1887

Abstract

Human herpesvirus 6B (HHV-6B) contains an domain spanning open reading frames , based on homology with human cytomegalovirus. Here, the protein product, U19, of the HHV-6B gene is identified as a 47 kDa transcriptional activator. HHV-6B infection or overexpression of U19 transactivated the RANTES promoter. Mutational analysis of the promoter indicated that transactivation was not critically dependent on the promoter sites CRE, NF-B, ISRE or NF-IL6. ND10 are nuclear substructures that are involved in several cellular regulatory pathways, including those controlling gene expression. HHV-6B infection resulted in a reduced number of ND10 structures, but with a concomitantly increased level of promyelocytic leukaemia (PML) protein expression and mRNA induction. The U19 protein co-located to ND10 with PML and heterochromatin protein 1 (HP1), but whilst PML formed a ring structure, U19 also localized to the centre of ND10. Knockdown of PML by small interfering RNA did not prevent U19 localization to ND10-like foci, but instead led to a fourfold increase in U19-induced transcription from the RANTES promoter. Generation of four truncated U19 proteins indicated that the N-terminal portion of the protein contains a sequence responsible for nuclear localization; a domain in the N-terminal half of U19 is responsible for its ND10 localization, whereas the C-terminal portion contains the transactivation domain. None of the truncated proteins retained full transactivating ability on the RANTES promoter. Thus, U19 is a transcriptional activator that co-localizes with PML and localizes to ND10-like foci independently of PML, yet is regulated negatively by PML or its associated proteins.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.83224-0
2008-01-01
2021-01-19
Loading full text...

Full text loading...

/deliver/fulltext/jgv/89/1/106.html?itemId=/content/journal/jgv/10.1099/vir.0.83224-0&mimeType=html&fmt=ahah

References

  1. Ahn J. H., Jang W. J., Hayward G. S. 1999; The human cytomegalovirus IE2 and UL112–113 proteins accumulate in viral DNA replication compartments that initiate from the periphery of promyelocytic leukemia protein-associated nuclear bodies (PODs or ND10). J Virol 73:10458–10471
    [Google Scholar]
  2. Alcalay M., Tomassoni L., Colombo E., Stoldt S., Grignani F., Fagioli M., Szekely L., Helin K., Pelicci P. G. 1998; The promyelocytic leukemia gene product (PML) forms stable complexes with the retinoblastoma protein. Mol Cell Biol 18:1084–1093
    [Google Scholar]
  3. Bartova E., Pachernik J., Kozubik A., Kozubek S. 2007; Differentiation-specific association of HP1 α and HP1 β with chromocentres is correlated with clustering of TIF1 β at these sites. Histochem Cell Biol 127:375–388 [CrossRef]
    [Google Scholar]
  4. Boisvert F. M., Kruhlak M. J., Box A. K., Hendzel M. J., Bazett-Jones D. P. 2001; The transcription coactivator CBP is a dynamic component of the promyelocytic leukemia nuclear body. J Cell Biol 152:1099–1106 [CrossRef]
    [Google Scholar]
  5. Caruso A., Favilli F., Rotola A., Comar M., Horejsh D., Alessandri G., Grassi M., Di L. D., Fiorentini S. 2003; Human herpesvirus-6 modulates RANTES production in primary human endothelial cell cultures. J Med Virol 70:451–458 [CrossRef]
    [Google Scholar]
  6. Casola A., Garofalo R. P., Haeberle H., Elliott T. F., Lin R., Jamaluddin M., Brasier A. R. 2001; Multiple cis regulatory elements control RANTES promoter activity in alveolar epithelial cells infected with respiratory syncytial virus. J Virol 75:6428–6439 [CrossRef]
    [Google Scholar]
  7. Chan P. K., Ng H. K., Hui M., Cheng A. F. 2001; Prevalence and distribution of human herpesvirus 6 variants A and B in adult human brain. J Med Virol 64:42–46 [CrossRef]
    [Google Scholar]
  8. Chelbi-Alix M. K., De T. H. 1999; Herpes virus induced proteasome-dependent degradation of the nuclear bodies-associated PML and Sp100 proteins. Oncogene 18:935–941 [CrossRef]
    [Google Scholar]
  9. Colberg-Poley A. M., Santomenna L. D., Harlow P. P., Benfield P. A., Tenney D. J. 1992; Human cytomegalovirus US3 and UL36-38 immediate-early proteins regulate gene expression. J Virol 66:95–105
    [Google Scholar]
  10. Csoma E., Deli T., Konya J., Csernoch L., Beck Z., Gergely L. 2006; Human herpesvirus 6A decreases the susceptibility of macrophages to R5 variants of human immunodeficiency virus 1: possible role of RANTES and IL-8. Virus Res 121:161–168 [CrossRef]
    [Google Scholar]
  11. Dellaire G., Bazett-Jones D. P. 2004; PML nuclear bodies: dynamic sensors of DNA damage and cellular stress. Bioessays 26:963–977 [CrossRef]
    [Google Scholar]
  12. Dominguez G., Dambaugh T. R., Stamey F. R., Dewhurst S., Inoue N., Pellett P. E. 1999; Human herpesvirus 6B genome sequence: coding content and comparison with human herpesvirus 6A. J Virol 73:8040–8052
    [Google Scholar]
  13. Donati D., Martinelli E., Cassiani-Ingoni R., Ahlqvist J., Hou J., Major E. O., Jacobson S. 2005; Variant-specific tropism of human herpesvirus 6 in human astrocytes. J Virol 79:9439–9448 [CrossRef]
    [Google Scholar]
  14. Everett R. D. 2001; DNA viruses and viral proteins that interact with PML nuclear bodies. Oncogene 20:7266–7273 [CrossRef]
    [Google Scholar]
  15. Everett R. D. 2006; Interactions between DNA viruses, ND10 and the DNA damage response. Cell Microbiol 8:365–374 [CrossRef]
    [Google Scholar]
  16. Everett R. D., Rechter S., Papior P., Tavalai N., Stamminger T., Orr A. 2006; PML contributes to a cellular mechanism of repression of herpes simplex virus type 1 infection that is inactivated by ICP0. J Virol 80:7995–8005 [CrossRef]
    [Google Scholar]
  17. Gompels U. A., Nicholas J., Lawrence G., Jones M., Thomson B. J., Martin M. E., Efstathiou S., Craxton M., Macaulay H. A. 1995; The DNA sequence of human herpesvirus-6: structure, coding content, and genome evolution. Virology 209:29–51 [CrossRef]
    [Google Scholar]
  18. Gravel A., Gosselin J., Flamand L. 2002; Human herpesvirus 6 immediate-early 1 protein is a sumoylated nuclear phosphoprotein colocalizing with promyelocytic leukemia protein-associated nuclear bodies. J Biol Chem 277:19679–19687 [CrossRef]
    [Google Scholar]
  19. He J., McCarthy M., Zhou Y., Chandran B., Wood C. 1996; Infection of primary human fetal astrocytes by human herpesvirus 6. J Virol 70:1296–1300
    [Google Scholar]
  20. Isegawa Y., Mukai T., Nakano K., Kagawa M., Chen J., Mori Y., Sunagawa T., Kawanishi K., Sashihara J. 1999; Comparison of the complete DNA sequences of human herpesvirus 6 variants A and B. J Virol 73:8053–8063
    [Google Scholar]
  21. Ishov A. M., Maul G. G. 1996; The periphery of nuclear domain 10 (ND10) as site of DNA virus deposition. J Cell Biol 134:815–826 [CrossRef]
    [Google Scholar]
  22. Ishov A. M., Sotnikov A. G., Negorev D., Vladimirova O. V., Neff N., Kamitani T., Yeh E. T. H., Strauss J. F., Maul G. G. 1999; PML is critical for ND10 formation and recruits the PML-interacting protein Daxx to this nuclear structure when modified by SUMO-1. J Cell Biol 147:221–234 [CrossRef]
    [Google Scholar]
  23. Josephs S. F., Salahuddin S. Z., Ablashi D. V., Schachter F., Wong-Staal F., Gallo R. C. 1986; Genomic analysis of the human B-lymphotropic virus (HBLV. Science 234:601–603 [CrossRef]
    [Google Scholar]
  24. Kumar P. P., Bischof O., Purbey P. K., Notani D., Urlaub H., Dejean A., Galande S. 2007; Functional interaction between PML and SATB1 regulates chromatin-loop architecture and transcription of the MHC class I locus. Nat Cell Biol 9:45–56 [CrossRef]
    [Google Scholar]
  25. Luciani J. J., Depetris D., Usson Y., Metzler-Guillemain C., Mignon-Ravix C., Mitchell M. J., Megarbane A., Sarda P., Sirma H. other authors 2006; PML nuclear bodies are highly organised DNA-protein structures with a function in heterochromatin remodelling at the G2 phase. J Cell Sci 119:2518–2531 [CrossRef]
    [Google Scholar]
  26. Luppi M., Barozzi P., Morris C., Maiorana A., Garber R., Bonacorsi G., Donelli A., Marasca R., Tabilio A. other authors 1999; Human herpesvirus 6 latently infects early bone marrow progenitors in vivo. J Virol 73:754–759
    [Google Scholar]
  27. Lusso P., Malnati M., De M. A., Balotta C., DeRocco S. E., Markham P. D., Gallo R. C. 1991; Productive infection of CD4+ and CD8+ mature human T cell populations and clones by human herpesvirus 6. Transcriptional down-regulation of CD3. J Immunol 147:685–691
    [Google Scholar]
  28. Lusso P., Malnati M. S., Garzino-Demo A., Crowley R. W., Long E. O., Gallo R. C. 1993; Infection of natural killer cells by human herpesvirus 6. Nature 362:458–462 [CrossRef]
    [Google Scholar]
  29. Mirandola P., Menegazzi P., Merighi S., Ravaioli T., Cassai E., Di L. D. 1998; Temporal mapping of transcripts in herpesvirus 6 variants. J Virol 72:3837–3844
    [Google Scholar]
  30. Nicholas J., Martin M. E. 1994; Nucleotide sequence analysis of a 38.5-kilobase-pair region of the genome of human herpesvirus 6 encoding human cytomegalovirus immediate-early gene homologs and transactivating functions. J Virol 68:597–610
    [Google Scholar]
  31. Okuno T., Takahashi K., Balachandra K., Shiraki K., Yamanishi K., Takahashi M., Baba K. 1989; Seroepidemiology of human herpesvirus 6 infection in normal children and adults. J Clin Microbiol 27:651–653
    [Google Scholar]
  32. Øster B., Höllsberg P. 2002; Viral gene expression patterns in human herpesvirus 6B-infected T cells. J Virol 76:7578–7586 [CrossRef]
    [Google Scholar]
  33. Øster B., Kaspersen M. D., Kofod-Olsen E., Bundgaard B., Höllsberg P. 2006; Human herpesvirus 6B inhibits cell proliferation by a p53-independent pathway. J Clin Virol 37:S63–68 [CrossRef]
    [Google Scholar]
  34. Pampin M., Simonin Y., Blondel B., Percherancier Y., Chelbi-Alix M. K. 2006; Cross talk between PML and p53 during poliovirus infection: implications for antiviral defense. J Virol 80:8582–8592 [CrossRef]
    [Google Scholar]
  35. Papanikolaou E., Kouvatsis V., Dimitriadis G., Inoue N., Arsenakis M. 2002; Identification and characterization of the gene products of open reading frame U86/87 of human herpesvirus 6. Virus Res 89:89–101 [CrossRef]
    [Google Scholar]
  36. Sadanari H., Yamada R., Ohnishi K., Matsubara K., Tanaka J. 2005; SUMO-1 modification of the major immediate-early (IE) 1 and 2 proteins of human cytomegalovirus is regulated by different mechanisms and modulates the intracellular localization of the IE1, but not IE2, protein. Arch Virol 150:1763–1782 [CrossRef]
    [Google Scholar]
  37. Salahuddin S. Z., Ablashi D. V., Markham P. D., Josephs S. F., Sturzenegger S., Kaplan M., Halligan G., Biberfield P., Wong-Staal F. other authors 1986; Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 234:596–601 [CrossRef]
    [Google Scholar]
  38. Santoro F., Kennedy P. E., Locatelli G., Malnati M. S., Berger E. A., Lusso P. 1999; CD46 is a cellular receptor for human herpesvirus 6. Cell 99:817–827 [CrossRef]
    [Google Scholar]
  39. Schirmer E. C., Wyatt L. S., Yamanishi K., Rodriguez W. J., Frenkel N. 1991; Differentiation between two distinct classes of viruses now classified as human herpesvirus 6. Proc Natl Acad Sci U S A 88:5922–5926 [CrossRef]
    [Google Scholar]
  40. Shen T. H., Lin H. K., Scaglioni P. P., Yung T. M., Pandolfi P. P. 2006; The mechanisms of PML-nuclear body formation. Mol Cell 24:331–339 [CrossRef]
    [Google Scholar]
  41. Stanton R., Fox J. D., Caswell R., Sherratt E., Wilkinson G. W. 2002; Analysis of the human herpesvirus-6 immediate-early 1 protein. J Gen Virol 83:2811–2820
    [Google Scholar]
  42. Takeda K., Nakagawa N., Yamamoto T., Inagi R., Kawanishi K., Isegawa Y., Yamanishi K. 1996; Prokaryotic expression of an immediate-early gene of human herpesvirus 6 and analysis of its viral antigen expression in human cells. Virus Res 41:193–200 [CrossRef]
    [Google Scholar]
  43. Tavalai N., Papior P., Rechter S., Leis M., Stamminger T. 2006; Evidence for a role of the cellular ND10 protein PML in mediating intrinsic immunity against human cytomegalovirus infections. J Virol 80:8006–8018 [CrossRef]
    [Google Scholar]
  44. Tomoiu A., Gravel A., Tanguay R. M., Flamand L. 2006; Functional interaction between human herpesvirus 6 immediate-early 2 protein and ubiquitin-conjugating enzyme 9 in the absence of sumoylation. J Virol 80:10218–10228 [CrossRef]
    [Google Scholar]
  45. Vallian S., Chin K. V., Chang K. S. 1998; The promyelocytic leukemia protein interacts with Sp1 and inhibits its transactivation of the epidermal growth factor receptor promoter. Mol Cell Biol 18:7147–7156
    [Google Scholar]
  46. Ward K. N., Gray J. J., Fotheringham M. W., Sheldon M. J. 1993; IgG antibodies to human herpesvirus-6 in young children: changes in avidity of antibody correlate with time after infection. J Med Virol 39:131–138 [CrossRef]
    [Google Scholar]
  47. Wu W. S., Vallian S., Seto E., Yang W. M., Edmondson D., Roth S., Chang K. S. 2001; The growth suppressor PML represses transcription by functionally and physically interacting with histone deacetylases. Mol Cell Biol 21:2259–2268 [CrossRef]
    [Google Scholar]
  48. Yamanishi K., Okuno T., Shiraki K., Takahashi M., Kondo T., Asano Y., Kurata T. 1988; Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet 1:1065–1067
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.83224-0
Loading
/content/journal/jgv/10.1099/vir.0.83224-0
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error