE, Park HE et al. The many mechanisms of viral membrane fusion proteins. Curr Top Microbiol Immunol 2005; 285:25–66.PubMedCrossRefGoogle Scholar
  59. 59.
    Zhang L, Ghosh HP. Characterization of the putative fusogenic domain in vesicular stomatitis virus glycoprotein G. J Virol 1994; 68(4):2186–2193.PubMedGoogle Scholar
  60. 60.
    Kielian M. Class II virus membrane fusion proteins. Virology 2006; 344(1):38–47.PubMedCrossRefGoogle Scholar
  61. 61.
    Durrer P, Gaudin Y, Ruigrok RW et al. Photolabeling identifies a putative fusion domain in the envelope glycoprotein of rabies and vesicular stomatitis viruses. J Biol Chem 1995; 270(29):17575–17581.PubMedCrossRefGoogle Scholar
  62. 62.
    Fredericksen BL, Whitt MA. Vesicular stomatitis virus glycoprotein mutations that affect membrane fusion activity and abolish virus infectivity. J Virol 1995; 69(3):1435–1443.PubMedGoogle Scholar
  63. 63.
    Li Y, Drone C, Sat E et al. Mutational analysis of the vesicular stomatitis virus glycoprotein G for membrane fusion domains. J Virol 1993; 67(7):4070–4077.PubMedGoogle Scholar
  64. 64.
    Shokralla S, He Y, Wanas E et al. Mutations in a carboxy-terminal region of vesicular stomatitis virus glycoprotein G that affect membrane fusion activity. Virology 1998; 75:39–50.CrossRefGoogle Scholar
  65. 65.
    Gaudin Y, Raux H, Flamand A et al. Identification of amino acids controlling the low-pH-induced conformational change of rabies virus glycoprotein. J Virol 1996; 70:7371–7378.PubMedGoogle Scholar
  66. 66.
    Shokralla S, Chernish R, Ghosh HP. Effect of double-site mutations of vesicular stomatitis virus glycoprotein G on membrane fusion activity. Virology 1999; 256:119–129.PubMedCrossRefGoogle Scholar
  67. 67.
    Carneiro FA, Stauffer F, Lima CS et al. Membrane fusion induced by vesicular stomatitis virus depends on histidine protonation. J Biol Chem 2003; 278(16):13789–13794.PubMedCrossRefGoogle Scholar
  68. 68.
    Nunez E, Fernandez AM, Estepa A et al. Phospholipid interactions of a peptide from the fusion-related domain of the glycoprotein of VHSV, a fish rhabdovirus. Virology 1998; 243(2):322–330.PubMedCrossRefGoogle Scholar
  69. 69.
    Carneiro FA, Bianconi ML, Weissmuller G et al. Membrane recognition by vesicular stomatits virus involves enthalpy-driven protein-lipid interactions. J Virol 2002; 76:3756–3764.PubMedCrossRefGoogle Scholar
  70. 70.
    Estepa AM, Rocha AI, Mas V et al. A protein G fragment from the salmonid viral hemorrhagic septicemia rhabdovirus induces cell-to-cell fusion and membrane phosphatidylserine translocation at low pH. J Biol Chem 2001; 276(49):46268–46275.PubMedCrossRefGoogle Scholar
  71. 71.
    Jeetendra E, Ghosh K, Odell D et al. The membrane-proximal region of vesicular stomatitis virus glycoprotein G ectodomain is critical for fusion and virus infectivity. J Virol 2003; 77(23):12807–12818.PubMedCrossRefGoogle Scholar
  72. 72.
    Jeetendra E, Robison CS, Albritton LM et al. The membrane-proximal domain of vesicular stomatitis virus G protein functions as a membrane fusion potentiator and can induce hemifusion. J Virol 2002; 76(23):12300–12311.PubMedCrossRefGoogle Scholar
  73. 73.
    Langosch D, Brosig B, Pipkorn R. Peptide mimics of the vesicular stomatitis virus G-protein transmembrane segment drive membrane fusion in vitro. J Biol Chem 2001; 276(34):32016–32021.PubMedCrossRefGoogle Scholar
  74. 74.
    Cleverley DZ, Lenard J. The transmembrane domain in viral fusion: Essential role for a conserved glycine residue in vesicular stomatitis virus G protein. Proc Natl Acad Sci USA 1998; 95(7):3425–3430.PubMedCrossRefGoogle Scholar
  75. 75.
    Odell D, Wanas E, Yan J et al. Influence of membrane anchoring and cytoplasmic domains on the fusogenic activity of vesicular stomatitis virus glycoprotein G. J Virol 1997; 71(10):7996–8000.PubMedGoogle Scholar
  76. 76.
    Skehel JJ, Wiley DC. Receptor binding and membrane fusion in virus entry: The influenza hemagglutinin. Annu Rev Biochem 2000; 69:531–569.PubMedCrossRefGoogle Scholar
  77. 77.
    Roberts PC, Kipperman T, Compans RW. Vesicular stomatitis virus G protein acquires pH-independent fusion activity during transport in a polarized endometrial cell line. J Virol 1999; 73(12): 10447–10457.PubMedGoogle Scholar
  78. 78.
    Simmons G, Reeves JD, Rennekamp AJ et al. Characterization of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) spike glycoprotein-mediated viral entry. Proc Natl Acad Sci USA 2004; 101(12):4240–4245.PubMedCrossRefGoogle Scholar
  79. 79.
    Tscherne DM, Jones CT, Evans MJ et al. Time-and temperature-dependent activation of hepatitis C virus for low-pH-triggered entry. J Virol 2006; 80(4): 1734–1741.PubMedCrossRefGoogle Scholar
  80. 80.
    Chu VC, McElroy LJ, Chu V et al. The avian coronavirus infectious bronchitis virus undergoes direct low-pH-dependent fusion activation during entry into host cells. J Virol 2006; 80(7):3180–3188.PubMedCrossRefGoogle Scholar
  81. 81.
    Finke S, Conzelmann KK. Recombinant rhabdo viruses: Vectors for vaccine development and gene therapy. Curr Top Microbiol Immunol 2005; 292:165–200.PubMedCrossRefGoogle Scholar
  82. 82.
    Roche S, Bressanelli S, Rey FA, Gaudin Y. Crystal structure of the low-pH form of the vesicular stomatitis virus glycoprotein G. Science 2006; 313(5784):187–191.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2006

Authors and Affiliations

  1. 1.Department of Microbiology and ImmunologyCornell UniversityIthacaUSA

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