1887

Abstract

Varicella-zoster virus (VZV) is ultimately dependent upon its host cell for replication. To ensure its reproduction, VZV reorganizes various cellular functions by taking advantage of pre-existing signalling pathways. Recently, it was demonstrated that the activation of stress-related mitogen-activated protein kinase pathways following infection led to increased phosphorylation of cellular transcription factors involved in VZV gene expression. Here, it was shown that members of the extracellular signal-regulated kinase (ERK) pathway are also influenced following VZV infection: c-Raf remained inactive in infected MeWo cells, whereas MEK1/2 and ERK1/2 were phosphorylated transiently, reaching their highest level of phosphorylation at between 10 and 12 h post-infection. Inhibition of this pathway resulted in a severe reduction in viral progeny and in an increased apoptotic response, indicating that the functionality of this cascade is essential for successful high-rate replication. In addition, the activities of Bad, a cytoplasmic target of ERK via ribosomal S6 kinase, and the nuclear-localized target c-Myc were analysed. Bad is a member of the Bcl-2 family and has a key function in regulating apoptosis. Pro-apoptotic functions of Bad are repressed by phosphorylation. A 10-fold increase in Bad phosphorylation at Ser-112 was detected following infection, which was suppressed after inhibition of ERK. The transcription factor c-Myc is involved in the regulation of cell growth and apoptosis. By performing immunoblots and quantitative RT-PCR, suppression of c-Myc expression was demonstrated at both the transcriptional and translational levels in VZV-infected cells. These results suggest that VZV optimizes the conditions for its replication in different ways: upregulation of proviral-acting systems and suppression of potentially antiviral-acting systems.

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2006-04-01
2021-01-27
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References

  1. Abendroth A., Slobedman B., Lee E., Mellins E., Wallace M., Arvin A. M. 2000; Modulation of major histocompatibility class II protein expression by varicella-zoster virus. J Virol 74:1900–1907 [CrossRef]
    [Google Scholar]
  2. Alessi D. R., Cuenda A., Cohen P., Dudley D. T., Saltiel A. R. 1995; PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo . J Biol Chem 270:27489–27494 [CrossRef]
    [Google Scholar]
  3. Alevizopoulos K., Vlach J., Hennecke S., Amati B. 1997; Cyclin E and c-Myc promote cell proliferation in the presence of p16INK4a and of hypophosphorylated retinoblastoma family proteins. EMBO J 16:5322–5333 [CrossRef]
    [Google Scholar]
  4. Arvin A. M. 1996; Varicella-zoster virus. In Fields Virology . , 3rd edn. pp  2547–2585 Edited by Fields B., Knipe D. M., Howley P. M. Philadelphia, PA: Lippincott–Raven;
  5. Benetti L., Roizman B. 2004; Herpes simplex virus protein kinase US3 activates and functionally overlaps protein kinase A to block apoptosis. Proc Natl Acad Sci U S A 101:9411–9416 [CrossRef]
    [Google Scholar]
  6. Chittenden T., Flemington C., Houghton A. B., Ebb R. G., Gallo G. J., Elangovan B., Chinnadurai G., Lutz R. J. 1995; A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. EMBO J 14:5589–5596
    [Google Scholar]
  7. Cohen J. I., Straus S. E. 1996; Varicella-zoster virus and its replication. In Fields Virology , 3rd edn. pp  2525–2545 Edited by Fields B., Knipe D. M., Howley P. M. Philadelphia, PA: Lippincott–Raven;
    [Google Scholar]
  8. Dang C. V. 1999; c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol 19:1–11
    [Google Scholar]
  9. del Peso L., González-García M., Page C., Herrera R., Nuñez G. 1997; Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278:687–689 [CrossRef]
    [Google Scholar]
  10. Desloges N., Rahaus M., Wolff M. H. 2005a; Role of the protein kinase PKR in the inhibition of varicella-zoster virus replication by beta interferon and gamma interferon. J Gen Virol 86:1–6 [CrossRef]
    [Google Scholar]
  11. Desloges N., Rahaus M., Wolff M. H. 2005b; The varicella-zoster virus-mediated delayed host shutoff: open reading frame 17 has no major function, whereas immediate-early 63 protein represses heterologous gene expression. Microbes Infect 7:1519–1529 [CrossRef]
    [Google Scholar]
  12. Desloges N., Rahaus M., Wolff M. H. 2005c; Varicella-zoster virus does not significantly induce the cell defence mechanism mediated by the 2-5A/RNase L pathway during its replication cycle. Med Microbiol Immunol 194:25–31 [CrossRef]
    [Google Scholar]
  13. Diaz B., Barnard D., Filson A., MacDonald S., King A., Marshall M. 1997; Phosphorylation of Raf-1 serine 338-serine 339 is an essential regulatory event for Ras-dependent activation and biological signaling. Mol Cell Biol 17:4509–4516
    [Google Scholar]
  14. Downward J. 1999; How BAD phosphorylation is good for survival. Nat Cell Biol 1:E33–E35 [CrossRef]
    [Google Scholar]
  15. Franke T. F., Cantley L. C. 1997; Apoptosis: a Bad kinase makes good. Nature 390:116–117 [CrossRef]
    [Google Scholar]
  16. Gao X., Wang H., Sairenji T. 2004; Inhibition of Epstein-Barr virus (EBV) reactivation by short interfering RNAs targeting p38 mitogen-activated protein kinase or c- myc in EBV-positive epithelial cells. J Virol 78:11798–11806 [CrossRef]
    [Google Scholar]
  17. Gregory M. A., Hann S. R. 2000; c-Myc proteolysis by the ubiquitin-proteasome pathway: stabilization of c-Myc in Burkitt's lymphoma cells. Mol Cell Biol 20:2423–2435 [CrossRef]
    [Google Scholar]
  18. Gupta S., Seth A., Davis R. J. 1993; Transactivation of gene expression by Myc is inhibited by mutation at the phosphorylation sites Thr-58 and Ser-62. Proc Natl Acad Sci U S A 90:3216–3220 [CrossRef]
    [Google Scholar]
  19. Harada H., Becknell B., Wilm M., Mann M., Huang L. J.-S., Taylor S. S., Scott J. D., Korsmeyer S. J. 1999; Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. Mol Cell 3:413–422 [CrossRef]
    [Google Scholar]
  20. Hsu S. Y., Kaipia A., Zhu L., Hsueh A. J. W. 1997; Interference of BAD (Bcl-xL/Bcl-2-associated death promoter)-induced apoptosis in mammalian cells by 14-3-3 isoforms and P11. Mol Endocrinol 11:1858–1867
    [Google Scholar]
  21. Jin S., Zhuo Y., Guo W., Field J. 2005; p21-activated kinase 1 (Pak-1)-dependent phosphorylation of Raf-1 regulates its mitochondrial localization, phosphorylation of Bad, and Bcl-2 association. J Biol Chem 280:24698–24705 [CrossRef]
    [Google Scholar]
  22. Marais R., Light Y., Paterson H. F., Marshall C. J. 1995; Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. EMBO J 14:3136–3145
    [Google Scholar]
  23. Meier J. L., Luo X., Sawadogo M., Straus S. E. 1994; The cellular transcription factor USF cooperates with varicella-zoster virus immediate-early protein 62 to symmetrically activate a bidirectional viral promoter. Mol Cell Biol 14:6896–6906
    [Google Scholar]
  24. Menssen A., Hermeking H. 2002; Characterization of the c-MYC-regulated transcriptome by SAGE: identification and analysis of c-MYC target genes. Proc Natl Acad Sci U S A 99:6274–6279 [CrossRef]
    [Google Scholar]
  25. Munger J., Roizman B. 2001; The US3 protein kinase of herpes simplex virus 1 mediates the posttranslational modification of BAD and prevents BAD-induced programmed cell death in the absence of other viral proteins. Proc Natl Acad Sci U S A 98:10410–10415 [CrossRef]
    [Google Scholar]
  26. Noguchi K., Kitanaka C., Yamana H., Kokubu A., Mochizuki T., Kuchino Y. 1999; Regulation of c-Myc through phosphorylation at Ser-62 and Ser-71 by c-Jun N-terminal kinase. J Biol Chem 274:32580–32587 [CrossRef]
    [Google Scholar]
  27. Ogg P. D., McDonell P. J., Ryckman B. J., Knudson C. M., Roller R. J. 2004; The HSV-1 Us3 protein kinase is sufficient to block apoptosis induced by overexpression of a variety of Bcl-2 family members. Virology 319:212–224 [CrossRef]
    [Google Scholar]
  28. Oltvai Z. N., Milliman C. L., Korsmeyer S. J. 1993; Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74:609–619 [CrossRef]
    [Google Scholar]
  29. Pastorino J. G., Chen S.-T., Tafani M., Snyder J. W., Farber J. L. 1998; The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition. J Biol Chem 273:7770–7775 [CrossRef]
    [Google Scholar]
  30. Perkins D., Pereira E. F. R., Aurelian L. 2003; The herpes simplex virus type 2 R1 protein kinase (ICP10 PK) functions as a dominant regulator of apoptosis in hippocampal neurons involving activation of the ERK survival pathway and upregulation of the antiapoptotic protein Bag-1. J Virol 77:1292–1305 [CrossRef]
    [Google Scholar]
  31. Rahaus M., Wolff M. H. 1999; Influence of different cellular transcription factors on the regulation of varicella-zoster virus glycoproteins E (gE) and I (gI) UTR's activity. Virus Res 62:77–88 [CrossRef]
    [Google Scholar]
  32. Rahaus M., Wolff M. H. 2000; Transcription factor Sp1 is involved in the regulation of varicella-zoster virus glycoprotein E. Virus Res 69:69–81 [CrossRef]
    [Google Scholar]
  33. Rahaus M., Wolff M. H. 2003; Reciprocal effects of varicella-zoster virus (VZV) and AP1: activation of jun , fos and ATF-2 after VZV infection and their importance for the regulation of viral genes. Virus Res 92:9–21 [CrossRef]
    [Google Scholar]
  34. Rahaus M., Desloges N., Yang M., Ruyechan W. T., Wolff M. H. 2003; Transcription factor USF, expressed during the entire phase of varicella-zoster virus infection, interacts physically with the major viral transactivator IE62 and plays a significant role in virus replication. J Gen Virol 84:2957–2967 [CrossRef]
    [Google Scholar]
  35. Rahaus M., Desloges N., Wolff M. H. 2004; Replication of varicella-zoster virus is influenced by the levels of JNK/SAPK and p38/MAPK activation. J Gen Virol 85:3529–3540 [CrossRef]
    [Google Scholar]
  36. Rahaus M., Desloges N., Wolff M. H. 2005; ORF61 protein of varicella-zoster virus influences JNK/SAPK and p38/MAPK phosphorylation. J Med Virol 76:424–433 [CrossRef]
    [Google Scholar]
  37. Ray N., Enquist L. W. 2004; Transcriptional response of a common permissive cell type to infection by two diverse alphaherpesviruses. J Virol 78:3489–3501 [CrossRef]
    [Google Scholar]
  38. Robinson M. J., Cobb M. H. 1997; Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 9:180–186 [CrossRef]
    [Google Scholar]
  39. Rolfs A., Schuller I., Finckh U., Weber-Rolfs I. 1992; Reverse transcription/PCR (RT-PCR. In PCR: Clinical Diagnostics and Research pp  99–102 Edited by Rolfs A. New York: Springer;
    [Google Scholar]
  40. Roux P. P., Blenis J. 2004; ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68:320–344 [CrossRef]
    [Google Scholar]
  41. Scheid M. P., Duronio V. 1998; Dissociation of cytokine-induced phosphorylation of Bad and activation of PKB/akt: involvement of MEK upstream of Bad phosphorylation. Proc Natl Acad Sci U S A 95:7439–7444 [CrossRef]
    [Google Scholar]
  42. Smalley K. S. M. 2003; A pivotal role for ERK in the oncogenic behaviour of malignant melanoma?. Int J Cancer 104:527–532 [CrossRef]
    [Google Scholar]
  43. Tan Y., Ruan H., Demeter M. R., Comb M. J. 1999; p90RSK blocks Bad-mediated cell death via a protein kinase C-dependent pathway. J Biol Chem 274:34859–34867 [CrossRef]
    [Google Scholar]
  44. Troppmair J., Rapp U. R. 2003; Raf and the road to cell survival: a tale of bad spells, ring bearers and detours. Biochem Pharmacol 66:1341–1345 [CrossRef]
    [Google Scholar]
  45. Wang H.-G., Rapp U. R., Reed J. C. 1996; Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell 87:629–638 [CrossRef]
    [Google Scholar]
  46. Waterboer T., Rahaus M., Wolff M. H. 2002; Varicella-zoster virus (VZV) mediates a delayed host shutoff independent of open reading frame (ORF) 17 expression. Virus Genes 24:49–56 [CrossRef]
    [Google Scholar]
  47. Yang M., Hay J., Ruyechan W. T. 2004; The DNA element controlling expression of the varicella-zoster virus open reading frame 28 and 29 genes consists of two divergent unidirectional promoters which have a common USF site. J Virol 78:10939–10952 [CrossRef]
    [Google Scholar]
  48. Yin X.-M., Oltvai Z. N., Korsmeyer S. J. 1994; BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 369:321–323 [CrossRef]
    [Google Scholar]
  49. Zha J., Harada H., Yang E., Jockel J., Korsmeyer S. J. 1996; Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-XL . Cell 87:619–628 [CrossRef]
    [Google Scholar]
  50. Zimmermann S., Moelling K. 1999; Phosphorylation and regulation of Raf by Akt (protein kinase B). Science 286:1741–1744 [CrossRef]
    [Google Scholar]
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