Reovirus Receptors, Cell Entry, and Proapoptotic Signaling

  • Pranav Danthi
  • Geoffrey H. Holm
  • Thilo Stehle
  • Terence S. DermodyEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 790)


Mammalian orthoreoviruses (reoviruses) are members of the Reoviridae. Reoviruses contain 10 double-stranded (ds) RNA gene segments enclosed in two concentric protein shells, called outer capsid and core. These viruses serve as a versatile experimental system for studies of viral replication events at the virus-cell interface, including engagement of cell-surface receptors, internalization and disassembly, and activation of the innate immune response, including NF-κB-dependent cellular signaling pathways. Reoviruses also provide a model system for studies of virus-induced apoptosis and organ-specific disease in vivo.

Reoviruses attach to host cells via the filamentous attachment protein, σ1. The σ1 protein of all reovirus serotypes engages junctional adhesion molecule-A (JAM-A), an integral component of intercellular tight junctions. The σ1 protein also binds to cell-surface carbohydrate, with the type of carbohydrate bound varying by serotype. Following attachment to JAM-A and carbohydrate, reovirus internalization is mediated by β1 integrins, most likely via clathrin-dependent endocytosis. In the endocytic compartment, reovirus outer-capsid protein σ3 is removed by acid-dependent cysteine proteases in most cell types. Removal of σ3 results in the exposure of a hydrophobic conformer of the viral membrane-penetration protein, μ1, which pierces the endosomal membrane and delivers transcriptionally active reovirus core particles into the cytoplasm.

Reoviruses induce apoptosis in both cultured cells and infected mice. Perturbation of reovirus disassembly using inhibitors of endosomal acidification or protease activity abrogates apoptosis. The μ1-encoding M2 gene is genetically linked to strain-specific differences in apoptosis-inducing capacity, suggesting a function for μ1 in induction of death signaling. Reovirus disassembly leads to activation of transcription factor NF-κB, which modulates apoptotic signaling in numerous types of cells. Inhibition of NF-κB nuclear translocation using either pharmacologic agents or expression of transdominant forms of IκB blocks reovirus-induced apoptosis, suggesting an essential role for NF-κB activation in the death response. Multiple effector pathway s downstream of NF-κB-directed gene expression execute reovirus-induced cell death. This chapter will focus on the mechanisms by which reovirus attachment and disassembly activate NF-κB and stimulate the cellular proapoptotic machinery.


Sialic Acid PROAPOPTOTIC Signaling Reovirus Infection Mammalian Reovirus Reovirus Strain 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Dermody TS, Parker JS, Sherry B. Orthoreoviruses. In: Knipe DM, Howley PM, eds. Fields Virology. Sixth Edition. Philadelphia: Lippincott Williams & Wilkins, In press.Google Scholar
  2. 2.
    Virgin HW, Tyler KL, Dermody TS. Reovirus. In: Nathanson N, ed. Viral Pathogenesis. New York: Lippincott-Raven, 1997:669–699.Google Scholar
  3. 3.
    Duncan R, Horne D, Cashdollar LW et al. Identification of conserved domains in the cell attachment proteins of the three serotypes of reovirus. Virology 1990; 174:399–409.PubMedGoogle Scholar
  4. 4.
    Nibert ML, Dermody TS, Fields BN. Structure of the reovirus cell-attachment protein: A model for the domain organization of σ1. J Virol 1990; 64:2976–2989.PubMedGoogle Scholar
  5. 5.
    Tyler KL, McPhee DA, Fields BN. Distinct pathways of viral spread in the host determined by reovirus S1 gene segment. Science 1986; 233:770–774.PubMedGoogle Scholar
  6. 6.
    Weiner HL, Powers ML, Fields BN. Absolute linkage of virulence and central nervous system tropism of reoviruses to viral hemagglutinin. J Infect Dis 1980; 141:609–616.PubMedGoogle Scholar
  7. 7.
    Weiner HL, Drayna D, Averill Jr DR et al. Molecular basis of reovirus virulence: Role of the S1 gene. Proc Natl Acad Sci USA 1977; 74:5744-5748.Google Scholar
  8. 8.
    Morrison LA, Sidman RL, Fields BN. Direct spread of reovirus from the intestinal lumen to the central nervous system through vagal autonomic nerve fibers. Proc Natl Acad Sci USA 1991; 88:3852–3856.PubMedGoogle Scholar
  9. 9.
    Tardieu M, Powers ML, Weiner HL. Age-dependent susceptibility to reovirus type 3 encephalitis: Role of viral and host factors. Ann Neurol 1983; 13:602–607.PubMedGoogle Scholar
  10. 10.
    Dichter MA, Weiner HL. Infection of neuronal cell cultures with reovirus mimics in vitro patterns of neurotropism. Ann Neurol 1984; 16:603–610.PubMedGoogle Scholar
  11. 11.
    Weiner HL, Ault KA, Fields BN. Interaction of reovirus with cell surface receptors. I. Murine and human lymphocytes have a receptor for the hemagglutinin of reovirus type 3. J Immunol 1980; 124:2143–2148.PubMedGoogle Scholar
  12. 12.
    Lee PW, Hayes EC, Joklik WK. Protein σ1 is thereovirus cell attachment protein. Virology 1981; 108:156–163.PubMedGoogle Scholar
  13. 13.
    Furlong DB, Nibert ML, Fields BN. Sigma 1 protein of mammalian reoviruses extends from the surfaces of viral particles. J Virol 1988; 62:246–256.PubMedGoogle Scholar
  14. 14.
    Fraser RDB, Furlong DB, Trus BL et al. Molecular structure of the cell-attachment protein of reovirus: Correlation of computer-processed electron micrographs with sequence-based predictions. J Virol 1990; 64:2990–3000.PubMedGoogle Scholar
  15. 15.
    Gentsch JR, Pacitti AF. Effect of neuraminidase treatment of cells and effect of soluble glycoproteins on type 3 reovirus attachment to murine L cells. J Virol 1985; 56:356–364.PubMedGoogle Scholar
  16. 16.
    Paul RW, Choi AH, Lee PWK. The α-anomeric form of sialic acid is the minimal receptor determinant recognized by reovirus. Virology 1989; 172:382–385.PubMedGoogle Scholar
  17. 17.
    Dermody TS, Nibert ML, Bassel-Duby R et al. Sequence diversity in S1 genes and S1 translation products of 11 serotype 3 reovirus strains. J Virol 1990; 64:4842–4850.PubMedGoogle Scholar
  18. 18.
    Chappell JD, Gunn VL, Wetzel JD et al. Mutations in type 3 reovirus that determine binding to sialic acid are contained in the fibrous tail domain of viral attachment protein sigmal. J Virol 1997; 71:1834–1841.PubMedGoogle Scholar
  19. 19.
    Chappell JD, Duong JL, Wright BW et al. Identification of carbohydrate-binding domains in the attachment proteins of type 1 and type 3 reoviruses. J Virol 2000; 74:8472–8479.PubMedGoogle Scholar
  20. 20.
    Barton ES, Forrest JC, Connolly JL et al. Junction adhesion molecule is a receptor for reovirus. Cell 2001; 104:441–451.PubMedGoogle Scholar
  21. 21.
    Martin-Padura I, Lostaglio S, Schneemann M et al. Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol 1998; 142:117–127.PubMedGoogle Scholar
  22. 22.
    Williams LA, Martin-Padura I, Dejana E et al. Identification and characterisation of human junctional adhesion molecule (JAM). Mol Immunol 1999; 36:1175–1188.PubMedGoogle Scholar
  23. 23.
    Liu Y, Nusrat A, Schnell FJ et al. Human junction adhesion molecule regulates tight junction resealing in epithelia. J Cell Sci 2000; 113:2363–2374.PubMedGoogle Scholar
  24. 24.
    Dryden KA, Wang G, Yeager M et al. Early steps in reovirus infection are associated with dramatic changes in supramolecular structure and protein conformation: Analysis of virions and subviral particles by cryoelectron microscopy and image reconstruction. J Cell Biol 1993; 122:1023–1041.PubMedGoogle Scholar
  25. 25.
    Chappell JD, Prota A, Dermody TS et al. Crystal structure of reovirus attachment protein σ1 reveals evolutionary relationship to adenovirus fiber. EMBO J 2002; 21:1–11.PubMedGoogle Scholar
  26. 26.
    Reiter DM, Frierson JM, Halvorson EE et al. Crystal structure of reovirus attachment protein σ1 in complex with sialylated oligosaccharides. PLoS Pathog 2011; 7:e1002166.PubMedGoogle Scholar
  27. 27.
    van Raaij MJ, Mitraki A, Lavigne G et al. A triple β-spiral in the adenovirus fibre shaft reveals a new structural motif for a fibrous protein. Nature 1999; 401:935–938.PubMedGoogle Scholar
  28. 28.
    Guardado CP, Fox GC, Hermo Parrado XL et al. Structure of the carboxy-terminal receptor-binding domain of avian reovirus fibre sigmaC. J Mol Biol 2005; 354:137–149.Google Scholar
  29. 29.
    Prota AE, Campbell JA, Schelling P et al. Crystal structure of human junctional adhesion molecule 1: Implications for reovirus binding. Proc Natl Acad Sci USA 2003; 100:5366–5371.PubMedGoogle Scholar
  30. 30.
    Stehle T, Dermody TS. Structural similarities in the cellular receptors used by adenovirus and reovirus. Viral Immunol 2004; 17:129–143.PubMedGoogle Scholar
  31. 31.
    Forrest JC, Campbell JA, Schelling P et al. Structure-function analysis of reovirus binding to junctional adhesion molecule 1. Implications for the mechanism of reovirus attachment. J Biol Chem 2003; 278:48434–48444.PubMedGoogle Scholar
  32. 32.
    Kirchner E, Guglielmi KM, Strauss H et al. Structure of reovirus al in complex with its receptor junctional adhesion molecule-A. PLoS Pathog 2008; 4:e1000235.PubMedGoogle Scholar
  33. 33.
    Bewley MC, Springer K, Zhang YB et al. Structural analysis of the mechanism of adenovirus binding to its human cellular receptor, CAR. Science 1999; 286:1579–1583.PubMedGoogle Scholar
  34. 34.
    van Raaij MJ, Chouin E, van der Zandt H et al. Dimeric structure of the coxsackievirus and adenovirus receptor D1 domain at 1.7 A resolution. Structure 2000; 8:1147–1155.PubMedGoogle Scholar
  35. 35.
    Spear PG. Viral interactions with receptors in cell junctions and effects on junctional stability. Dev Cell 2002; 3:462–464.PubMedGoogle Scholar
  36. 36.
    Compton T. Receptors and immune sensors: The complex entry path of human cytomegalovirus. Trends Cell Biol 2004; 14:5–8.PubMedGoogle Scholar
  37. 37.
    Ugolini S, Mondor I, Sattentau QJ. HIV-1 attachment: Another look. Trends Microbiol 1999; 7:144–149.PubMedGoogle Scholar
  38. 38.
    Berger EA, Murphy PM, Farber JM. Chemokine receptors as HIV-1 coreceptors: Roles in viral entry, tropism, and disease. Annu Rev Immunol 1999; 17:657–700.PubMedGoogle Scholar
  39. 39.
    Barton ES, Connolly JL, Forrest JC et al. Utilization of sialic acid as a coreceptor enhances reovirus attachment by multistep adhesion strengthening. J Biol Chem 2001; 276:2200–2211.PubMedGoogle Scholar
  40. 40.
    Maginnis MS, Forrest JC, Kopecky-Bromberg SA et al. β1 integrin mediates internalization of mammalian reovirus. J Virol 2006; 80:2760–2770.PubMedGoogle Scholar
  41. 41.
    Breun LA, Broering TJ, McCutcheon AM et al. Mammalian reovirus L2 gene and λ2 core spike protein sequences and whole-genome comparisons of reoviruses type 1 Lang, type 2 Jones, and type 3 Dearing. Virology 2001; 287:333–348.PubMedGoogle Scholar
  42. 42.
    Hynes RO. Integrins: Versatility, modulation, and signaling in cell adhesion. Cell 1992; 69:11–25.PubMedGoogle Scholar
  43. 43.
    Hynes R. Integrins: Bidirectional, allosteric signaling machines. Cell 2002; 110:673–687.PubMedGoogle Scholar
  44. 44.
    Maginnis MS, Mainou BA, Derdowski AM et al. NPXY motifs in the β1 integrin cytoplasmic tail are required for functional reovirus entry. J Virol 2008; 82:3181–3191.PubMedGoogle Scholar
  45. 45.
    Sturzenbecker LJ, Nibert ML, Furlong DB et al. Intracellular digestion of reovirus particles requires a low pH and is an essential step in the viral infectious cycle. J Virol 1987; 61:2351–2361.PubMedGoogle Scholar
  46. 46.
    Borsa J, Morash BD, Sargent MD et al. Two modes of entry of reovirus particles into L cells. J Gen Virol 1979; 45:161–170.PubMedGoogle Scholar
  47. 47.
    Borsa J, Sargent MD, Lievaart PA et al. Reovirus: Evidence for a second step in the intracellular uncoating and transcriptase activation process. Virology 1981; 111:191–200.PubMedGoogle Scholar
  48. 48.
    Rubin DH, Weiner DB, Dworkin C et al. Receptor utilization by reovirus type 3: Distinct binding sites on thymoma and fibroblast cell lines result in differential compartmentalization of virions. Microb Pathog 1992; 12:351–365.PubMedGoogle Scholar
  49. 49.
    Ehrlich M, Boll W, Van Oijen A et al. Endocytosis by random initiation and stabilization of clathrin-coated pits. Cell 2004; 118:591–605.PubMedGoogle Scholar
  50. 50.
    Georgi A, Mottola-Hartshorn C, Warner A et al. Detection of individual fluorescently labeled reovirions in living cells. Proc Natl Acad Sci USA 1990; 87:6579–6583.PubMedGoogle Scholar
  51. 51.
    Mainou BA, Dermody TS. Transport to late endosomes is required for efficient reovirus infection. J Virol 2012; 86:8346–8358.PubMedGoogle Scholar
  52. 52.
    Canning WM, Fields BN. Ammonium chloride prevents lytic growth of reovirus and helps to establish persistent infection in mouse L cells. Science 1983; 219:987–988.PubMedGoogle Scholar
  53. 53.
    Maratos-Flier E, Goodman MJ, Murray AH et al. Ammonium inhibits processing and cytotoxicity of reovirus, a nonenveloped virus. J Clin Invest 1986; 78:617–625.Google Scholar
  54. 54.
    Maxfield FR. Weak bases and ionophores rapidly and reversibly raise the pH in endocytic vesicles in cultured mouse fibroblasts. J Cell Biol 1982; 95:676–681.PubMedGoogle Scholar
  55. 55.
    Ohkuma S, Poole B. Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proc Natl Acad Sci USA 1978; 75:3327–3331.PubMedGoogle Scholar
  56. 56.
    Barrett AJ, Kembhavi AA, Brown MA et al. L-trans-Epoxysuccinyl-leucylamido(4-guanidino)butane (E-64) and its analogues as inhibitors of cysteine proteinases including cathepsins B, H and L. Biochem J 1982; 201:189–198.PubMedGoogle Scholar
  57. 57.
    Baer GS, Dermody TS. Mutations in reovirus outer-capsid protein σ3 selected during persistent infections of L cells confer resistance to protease inhibitor E64. J Virol 1997; 71:4921–4928.PubMedGoogle Scholar
  58. 58.
    Chandran K, Nibert ML. Protease cleavage of reovirus capsid protein μ1/μ1C is blocked by alkyl sulfate detergents, yielding a new type of infectious subvirion particle. J Virol 1998; 762:467–475.Google Scholar
  59. 59.
    Ebert DH, Wetzel JD, Brumbaugh DE et al. Adaptation of reovirus to growth in the presence of protease inhibitor E64 segregates with a mutation in the carboxy terminus of viral outer-capsid protein σ3. J Virol 2001; 75:3197–3206.PubMedGoogle Scholar
  60. 60.
    Jané-Valbuena J, Nibert ML, Spencer SM et al. Reovirus virion-like particles obtained by recoating infectious subvirion particles with baculovirus-expressed σ3 protein: An approach for analyzing σ3 functions during virus entry. J Virol 1999; 73:2963–2973.PubMedGoogle Scholar
  61. 61.
    Bond JS, Butler PE. Intracellular proteases. Annu Rev Biochem 1987; 56:333–364.PubMedGoogle Scholar
  62. 62.
    Gal S, Gottesman MM. The major excreted protein (MEP) of transformed mouse cells and cathepsin L have similar protease specificity. Biochem Biophys Res Commun 1986; 139:156–162.PubMedGoogle Scholar
  63. 63.
    Gottesman MM, Sobel ME. Tumor promoters and Kirsten sarcoma virus increase synthesis of a secreted glycoprotein by regulating levels of translatable mRNA. Cell 1980; 19:449–455.PubMedGoogle Scholar
  64. 64.
    Kirschke H, Langner J, Wiederanders B et al. Cathepsin L. A new proteinase from rat-liver lysosomes. Eur J Biochem 1977; 74:293–301.PubMedGoogle Scholar
  65. 65.
    Ebert DH, Deussing J, Peters C et al. Cathepsin L and cathepsin B mediate reovirus disassembly in murine fibroblast cells. J Biol Chem 2002; 277:24609–24617.PubMedGoogle Scholar
  66. 66.
    Riese RJ, Wolf PR, Bromme D et al. Essential role for cathepsin S in MHC class II-associated invariant chain processing and peptide loading. Immunity 1996; 4:357–366.PubMedGoogle Scholar
  67. 67.
    Golden JW, Bahe JA, Lucas WT et al. Cathepsin S supports acid-independent infection by some reoviruses. J Biol Chem 2004; 279:8547–8557.PubMedGoogle Scholar
  68. 68.
    Johnson EM, Wetzel JD, Doyle JD et al. Genetic and pharmacologic alteration of cathepsin expression influences reovirus pathogenesis. J Virol 2009; 83:9630–9640.PubMedGoogle Scholar
  69. 69.
    Nygaard RM, Golden JW, Schiff LA. Impact of host proteases on reovirus infection in the respiratory tract. J Virol 2012; 86:1238–1243.PubMedGoogle Scholar
  70. 70.
    Tosteson MT, Nibert ML, Fields BN. Ion channels induced in lipid bilayers by subvirion particles of the nonenveloped mammalian reoviruses. Proc Natl Acad Sci USA 1993; 90:10549–10552.PubMedGoogle Scholar
  71. 71.
    Lucia-Jandris P, Hooper JW, Fields BN. Reovirus M2 gene is associated with chromium release from mouse L cells. J Virol 1993; 67:5339–5345.PubMedGoogle Scholar
  72. 72.
    Hooper JW, Fields BN. Role of the μ1 protein in reovirus stability and capacity to cause chromium release from host cells. J Virol 1996; 70:459–467.PubMedGoogle Scholar
  73. 73.
    Olland AM, Jané-Valbuena J, Schiff LA et al. Structure of the reovirus outer capsid and dsRNA-binding protein σ3 at 1.8 Å resolution. EMBO J 2001; 20:979–989.PubMedGoogle Scholar
  74. 74.
    Nason E, Wetzel J, Mukherjee S et al. A monoclonal antibody specific for reovirus outer-capsid protein σ3 inhibits σ1-mediated hemagglutination by steric hindrance. J Virol 2001; 75:6625–6634.PubMedGoogle Scholar
  75. 75.
    Wetzel JD, Wilson GJ, Baer GS et al. Reovirus variants selected duringpersistent infections of L cells contain mutations in the viral S1 and S4 genes and are altered in viral disassembly. J Virol 1997; 71:1362–1369.PubMedGoogle Scholar
  76. 76.
    Clark KM, Wetzel JD, Bayley J et al. Reovirus variants selected for resistance to ammonium chloride have mutations in viral outer-capsid protein σ3. J Virol 2006; 80:671–681.PubMedGoogle Scholar
  77. 77.
    Doyle JD, Danthi P, Kendall EA et al. Molecular determinants of proteolytic disassembly of the reovirus outer capsid. J Biol Chem2012; 287:8029–8038.PubMedGoogle Scholar
  78. 78.
    Nibert ML, Schiff LA, Fields BN. Mammalian reoviruses contain a myristoylated structural protein. J Virol 1991; 65:1960–1967.PubMedGoogle Scholar
  79. 79.
    Smith RE, Zweerink HJ, Joklik WK. Polypeptide components of virions, top component and cores of reovirus type 3. Virology 1969; 39:791–810.PubMedGoogle Scholar
  80. 80.
    Odegard AL, Chandran K, Zhang X et al. Putative autocleavage of outer capsid protein μ1, allowing release of myristoylated peptide μ1N during particle uncoating, is critical for cell entry by reovirus. J Virol 2004; 78:8732–8745.PubMedGoogle Scholar
  81. 81.
    Nibert ML, Odegard AL, Agosto MA et al. Putative autocleavage of reovirus μ1 protein in concert with outer-capsid disassembly and activation for membrane permeabilization. J Mol Biol 2005; 345:461–474.PubMedGoogle Scholar
  82. 82.
    Bodkin DK, Nibert ML, Fields BN. Proteolytic digestion of reovirus in the intestinal lumens of neonatal mice. J Virol 1989; 63:4676–4681.PubMedGoogle Scholar
  83. 83.
    Nibert ML, Fields BN. A carboxy-terminal fragment of protein μ1/μ1C is present in infectious subvirion particles of mammalian reoviruses and is proposedto have arole in penetration. J Virol 1992; 66:6408–6418.PubMedGoogle Scholar
  84. 84.
    Chandran K, Walker SB, Chen Y et al. In vitro recoating of reovirus cores with baculovirus-expressed outer-capsid proteins μ1 and μ3. J Virol 1999; 73:3941–3950.PubMedGoogle Scholar
  85. 85.
    Chandran K, Parker JS, Ehrlich M et al. The deltaregion of outer-capsid protein μ1 undergoes conformational change and release from reovirus particles during cell entry. J Virol 2003; 77:13361–13375.PubMedGoogle Scholar
  86. 86.
    Ivanovic T, Agosto MA, Zhang L et al. Peptides released from reovirus outer capsid form membrane pores that recruit virus particles. EMBO J 2008; 27:1289–1298.PubMedGoogle Scholar
  87. 87.
    Chandran K, Farsetta DL, Nibert ML. Strategy for nonenveloped virus entry: A hydrophobic conformer of the reovirus membrane penetration protein μ1 mediates membrane disruption. J Virol 2002; 76:9920–9933.PubMedGoogle Scholar
  88. 88.
    Liemann S, Chandran K, Baker TS et al. Structure of the reovirus membrane-penetration protein, μ1, in a complex with its protector protein, σ3. Cell 2002; 108:283–295.PubMedGoogle Scholar
  89. 89.
    Tyler KL, Squier MK, Rodgers SE et al. Differences in the capacity of reovirus strains to induce apoptosis are determined by the viral attachment protein μ1. J Virol 1995; 69:6972–6979.PubMedGoogle Scholar
  90. 90.
    Rodgers SE, Barton ES, Oberhaus SM et al. Reovirus-induced apoptosis of MDCK cells is not linked to viral yield and is blocked by Bcl-2. J Virol 1997; 71:2540–2546.PubMedGoogle Scholar
  91. 91.
    Connolly JL, Rodgers SE, Clarke P et al. Reovirus-induced apoptosis requires activation of transcription factor NF-κB. J Virol 2000; 74:2981–2989.PubMedGoogle Scholar
  92. 92.
    Oberhaus SM, Smith RL, Clayton GH et al. Reovirus infection and tissue injury in the mouse central nervous system are associated with apoptosis. J Virol 1997; 71:2100–2106.PubMedGoogle Scholar
  93. 93.
    O’Donnell SM, Hansberger MW, Connolly JL et al. Organ-specific roles for transcription factor NF-κB in reovirus-induced apoptosis and disease. J Clin Invest 2005; 115:2341–2350.Google Scholar
  94. 94.
    DeBiasi R, Edelstein C, Sherry B et al. Calpain inhibition protects against virus-induced apoptotic myocardial injury. J Virol 2001; 75:351–361.PubMedGoogle Scholar
  95. 95.
    DeBiasi RL, Robinson BA, Sherry B et al. Caspase inhibition protects against reovirus-induced myocardial injury in vitro and in vivo. J Virol 2004; 78:11040–11050.PubMedGoogle Scholar
  96. 96.
    Connolly JL, Barton ES, Dermody TS. Reovirus binding to cell surface sialic acid potentiates virus-induced apoptosis. J Virol 2001; 75:4029–4039.PubMedGoogle Scholar
  97. 97.
    Tyler KL, Squier MKT, Brown AL et al. Linkage between reovirus-induced apoptosis and inhibition of cellular DNA synthesis: Role of the S1 and M2 genes. J Virol 1996; 70:7984–7991.PubMedGoogle Scholar
  98. 98.
    Ernst H, Shatkin AJ. Reovirus hemagglutinin mRNA codes for two polypeptides in overlapping reading frames. Proc Natl Acad Sci USA 1985; 82:48–52.PubMedGoogle Scholar
  99. 99.
    Jacobs BL, Atwater JA, Munemitsu SM et al. Biosynthesis of reovirus-specified polypeptides. The S1 mRNA synthesized in vivo is structurally and functionally indistinguishable from in vitro-synthesized S1 mRNA and encodes two polypeptides, σ1a and σ1bNS. Virology 1985; 147:9–18.PubMedGoogle Scholar
  100. 100.
    Sarkar G, Pelletier J, Bassel-Duby R et al. Identification of a new polypeptide coded by reovirus gene S1. J Virol 1985; 54:720–725.PubMedGoogle Scholar
  101. 101.
    Rodgers SE, Connolly JL, Chappell JD et al. Reovirus growth in cell culture does not require the full complement of viral proteins: Identification of a σ1s-null mutant. J Virol 1998; 72:8597–8604.PubMedGoogle Scholar
  102. 102.
    Hoyt CC, Richardson-Burns SM, Goody RJ et al. Nonstructural protein sigmals is a determinant of reovirus virulence and influences the kinetics and severity of apoptosis induction in the heart and central nervous system. J Virol 2005; 79:2743–2753.PubMedGoogle Scholar
  103. 103.
    Boehme KW, Guglielmi KM, Dermody TS. Reovirus nonstructural protein σ1s is requiredfor establishment of viremia and systemic dissemination. Proc Natl Acad Sci USA 2009; 106:19986–19991.PubMedGoogle Scholar
  104. 104.
    Boehme KW, Frierson JM, Konopka JL et al. The reovirus als protein is a determinant of hematogenous but not neural viral dissemination in mice. J Virol 2011; 85:11781–11790.PubMedGoogle Scholar
  105. 105.
    Campbell JA, Shelling P, Wetzel JD et al. Junctional adhesion molecule-A serves as areceptor for prototype and field-isolate strains of mammalian reovirus. J Virol 2005; 79:7967–7978.PubMedGoogle Scholar
  106. 106.
    Dermody TS, Nibert ML, Bassel-Duby R et al. A sigma 1 region important for hemagglutination by serotype 3 reovirus strains. J Virol 1990; 64:5173–5176.PubMedGoogle Scholar
  107. 107.
    Connolly JL, Dermody TS. Virion disassembly is required for apoptosis induced by reovirus. J Virol 2002; 76:1632–1641.PubMedGoogle Scholar
  108. 108.
    Danthi P, Hansberger MW, Campbell JA et al. JAM-A-independent, antibody-mediated uptake of reovirus into cells leads to apoptosis. J Virol 2006; 80:1261–1270.PubMedGoogle Scholar
  109. 109.
    Hazelton PR, Coombs KM. The reovirus mutanttsA279 has temperature-sensitive lesions in the M2 and L2 genes: The M2 gene is associated with decreased viral protein production and blockade in transmembrane transport. Virology 1995; 207:46–58.PubMedGoogle Scholar
  110. 110.
    Danthi P, Kobayashi T, Holm GH et al. Reovirus apoptosis and virulence are regulated by host cell membrane penetration efficiency. J Virol 2008; 82:161–172.PubMedGoogle Scholar
  111. 111.
    Danthi P, Kobayashi T, Coffey CM et al. Independent regulation of reovirus membrane penetration and apoptosis by the μ1 f domain. PLoS Pathog 2008; 4:e1000248.PubMedGoogle Scholar
  112. 112.
    Clarke P, Meintzer SM, Moffitt LA et al. Two distinct phases of virus-induced nuclear factor kappa B regulation enhance tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in virus-infected cells. J Biol Chem 2003; 278:18092–18100.PubMedGoogle Scholar
  113. 113.
    Beg A, Finco T, Nantermet P et al. Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of IκBα: A mechanism for NF-κB activation. Mol Cell Biol 1993; 13:3301–3310.PubMedGoogle Scholar
  114. 114.
    Cahir McFarland ED, Izumi KM, Mosialos G. Epstein-barr virus transformation: Involvement of latent membrane protein 1-mediated activation of NF-kappaB. Oncogene 1999; 18:6959–6964.PubMedGoogle Scholar
  115. 115.
    McKinsey TA, Brockman JA, Scherer DC et al. Inactivation of IkappaBbeta by the tax protein of human T-cell leukemia virus type 1: A potential mechanism for constitutive induction of NF-kappaB. Mol Cell Biol 1996; 16:2083–2090.PubMedGoogle Scholar
  116. 116.
    Abbadie C, Kabrun N, Bouali F et al. High levels of c-rel expression are associated with programmed cell death in the developing avian embryo and in bone marrow cells in vitro. Cell 1993; 75:899–912.PubMedGoogle Scholar
  117. 117.
    Grimm S, Bauer MKA, Baeuerle PA et al. Bcl-2 down-regulates the activity of transcription factor NF-κB induced upon apoptosis. J Cell Biol 1996; 134:13–23.PubMedGoogle Scholar
  118. 118.
    Jung M, Zhang Y, Lee S et al. Correction of radiation sensitivity in ataxiatelangiectasia cells by atruncated IκB-α. Science 1995; 268:1619–1621.PubMedGoogle Scholar
  119. 119.
    Beg A, Baltimore D. An essential role for NF-κB in preventing TNF-α-induced cell death. Science 1996; 274:782–784.PubMedGoogle Scholar
  120. 120.
    Liu ZG, Hsu H, Goeddel D et al. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-κB activation prevents cell death. Cell 1996; 87:565–576.PubMedGoogle Scholar
  121. 121.
    Van Antwerp D, Martin S, Kafri T et al. Suppression of TNF-α-induced apoptosis by NF-κB. Science 1996; 274:787–789.PubMedGoogle Scholar
  122. 122.
    Clarke P, Meintzer SM, Widmann C et al. Reovirus infection activates JNK and the JNK-dependent transcription factor c-Jun. J Virol 2001; 75:11275–11283.PubMedGoogle Scholar
  123. 123.
    Clarke P, Meintzer SM, Wang Y et al. JNK regulates the release of proapoptotic mitochondrial factors in reovirus-infected cells. J Virol2004; 78:13132–13138.PubMedGoogle Scholar
  124. 124.
    Norman KL, Hirasawa K, Yang AD et al. Reovirus oncolysis: The Ras/RalGEF/p38 pathway dictates host cell permissiveness to reovirus infection. Proc Natl Acad Sci USA 2004; 101:11099–11104.PubMedGoogle Scholar
  125. 125.
    Meusel TR, Imani F. Viral induction of inflammatory cytokines in human epithelial cells follows a p38 mitogen-activated protein kinase-dependent but NF-kappa B-independent pathway. J Immunol 2003; 171:3768–3774.PubMedGoogle Scholar
  126. 126.
    Duncan MR, Stanish SM, Cox DC. Differential sensitivity of normal and transformed human cells to reovirus infection. J Virol 1978; 28:444–449.PubMedGoogle Scholar
  127. 127.
    Strong JE, Coffey MC, Tang D et al. The molecular basis of viral oncolysis: Usurpation of the Ras signaling pathway by reovirus. EMBO J 1998; 17:3351–3362.PubMedGoogle Scholar
  128. 128.
    Strong JE, Lee PW. The v-erbB oncogene confers enhanced cellular susceptibility to reovirus infection. J Virol 1996; 70:612–616.PubMedGoogle Scholar
  129. 129.
    Coffey MC, Strong JE, Forsyth PA et al. Reovirus therapy of tumors with activated Ras pathway. Science 1998; 282:1332–1334.PubMedGoogle Scholar
  130. 130.
    Mundschau LJ, Faller DV. Oncogenic ras induces an inhibitor of double-stranded RNA-dependent eukaryotic initiation factor 2 alpha-kinase activation. J Biol Chem 1992; 267:23092–23098.PubMedGoogle Scholar
  131. 131.
    Williams ME, Cox DC, Stevenson JR. Rejection of reovirus-treated L1210 leukemia cells by mice. Cancer Immunol Immunother 1986; 23:87–92.PubMedGoogle Scholar
  132. 132.
    Wilcox ME, Yang W, Senger D et al. Reovirus as an oncolytic agent against experimental human malignant gliomas. J Natl Cancer Inst 2001; 93:903–912.PubMedGoogle Scholar
  133. 133.
    Norman KL, Coffey MC, Hirasawa K et al. Reovirus oncolysis of human breast cancer. Hum Gene Ther 2002; 13:641–652.PubMedGoogle Scholar
  134. 134.
    Holm GH, Zurney J, Tumilasci V et al. Retinoic acid-inducible gene-I and interferon-β promoter stimulator-1 augment proapoptotic responses following mammalian reovirus infection via interferon regulatoryfactor-3. J Biol Chem 2007; 282:21953–21961.PubMedGoogle Scholar
  135. 135.
    Kato H, Takeuchi O, Mikamo-Satoh E et al. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med 2008; 205:1601–1610PubMedGoogle Scholar
  136. 136.
    Loo YM, Fornek J, Crochet N et al. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J Virol 2008; 82:335–345.PubMedGoogle Scholar
  137. 137.
    Knowlton JJ, Dermody TS, Holm GH. Apoptosis induced by mammalian reovirus is interferon-β-independent and enhanced by IRF-3-and NF-κB-dependent expression of Noxa. J. Virol 2012; 86:1650–1660.PubMedGoogle Scholar
  138. 138.
    DeBiasi RL, Clarke P, Meintzer SM et al. Reovirus-induced alteration in expression of apoptosis and DNA repair genes with potential roles in viral pathogenesis. J Virol 2003; 77:8934–8947.PubMedGoogle Scholar
  139. 139.
    O’Donnell SM, Holm GH, Pierce JM et al. Identification of an NF-κB-dependent gene network in cells infected by mammalian reovirus. J Virol 2006; 80:1077–1086.Google Scholar
  140. 140.
    Smith JA, Schmechel SC, Raghavan A et al. Reovirus induces and benefits from an integrated cellular stress response. J Virol 2006; 80:2019–2033.PubMedGoogle Scholar
  141. 141.
    Webster GA, Perkins ND. Transcriptional cross talk between NF-κ B and p53. Mol Cell Biol 1999; 19:3485–3495.PubMedGoogle Scholar
  142. 142.
    Dreyfus D, Nagasawa M, Gelfand E et al. Modulation of p53 activity by IκBα: Evidence suggesting a common phylogeny between NF-κB and p53 transcription factors. BMC Immunol 2005; 6:12.PubMedGoogle Scholar
  143. 143.
    Li Z, Niu J, Uwagawa T et al. Function of polo-like kinase 3 in NF-κB-mediated proapoptotic response. J Biol Chem 2005; 280:16843–16850.PubMedGoogle Scholar
  144. 144.
    Huang YH, Wu JY, Zhang Y et al. Synergistic and opposing regulation of the stress-responsive gene IEX-1 by p53, c-Myc, and multiple NF-kappaB/rel complexes. Oncogene 2002; 21:6819–6828.PubMedGoogle Scholar
  145. 145.
    Liu CY, Schröder M, Kaufman RJ. Ligand-independent dimerization activates the stress response kinases IRE1 and PERK in the lumen of the endoplasmic reticulum. J Biol Chem 2000; 275:24881–24885.PubMedGoogle Scholar
  146. 146.
    Harding HP, Zhang Y, Bertolotti A et al. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 2000; 5:897–904.PubMedGoogle Scholar
  147. 147.
    Sen GC. Viruses and interferons. Annu Rev Microbiol 2001; 55:255–281.PubMedGoogle Scholar
  148. 148.
    Stark GR, Kerr IM, Williams BR et al. How cells respond to interferons. Annu Rev Biochem 1998; 67:227–264.PubMedGoogle Scholar
  149. 149.
    Kunzi MS, Pitha PM. Interferon targeted genes in host defense. Autoimmunity 2003; 36:457–461.PubMedGoogle Scholar
  150. 150.
    Tanaka N, Sato M, Lamphier MS et al. Type I interferons are essential mediators of apoptotic death in virally infected cells. Genes Cells 1998; 3:29–37.PubMedGoogle Scholar
  151. 151.
    Bingle CD, Craig RW, Swales BM et al. Exon skipping in Mcl-1 results in a Bcl-2 homology domain 3 only gene product that promotes cell death. J Biol Chem 2000; 275:22136–22146.PubMedGoogle Scholar
  152. 152.
    Gurumurthy S, Goswami A, Vasudevan KM et al. Phosphorylation of Par-4 by protein kinase A is critical for apoptosis. Mol Cell Biol 2005; 25:1146–1161.PubMedGoogle Scholar
  153. 153.
    Imazu T, Shimizu S, Tagami S et al. Bcl-2/E1B 19 kDa-interacting protein 3-like protein (Bnip3L) interacts with Bcl-2/Bcl-xL and induces apoptosis by altering mitochondrial membrane permeability. Oncogene 1999; 18:4523–4529.PubMedGoogle Scholar
  154. 154.
    Tan KO, Tan KML, Chan SL et al. MAP-1, a novel proapoptotic protein containing a BH3-like motif that associates with bax through its Bcl-2 homology domains. J Biol Chem 2001; 276:2802–2807.PubMedGoogle Scholar
  155. 155.
    Clarke P, Meintzer SM, Gibson S et al. Reovirus-induced apoptosis is mediated by TRAIL. J Virol 2000; 74:8135–8139.PubMedGoogle Scholar
  156. 156.
    Torii S, Egan DA, Evans RA et al. Human Daxx regulates Fas-induced apoptosis from nuclear PML oncogenic domains (PODs). EMBO J 1999; 18:6037–6049.PubMedGoogle Scholar
  157. 157.
    Takahashi Y, Lallemand-Breitenbach V, Zhu J et al. PML nuclear bodies and apoptosis. Oncogene 2004; 23:2819–2824.PubMedGoogle Scholar
  158. 158.
    Richardson-Burns SM, Kominsky DJ, Tyler KL. Reovirus-induced neuronal apoptosis is mediated by caspase 3 and is associated with the activation of death receptors. J Neurovirol 2002; 8:365–380.PubMedGoogle Scholar
  159. 159.
    Blatt NB, Glick GD. Signaling pathways and effector mechanisms preprogrammed cell death. Bioorg Med Chem 2001; 9:1371–1384.PubMedGoogle Scholar
  160. 160.
    Kominsky DJ, Bickel RJ, Tyler KL. Reovirus-induced apoptosis requires both death receptor-and mitochondrial-mediated caspase-dependent pathways of cell death. Cell Death Differ 2002; 9:926–933.PubMedGoogle Scholar
  161. 161.
    Wajant H, Johannes FJ, Haas E et al. Dominant-negative FADD inhibits TNFR60-, Fas/Apol-and TRAIL-R/Apo2-mediated cell death but not gene induction. Curr Biol 1998; 8:113–116.PubMedGoogle Scholar
  162. 162.
    Clarke P, Debiasi RL, Meintzer SM et al. Inhibition of NF-kappa B activity and cFLIP expression contribute to viral-induced apoptosis. Apoptosis 2005; 10:513–524.PubMedGoogle Scholar
  163. 163.
    Chawla-Sarkar M, Lindner DJ, Liu YF et al. Apoptosis and interferons: Role of interferon-stimulated genes as mediators of apoptosis. Apoptosis 2003; 8:237–249.PubMedGoogle Scholar
  164. 164.
    Shigeno M, Nakao K, Ichikawa T et al. Interferon-alphasensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-kappa B inactivation. Oncogene 2003; 22:1653–1662.PubMedGoogle Scholar
  165. 165.
    Li P, Nijhawan D, Budhardjo I et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997; 91:479–489.PubMedGoogle Scholar
  166. 166.
    Verhagen AM, Ekert PG, Pakusch M et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 2000; 102:43–53.PubMedGoogle Scholar
  167. 167.
    Du C, Fang M, Li Y et al. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000; 102:33–42.PubMedGoogle Scholar
  168. 168.
    Joza N, Susin SA, Daugas E et al. Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 2001; 410:549–554.PubMedGoogle Scholar
  169. 169.
    Li H, Zhu H, Xu CJ et al. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998; 94:491–501.PubMedGoogle Scholar
  170. 170.
    Kominsky DJ, Bickel RJ, Tyler KL. Reovirus-induced apoptosis requires mitochondrial release of Smac/DIABLO and involves reduction of cellular inhibitor of apoptosis protein levels. J Virol 2002; 76:11414–11424.PubMedGoogle Scholar
  171. 171.
    Danthi P, Pruijssers AJ, Berger AK et al. Bid regulates the pathogenesis of neurotropic reovirus. PLoS Pathog 2010; 6:e1000980.PubMedGoogle Scholar
  172. 172.
    Luo X, Budihardjo I, Zou H et al. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 1998; 94:481–490.PubMedGoogle Scholar
  173. 173.
    Richardson-Burns SM, Tyler KL. Regional differences in viral growth and central nervous system injury correlate with apoptosis. J Virol 2004; 78:5466–5475.PubMedGoogle Scholar
  174. 174.
    Richardson-Burns SM, Tyler KL. Minocycline delays disease onset and mortality in reovirus encephalitis. Exp Neurol 2005; 192:331–339.PubMedGoogle Scholar
  175. 175.
    Sherry B, Torres J, Blum MA. Reovirus induction of and sensitivity to beta interferon in cardiac myocyte cultures correlate with induction of myocarditis and are determined by viral core proteins. J Virol 1998; 72:1314–1323.PubMedGoogle Scholar
  176. 176.
    Azzam-Smoak K, Noah DL, Stewart MJ et al. Interferon regulatory factor-1, interferon-beta, and reovirus-induced myocarditis. Virology 2002; 298:20–29.PubMedGoogle Scholar
  177. 177.
    Stewart MJ, Blum MA, Sherry B. PKR’s protective role in viral myocarditis. Virology 2003; 314:92–100.PubMedGoogle Scholar
  178. 178.
    Noah DL, Blum MA, Sherry B. Interferon regulatory factor 3 is required for viral induction of beta interferon in primary cardiac myocyte cultures. J Virol 1999; 73:10208–10213.PubMedGoogle Scholar
  179. 179.
    Bazzoni G, Martinez-Estrada OM, Orsenigo F et al. Interaction of junctional adhesion molecule with the tight junction components ZO-1, cingulin, and occludin. J Biol Chem 2000; 275:20520–20526.PubMedGoogle Scholar
  180. 180.
    Ebnet K, Schulz CU, Meyer Zu Brickwedde MK et al. Junctional adhesion molecule interacts with the PDZ domain-containing proteins AF-6 and ZO-1. J Biol Chem 2000; 275:27979–27988.PubMedGoogle Scholar
  181. 181.
    Pfaff M, Liu S, Erle DJ et al. Integrin beta cytoplasmic domains differentially bind to cytoskeletal proteins. J Biol Chem 1998; 273:6104–6109.PubMedGoogle Scholar
  182. 182.
    Otey CA, Pavalko FM, Burridge K. An interaction between alpha-actinin and the beta 1 integrin subunit in vitro. J Cell Biol 1990; 111:721–729.PubMedGoogle Scholar
  183. 183.
    Schaller MD, Otey CA, Hildebrand JD et al. Focal adhesion kinase and paxillin bind to peptides mimicking beta integrin cytoplasmic domains. J Cell Biol 1995; 130:1181–1187.PubMedGoogle Scholar
  184. 184.
    Reszka AA, Hayashi Y, Horwitz AF. Identification of amino acid sequences in the integrinbeta 1 cytoplasmic domain implicated in cytoskeletal association. J Cell Biol 1992; 117:1321–1330.PubMedGoogle Scholar
  185. 185.
    Chen WJ, Goldstein JL, Brown MS. NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor. J Biol Chem 1990; 265:3116–3123.PubMedGoogle Scholar
  186. 186.
    Deiss LP, Galinka H, Berissi H et al. Cathepsin D protease mediates programmed cell death induced by interferon-gamma, Fas/APO-1 and TNF-alpha. EMBO J 1996; 15:3861–3870.PubMedGoogle Scholar
  187. 187.
    Guicciardi ME, Deussing J, Miyoshi H et al. Cathepsin B contributes to TNF-alpha-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c. J Clin Invest 2000; 106:1127–1137.PubMedGoogle Scholar
  188. 188.
    Roberg K. Relocalization of cathepsin D and cytochrome c early in apoptosis revealed by immunoelectron microscopy. Lab Invest 2001; 81:149–158.PubMedGoogle Scholar
  189. 189.
    Stoka V, Turk B, Schendel SL et al. Lysosomal protease pathways to apoptosis. Cleavage of bid, not pro-caspases, is the most likely route. J Biol Chem 2001; 276:3149–3157.PubMedGoogle Scholar
  190. 190.
    Coffey CM, Sheh A, Kim IS et al. Reovirus outer capsid protein μ1 induces apoptosis and associates with lipid droplets, endoplasmic reticulum, and mitochondria. J. Virol. 80:8422–38, 2006.Google Scholar
  191. 191.
    Kim JW, Lyi SM, Parrish CR, Parker JS. A proapoptotic peptide derived from reovirus outer capsid protein μ1 has membrane-destabilizing activity. J Virol 2011; 85:1507–16.PubMedGoogle Scholar
  192. 192.
    Wisniewski ML, Werner BG, Horn LG et al. Reovirus infection or ectopic expression of outer capsid protein μ1 induces apoptosis independently of the cellular proapoptotic proteins Bax and Bak. J Virol 2011; 85:296–304.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2013

Authors and Affiliations

  • Pranav Danthi
    • 1
  • Geoffrey H. Holm
    • 2
  • Thilo Stehle
    • 3
    • 4
  • Terence S. Dermody
    • 3
    • 5
    • 6
    Email author
  1. 1.Department of BiologyIndiana UniversityBloomingtonUSA
  2. 2.Department of BiologyColgate UniversityHamiltonUSA
  3. 3.Department of PediatricsVanderbilt University School of MedicineNashvilleUSA
  4. 4.Interfakultäres Institut für BiochemieEberhard-Karls UniversitätTübingenGermany
  5. 5.Lamb Center for Pediatric ResearchVanderbilt University School of MedicineNashvilleUSA
  6. 6.Department of Pathology, Microbiology and ImmunologyVanderbilt University School of MedicineNashvilleUSA

Personalised recommendations