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
2019-11-21
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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 B. Fields, D. M. Knipe & P. M. Howley. 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 B. Fields, D. M. Knipe & P. M. Howley. Philadelphia, PA: Lippincott–Raven.
  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 A. Rolfs. New York: Springer.
  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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