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The phosphorylation profile of protein kinase A substrates is modulated during Varicella-zoster virus infection

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Abstract

The cAMP-dependent protein kinase A (PKA) is a key enzyme for many cellular mechanisms. In this study, we investigated the importance of this kinase for the replication of the alphaherpesvirus Varicella-zoster virus (VZV). We report that the expression of the catalytic subunit of PKA was strongly increased at the beginning of the viral cycle. The presence of a peptide inhibitor of PKA had no consequence on viral replication in a melanoma cell line whereas in fibroblasts, it resulted in a drastic decrease of replication. An overall analysis of PKA substrates phosphorylation patterns during VZV replication showed that the phosphorylation of PKA substrates was modulated. These results were completed by investigating the accumulation and phosphorylation patterns of the PKA target cAMP response element binding protein (CREB). This transcription factor remained available throughout the VZV replication, but its phosphorylation decreased in the early phase of infection before it rose later on. These results indicate that the PKA signalling plays a cell-type dependent role for VZV replication and that the infection resulted in a regulated CREB-dependent gene expression.

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References

  1. 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 USA 101:9411–9416

    Article  PubMed  CAS  Google Scholar 

  2. Cartier C, Hemonnot B, Gay B, Bardy M, Sanchiz C, Devaux C, Briant L (2003) Active cAMP-dependent protein kinase incorporated within highly purified HIV-1 particles is required for viral infectivity and interacts with viral capsid protein. J Biol Chem 278:35211–35219

    Article  PubMed  CAS  Google Scholar 

  3. Dell’Acqua ML, Scott JD (1997) Protein kinase A anchoring. J Biol Chem 272:12881–12884

    Article  PubMed  CAS  Google Scholar 

  4. Desloges N, Rahaus M, Wolff MH (2005) 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

    Article  PubMed  CAS  Google Scholar 

  5. Eisfeld AJ, Turse SE, Jackson SA, Lerner EC, Kinchington PR (2006) Phosphorylation of the Varicella-zoster virus (VZV) major transcriptional regulatory protein IE62 by the VZV open reading frame 66 protein kinase. J Virol 80:1710–1723

    Article  PubMed  CAS  Google Scholar 

  6. Gonzalez GA, Montminy MR (1989) Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59:675–680

    Article  PubMed  CAS  Google Scholar 

  7. Ito H, Sommer MH, Zerboni L, He H, Boucaud D, Hay J, Ruyechan W, Arvin AM (2003) Promoter sequences of Varicella-zoster virus glycoprotein I targeted by cellular transactivating factors Sp1 and USF determine virulence in skin and T cells in SCIDhu mice in vivo. J Virol 77:489–498

    Article  PubMed  CAS  Google Scholar 

  8. Jones JO, Arvin AM (2006) Inhibition of the NF-kappaB pathway by Varicella-zoster virus in vitro and in human epidermal cells in vivo. J Virol 80:5113–5124

    Article  PubMed  CAS  Google Scholar 

  9. Jones JO, Sommer M, Stamatis S, Arvin AM (2006) Mutational analysis of the Varicella-zoster virus ORF62/63 intergenic region. J Virol 80:3116–3121

    Article  PubMed  CAS  Google Scholar 

  10. Leisenfelder SA, Moffat JF (2006) Varicella-zoster virus infection of human foreskin fibroblast cells results in atypical cyclin expression and cyclin-dependent kinase activity. J Virol 80:5577–5587

    Article  PubMed  CAS  Google Scholar 

  11. Li PL, Wang T, Buckley KA, Chenine AL, Popov S, Ruprecht RM (2005) Phosphorylation of HIV Nef by cAMP-dependent protein kinase. Virology 331:367–374

    Article  PubMed  CAS  Google Scholar 

  12. Majeau N, Bolduc M, Duvignaud JB, Fromentin R, Leclerc D (2007) Effect of cAMP-dependent protein kinase A (PKA) on HCV nucleocapsid assembly and degradation. Biochem Cell Biol 85:78–87

    Article  PubMed  CAS  Google Scholar 

  13. Narayanan A, Nogueira ML, Ruyechan WT, Kristie TM (2005) Combinatorial transcription of herpes simplex virus and Varicella zoster virus immediate early genes is strictly determined by the cellular coactivator HCF-1. J Biol Chem 280:1369–1375

    Article  PubMed  CAS  Google Scholar 

  14. Peng H, He H, Hay J, Ruyechan WT (2003) Interaction between the Varicella zoster virus IE62 major transactivator and cellular transcription factor Sp1. J Biol Chem 278:38068–38075

    Article  PubMed  CAS  Google Scholar 

  15. Rahaus M, Desloges N, Yang M, Ruyechan WT, Wolff MH (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

    Article  PubMed  CAS  Google Scholar 

  16. Rahaus M, Desloges N, Wolff MH (2004) Replication of Varicella-zoster virus is influenced by the levels of JNK/SAPK and p38/MAPK activation. J Gen Virol 85:3529–3540

    Article  PubMed  CAS  Google Scholar 

  17. Rahaus M, Desloges N, Wolff MH (2005) ORF61 protein of Varicella-zoster virus influences JNK/SAPK and p38/MAPK phosphorylation. J Med Virol 76:424–433

    Article  PubMed  CAS  Google Scholar 

  18. Rahaus M, Desloges N, Wolff MH (2006) Varicella-zoster virus influences the activities of components and targets of the ERK signalling pathway. J Gen Virol 87:749–758

    Article  PubMed  CAS  Google Scholar 

  19. Rahaus M, Desloges N, Wolff MH (2007) Varicella-zoster virus requires a functional PI3K/Akt/GSK-3a/b signaling cascade for efficient replication. Cell Signal 19:312–320

    Article  PubMed  CAS  Google Scholar 

  20. Rahaus M, Wolff MH (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

    Article  PubMed  CAS  Google Scholar 

  21. Stevenson D, Colman KL, Davison AJ (1994) Characterization of the putative protein kinases specified by Varicella-zoster virus genes 47 and 66. J Gen Virol 75:317–326

    Article  PubMed  CAS  Google Scholar 

  22. Tacke F, Liedtke C, Bocklage S, Manns MP, Trautwein C (2005) CREB/PKA sensitive signalling pathways activate and maintain expression levels of the hepatitis B virus pre-S2/S promoter. Gut 54:1309–1317

    Article  PubMed  CAS  Google Scholar 

  23. Xia K, Knipe DM, DeLuca NA (1996) Role of protein kinase A and the serine-rich region of herpes simplex virus type 1 ICP4 in viral replication. J Virol 70:1050–1060

    PubMed  CAS  Google Scholar 

  24. Zuranski T, Nawar H, Czechowski D, Lynch JM, Arvin A, Hay J, Ruyechan WT (2005) Cell-type-dependent activation of the cellular EF-1alpha promoter by the Varicella-zoster virus IE63 protein. Virology 338:35–42

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors sincerely thank B. Rentier (University of Liège, Liège, Belgium) for providing the VZV IE63 antibody. This work was supported by the Alfried Krupp von Bohlen und Halbach Stiftung, Germany. N. Desloges was supported by the Lise-Meitner-Programm from the “Ministerium für Wissenschaft und Forschung des Landes Nordrhein-Westfalen”, Germany and by the “Deutsche Forschungsgemeinschaft” (DFG grant De 1371/1-1), Germany.

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  1. Institute of Microbiology and Virology, Private University Witten/Herdecke gGmbH, Stockumer Str. 10, 58448, Witten, Germany

    Nathalie Desloges, Markus Rahaus & Manfred H. Wolff

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  1. Nathalie Desloges
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  2. Markus Rahaus
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  3. Manfred H. Wolff
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Correspondence to Nathalie Desloges.

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Desloges, N., Rahaus, M. & Wolff, M.H. The phosphorylation profile of protein kinase A substrates is modulated during Varicella-zoster virus infection. Med Microbiol Immunol 197, 353–360 (2008). https://doi.org/10.1007/s00430-007-0068-8

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  • DOI: https://doi.org/10.1007/s00430-007-0068-8

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