Archives of Virology

, Volume 155, Issue 3, pp 305–313 | Cite as

Inhibition of protein deacetylation augments herpes simplex virus type 1-activated transcription of host fucosyltransferase genes associated with virus-induced sLex expression

  • Rickard Nordén
  • Kristina Nyström
  • Sigvard OlofssonEmail author
Original Article


Herpes simplex virus type 1 induces expression of the selectin ligand sialyl Lewis X in infected cells by activating transcription of three normally silent host glycosyltransferase genes, FUT3, FUT5, and FUT6, a process that is initiated by binding of viral RNA to cellular protein kinase R. We investigated the involvement of protein deacetylation and promoter methylation in viral activation of host FUT genes by analysing the effects of appropriate inhibitors on the transcription rates of the FUT genes in virus-infected cells. The histone deacetylase inhibitor trichostatin A augmented the viral activation of FUT transcription, whereas inhibition of DNA methylation did not affect transcription of these genes. The trichostatin A enhancement did not involve interference with expression of viral late genes or viral DNA replication. Thus, the virus-activated FUT genes are at least partially suppressed by deacetylation of histones or other regulatory proteins in uninfected HEL cells, whereas promoter methylation is a less important factor.


Gastric Cancer Cell Herpes Simplex Virus Type Immediate Early Zebularine Selectin Ligand 
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.



This work was supported by the Swedish Research Council (grant15283) and by grants from the LUA-ALF Foundation, Sahlgrenska University Hospital, Gothenburg. The authors acknowledge the Centre for Cellular Imaging at Gothenburg University for use of imaging equipment and for the support from the staff.


  1. 1.
    Anderson JD, Lowary PT, Widom J (2001) Effects of histone acetylation on the equilibrium accessibility of nucleosomal DNA target sites. J Mol Biol 307:977–985CrossRefPubMedGoogle Scholar
  2. 2.
    Bakand S, Winder C, Hayes A (2007) Comparative in vitro cytotoxicity assessment of selected gaseous compounds in human alveolar epithelial cells. Toxicol In Vitro 21:1341–1347CrossRefPubMedGoogle Scholar
  3. 3.
    Cao W, Bao C, Padalko E, Lowenstein CJ (2008) Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling. J Exp Med 205:1491–1503CrossRefPubMedGoogle Scholar
  4. 4.
    Cebulla CM, Miller DM, Knight DA, Briggs BR, McGaughy V, Sedmak DD (2000) Cytomegalovirus induces sialyl Lewis(x) and Lewis(x) on human endothelial cells. Transplantation 69:1202–1209CrossRefPubMedGoogle Scholar
  5. 5.
    Chambers AE, Banerjee S, Chaplin T, Dunne J, Debernardi S, Joel SP, Young BD (2003) Histone acetylation-mediated regulation of genes in leukaemic cells. Eur J Cancer 39:1165–1175CrossRefPubMedGoogle Scholar
  6. 6.
    Chen CS, Weng SC, Tseng PH, Lin HP (2005) Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes. J Biol Chem 280:38879–38887CrossRefPubMedGoogle Scholar
  7. 7.
    Dabrowska A, Baczynska D, Widerak K, Laskowska A, Ugorski M (2005) Promoter analysis of the human alpha1, 3/4-fucosyltransferase gene (FUT III). Biochim Biophys Acta 1731:66–73PubMedGoogle Scholar
  8. 8.
    de Vries T, Knegtel RM, Holmes EH, Macher BA (2001) Fucosyltransferases: structure/function studies. Glycobiology 11:119R–128RCrossRefPubMedGoogle Scholar
  9. 9.
    Garcia MA, Gil J, Ventoso I, Guerra S, Domingo E, Rivas C, Esteban M (2006) Impact of protein kinase PKR in cell biology: from antiviral to antiproliferative action. Microbiol Mol Biol Rev 70:1032–1060CrossRefPubMedGoogle Scholar
  10. 10.
    Garcia MA, Meurs EF, Esteban M (2007) The dsRNA protein kinase PKR: virus and cell control. Biochimie 89:799–811CrossRefPubMedGoogle Scholar
  11. 11.
    Gu H, Liang Y, Mandel G, Roizman B (2005) Components of the REST/CoREST/histone deacetylase repressor complex are disrupted, modified, and translocated in HSV-1-infected cells. Proc Natl Acad Sci USA 102:7571–7576CrossRefPubMedGoogle Scholar
  12. 12.
    Günalp A (1965) Growth and cytopathic effects of rubella virus in a line of green monkey kidney cells. Proc Soc Exp Biol Med 118:09–85Google Scholar
  13. 13.
    Higai K, Miyazaki N, Azuma Y, Matsumoto K (2008) Transcriptional regulation of the fucosyltransferase VI gene in hepatocellular carcinoma cells. Glycoconj J 25:225–235CrossRefPubMedGoogle Scholar
  14. 14.
    Hiraiwa N, Yabuta T, Yoritomi K, Hiraiwa M, Tanaka Y, Suzuki T, Yoshida M, Kannagi R (2003) Transactivation of the fucosyltransferase VII gene by human T-cell leukemia virus type 1 Tax through a variant cAMP-responsive element. Blood 101:3615–3621CrossRefPubMedGoogle Scholar
  15. 15.
    Kannagi R (2001) Transcriptional regulation of expression of carbohydrate ligands for cell adhesion molecules in the selectin family. Adv Exp Med Biol 491:267–278PubMedGoogle Scholar
  16. 16.
    Kannagi R (2002) Regulatory roles of carbohydrate ligands for selectins in the homing of lymphocytes. Curr Opin Struct Biol 12:599–608CrossRefPubMedGoogle Scholar
  17. 17.
    Kullberg-Lindh C, Olofsson S, Brune M, Lindh M (2008) Comparison of serum and whole blood levels of cytomegalovirus and Epstein-Barr virus DNA. Transpl Infect Dis 10:308–315CrossRefPubMedGoogle Scholar
  18. 18.
    Lundström M, Jeansson S, Olofsson S (1987) Host cell-induced differences in the O-glycosylation of herpes simplex virus gC-1. II. Demonstration of cell-specific galactosyltransferase essential for formation of O-linked oligosaccharides. Virology 161:395–402CrossRefPubMedGoogle Scholar
  19. 19.
    Magnani JL (2004) The discovery, biology, and drug development of sialyl Lea and sialyl Lex. Arch Biochem Biophys 426:122–131CrossRefPubMedGoogle Scholar
  20. 20.
    McCurley RS, Recinos A 3rd, Olsen AS, Gingrich JC, Szczepaniak D, Cameron HS, Krauss R, Weston BW (1995) Physical maps of human alpha (1, 3)fucosyltransferase genes FUT3-FUT6 on chromosomes 19p13.3 and 11q21. Genomics 26:142–146CrossRefPubMedGoogle Scholar
  21. 21.
    Mohr I (2004) Neutralizing innate host defenses to control viral translation in HSV-1 infected cells. Int Rev Immunol 23:199–220CrossRefPubMedGoogle Scholar
  22. 22.
    Muramatsu T (2000) Protein-bound carbohydrates on cell-surface as targets of recognition: an odyssey in understanding them. Glycoconj J 17:577–595CrossRefPubMedGoogle Scholar
  23. 23.
    Namvar L, Olofsson S, Bergstrom T, Lindh M (2005) Detection and typing of herpes simplex virus in mucocutaneous samples using a TaqMan PCR targeting a gB segment homologous for type 1 and 2. J Clin Microbiol 43:2058–2064CrossRefPubMedGoogle Scholar
  24. 24.
    Narlikar GJ, Fan HY, Kingston RE (2002) Cooperation between complexes that regulate chromatin structure and transcription. Cell 108:475–487CrossRefPubMedGoogle Scholar
  25. 25.
    Nordén R, Nyström K, Olofsson S (2009) Activation of host antiviral RNA-sensing factors necessary for herpes simplex virus type 1-activated transcription of host cell fucosyltransferase genes FUT3, FUT5, and FUT6 and subsequent expression of sLex in virus-infected cells. Glycobiology 19:776–788CrossRefPubMedGoogle Scholar
  26. 26.
    Nyberg K, Ekblad M, Bergstrom T, Freeman C, Parish CR, Ferro V, Trybala E (2004) The low molecular weight heparan sulfate-mimetic, PI-88, inhibits cell-to-cell spread of herpes simplex virus. Antiviral Res 63:15–24CrossRefPubMedGoogle Scholar
  27. 27.
    Nyström K, Biller M, Grahn A, Lindh M, Larson G, Olofsson S (2004) Real time PCR for monitoring regulation of host gene expression in herpes simplex virus type 1-infected human diploid cells. J Virol Methods 118:83–94CrossRefPubMedGoogle Scholar
  28. 28.
    Nyström K, Grahn A, Lindh M, Brytting M, Mandel U, Larson G, Olofsson S (2007) Virus-induced transcriptional activation of host FUT genes associated with neo-expression of Ley in cytomegalovirus- and sialyl-Lex in varicella-zoster virus-infected diploid human cells. Glycobiology 17:355–366CrossRefPubMedGoogle Scholar
  29. 29.
    Nyström K, Nordén R, Muylaert I, Elias P, Larson G, Olofsson S (2009) Induction of sialyl-Le(x) expression by herpes simplex virus type 1 is dependent on viral immediate early RNA-activated transcription of host fucosyltransferase genes. Glycobiology 19:847–859CrossRefPubMedGoogle Scholar
  30. 30.
    Olofsson S, Hansen JS (1998) Host cell carbohydrate tagging of viral glycoproteins. A battlefield for the struggle between host defence and viral resistance mechanisms. Scand J Infect Dis 30:435–440CrossRefPubMedGoogle Scholar
  31. 31.
    Olofsson S, Bergstrom T (2005) Glycoconjugate glycans as viral receptors. Ann Med 37:154–172CrossRefPubMedGoogle Scholar
  32. 32.
    Pinnoji RC, Bedadala GR, George B, Holland TC, Hill JM, Hsia SC (2007) Repressor element-1 silencing transcription factor/neuronal restrictive silencer factor (REST/NRSF) can regulate HSV-1 immediate-early transcription via histone modification. Virol J 4:56CrossRefPubMedGoogle Scholar
  33. 33.
    Reguigne-Arnould I, Couillin P, Mollicone R, Faure S, Fletcher A, Kelly RJ, Lowe JB, Oriol R (1995) Relative positions of two clusters of human alpha-L-fucosyltransferases in 19q (FUT1-FUT2) and 19p (FUT6-FUT3-FUT5) within the microsatellite genetic map of chromosome 19. Cytogenet Cell Genet 71:158–162CrossRefPubMedGoogle Scholar
  34. 34.
    Roizman B (1999) HSV gene functions: what have we learned that could be generally applicable to its near and distant cousins? Acta Virol 43:75–80PubMedGoogle Scholar
  35. 35.
    Roy S, Tenniswood M (2007) Site-specific acetylation of p53 directs selective transcription complex assembly. J Biol Chem 282:4765–4771CrossRefPubMedGoogle Scholar
  36. 36.
    Serpa J, Mesquita P, Mendes N, Oliveira C, Almeida R, Santos-Silva F, Reis CA, LePendu J, David L (2006) Expression of Lea in gastric cancer cell lines depends on FUT3 expression regulated by promoter methylation. Cancer Lett 242:191–197CrossRefPubMedGoogle Scholar
  37. 37.
    Sewack GF, Ellis TW, Hansen U (2001) Binding of TATA binding protein to a naturally positioned nucleosome is facilitated by histone acetylation. Mol Cell Biol 21:1404–1415CrossRefPubMedGoogle Scholar
  38. 38.
    Syrbe U, Jennrich S, Schottelius A, Richter A, Radbruch A, Hamann A (2004) Differential regulation of P-selectin ligand expression in naive versus memory CD4+ T cells: evidence for epigenetic regulation of involved glycosyltransferase genes. Blood 104:3243–3248CrossRefPubMedGoogle Scholar
  39. 39.
    Uchimura K, Gauguet JM, Singer MS, Tsay D, Kannagi R, Muramatsu T, von Andrian UH, Rosen SD (2005) A major class of L-selectin ligands is eliminated in mice deficient in two sulfotransferases expressed in high endothelial venules. Nat Immunol 6:1105–1113CrossRefPubMedGoogle Scholar
  40. 40.
    Van Lint C, Emiliani S, Verdin E (1996) The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. Gene Expr 5:245–253PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Rickard Nordén
    • 1
  • Kristina Nyström
    • 1
    • 2
  • Sigvard Olofsson
    • 1
    Email author
  1. 1.Department of VirologyUniversity of GothenburgGöteborgSweden
  2. 2.INSERM U892Université de NantesNantesFrance

Personalised recommendations