1887

Journal of General Virology header logo

Volume 87, Issue 11

Human papillomaviruses target the double-stranded RNA protein kinase pathway Free

Abstract

The double-stranded RNA protein kinase (PKR) pathway plays a vital role in the innate immune response to viral infection. Activation of PKR following virus entry can lead to a shutdown in translation, thereby inhibiting viral protein synthesis and replication. Little is currently known about whether human papillomaviruses (HPVs) modulate PKR expression and activity. In this study, normal human foreskin keratinocytes (NHKs) transfected stably with the HPV 31 or 16 genomes and cell lines expressing the HPV 16 E6 and E7 oncoproteins were used to examine effects on the PKR pathway. HPV gene products were found to modulate PKR phosphorylation, activity and localization. The levels of total PKR protein were reduced modestly in cells that maintained HPV 16 or 31 episomes through a reduction in PKR transcription. However, levels of phosphorylated PKR were decreased 4-fold through a post-transcriptional mechanism mediated by E6 and E7 that was independent of the transcriptional downregulation mediated by HPV. In response to infection by vesicular stomatitis virus, phosphorylation of eIF2 was blocked in cells expressing HPV oncoproteins, but not in NHKs. Finally, it was observed that the cellular localization of PKR was altered by HPV gene products in HPV raft cultures, as well as HPV-positive patient biopsies. This effect was mediated by the HPV E6 oncoprotein and leads to the co-localization of PKR with P-bodies. These studies demonstrate that high-risk HPVs target the PKR pathway by multiple mechanisms.

  • Received:
  • Accepted:
  • Published Online:
SGM
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.82098-0
2006-11-01
2024-04-25
Loading full text...

Full text loading...

/deliver/fulltext/jgv/87/11/3183.html?itemId=/content/journal/jgv/10.1099/vir.0.82098-0&mimeType=html&fmt=ahah

References

  1. Balachandran S., Barber G. N. 2004; Defective translational control facilitates vesicular stomatitis virus oncolysis. Cancer Cell 5:51–65 [CrossRef]
     [Google Scholar]
  2. Barber G. N. 2001; Host defense, viruses and apoptosis. Cell Death Differ 8:113–126 [CrossRef]
     [Google Scholar]
  3. Brierley M. M., Fish E. N. 2002; IFN- α / β receptor interactions to biologic outcomes: understanding the circuitry. J Interferon Cytokine Res 22:835–845 [CrossRef]
     [Google Scholar]
  4. Burgert H.-G., Ruzsics Z., Obermeier S., Hilgendorf A., Windheim M., Elsing A. 2002; Subversion of host defense mechanisms by adenoviruses. Curr Top Microbiol Immunol 269:273–318
     [Google Scholar]
  5. Chang Y. E., Laimins L. A. 2000; Microarray analysis identifies interferon-inducible genes and Stat-1 as major transcriptional targets of human papillomavirus type 31. J Virol 74:4174–4182 [CrossRef]
     [Google Scholar]
  6. Cheng S., Schmidt-Grimminger D. C., Murant T., Broker T. R., Chow L. T. 1995; Differentiation-dependent up-regulation of the human papillomavirus E7 gene reactivates cellular DNA replication in suprabasal differentiated keratinocytes. Genes Dev 9:2335–2349 [CrossRef]
     [Google Scholar]
  7. Clemens M. J. 1997; PKR – a protein kinase regulated by double-stranded RNA. Int J Biochem Cell Biol 29:945–949 [CrossRef]
     [Google Scholar]
  8. Cuddihy A. R., Li S., Tam N. W. N., Wong A. H.-T., Taya Y., Abraham N., Bell J. C., Koromilas A. E. 1999a; Double-stranded-RNA-activated protein kinase PKR enhances transcriptional activation by tumor suppressor p53. Mol Cell Biol 19:2475–2484
     [Google Scholar]
  9. Cuddihy A. R., Wong A. H.-T., Tam N. W. N., Li S., Koromilas A. E. 1999b; The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro . Oncogene 18:2690–2702 [CrossRef]
     [Google Scholar]
  10. de Haro C., Méndez R., Santoyo J. 1996; The eIF-2 α kinases and the control of protein synthesis. FASEB J 10:1378–1387
     [Google Scholar]
  11. de Villiers E.-M. 1994; Human pathogenic papillomavirus types: an update. Curr Top Microbiol Immunol 186:1–12
     [Google Scholar]
  12. Dyson N., Howley P. M., Munger K., Harlow E. 1989; The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243:934–937 [CrossRef]
     [Google Scholar]
  13. Elia A., Laing K. G., Schofield A., Tilleray V. J., Clemens M. J. 1996; Regulation of the double-stranded RNA-dependent protein kinase PKR by RNAs encoded by a repeated sequence in the Epstein-Barr virus genome. Nucleic Acids Res 24:4471–4478 [CrossRef]
     [Google Scholar]
  14. Fehrmann F., Laimins L. A. 2003; Human papillomaviruses: targeting differentiating epithelial cells for malignant transformation. Oncogene 22:5201–5207 [CrossRef]
     [Google Scholar]
  15. Fehrmann F., Klumpp D. J., Laimins L. A. 2003; Human papillomavirus type 31 E5 protein supports cell cycle progression and activates late viral functions upon epithelial differentiation. J Virol 77:2819–2831 [CrossRef]
     [Google Scholar]
  16. Frattini M. G., Lim H. B., Laimins L. A. 1996; In vitro synthesis of oncogenic human papillomaviruses requires episomal genomes for differentiation-dependent late expression. Proc Natl Acad Sci U S A 93:3062–3067 [CrossRef]
     [Google Scholar]
  17. Galloway D. A., McDougall J. K. 1996; The disruption of cell cycle checkpoints by papillomavirus oncoproteins contributes to anogenital neoplasia. Semin Cancer Biol 7:309–315 [CrossRef]
     [Google Scholar]
  18. Halbert C. L., Demers G. W., Galloway D. A. 1991; The E7 gene of human papillomavirus type 16 is sufficient for immortalization of human epithelial cells. J Virol 65:473–478
     [Google Scholar]
  19. Hershey J. W. B. 1991; Translational control in mammalian cells. Annu Rev Biochem 60:717–755 [CrossRef]
     [Google Scholar]
  20. Howley P. M. 1996; Papillomavirinae : the viruses and their replication. In Fundamental Virology , 3rd edn. pp  947–978 Edited by Fields B. N., Knipe D. M., Howley P. M. Philadelphia, PA: Lippincott–Raven;
     [Google Scholar]
  21. Huibregtse J. M., Scheffner M., Howley P. M. 1991; A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. EMBO J 10:4129–4135
     [Google Scholar]
  22. Hummel M., Hudson J. B., Laimins L. A. 1992; Differentiation-induced and constitutive transcription of human papillomavirus type 31b in cell lines containing viral episomes. J Virol 66:6070–6080
     [Google Scholar]
  23. Kazemi S., Papadopoulou S., Li S., Su Q., Wang S., Yoshimura A., Matlashewski G., Dever T. E., Koromilas A. E. 2004; Control of α subunit of eukaryotic translation initiation factor 2 (eIF2 α ) phosphorylation by the human papillomavirus type 18 E6 oncoprotein: implications for eIF2 α -dependent gene expression and cell death. Mol Cell Biol 24:3415–3429 [CrossRef]
     [Google Scholar]
  24. Longworth M. S., Laimins L. A. 2004; The binding of histone deacetylases and the integrity of zinc finger-like motifs of the E7 protein are essential for the life cycle of human papillomavirus type 31. J Virol 78:3533–3541 [CrossRef]
     [Google Scholar]
  25. Malmgaard L. 2004; Induction and regulation of IFNs during viral infections. J Interferon Cytokine Res 24:439–454 [CrossRef]
     [Google Scholar]
  26. Martin L. G., Demers G. W., Galloway D. A. 1998; Disruption of the G1/S transition in human papillomavirus type 16 E7-expressing human cells is associated with altered regulation of cyclin E. J Virol 72:975–985
     [Google Scholar]
  27. Marx J. 2005; P-bodies mark the spot for controlling protein production. Science 310:764–765 [CrossRef]
     [Google Scholar]
  28. Meyers C., Laimins L. A. 1994; In vitro systems for the study and propagation of human papillomaviruses. Curr Top Microbiol Immunol 186:199–215
     [Google Scholar]
  29. Miyaji K., Nakagawa Y., Matsumoto K. & 9 other authors 2003; Overexpression of a DEAD box/RNA helicase protein, rck/p54, in human hepatocytes from patients with hepatitis C virus-related chronic hepatitis and its implication in hepatocellular carcinogenesis. J Viral Hepat 10:241–248 [CrossRef]
     [Google Scholar]
  30. Mohr I. 2004; Neutralizing innate host defenses to control viral translation in HSV-1 infected cells. Int Rev Immunol 23:199–220 [CrossRef]
     [Google Scholar]
  31. Monsonego J., Bosch F. X., Coursaget P. & 12 other authors 2004; Cervical cancer control, priorities and new directions. Int J Cancer 108:329–333 [CrossRef]
     [Google Scholar]
  32. Münger K., Werness B. A., Dyson N., Phelps W. C., Harlow E., Howley P. M. 1989; Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. EMBO J 8:4099–4105
     [Google Scholar]
  33. Nakagawa Y., Morikawa H., Hirata I. & 9 other authors 1999; Overexpression of rck/p54, a DEAD box protein, in human colorectal tumours. Br J Cancer 80:914–917 [CrossRef]
     [Google Scholar]
  34. Nees M., Geoghegan J. M., Hyman T., Frank S., Miller L., Woodworth C. D. 2001; Papillomavirus type 16 oncogenes downregulate expression of interferon-responsive genes and upregulate proliferation-associated and NF- κ B-responsive genes in cervical keratinocytes. J Virol 75:4283–4296 [CrossRef]
     [Google Scholar]
  35. Nguyen M., Song S., Liem A., Androphy E., Liu Y., Lambert P. F. 2002; A mutant of human papillomavirus type 16 E6 deficient in binding α -helix partners displays reduced oncogenic potential in vivo. J Virol 76:13039–13048 [CrossRef]
     [Google Scholar]
  36. Ozbun M. A., Meyers C. 1998; Temporal usage of multiple promoters during the life cycle of human papillomavirus type 31b. J Virol 72:2715–2722
     [Google Scholar]
  37. Park J.-S., Kim E.-J., Kwon H.-J., Hwang E.-S., Namkoong S.-E., Um S.-J. 2000; Inactivation of interferon regulatory factor-1 tumor suppressor protein by HPV E7 oncoprotein. Implication for the E7-mediated immune evasion mechanism in cervical carcinogenesis. J Biol Chem 275:6764–6769 [CrossRef]
     [Google Scholar]
  38. Patel R. C., Sen G. C. 1998; PACT, a protein activator of the interferon-induced protein kinase, PKR. EMBO J 17:4379–4390 [CrossRef]
     [Google Scholar]
  39. Roizman B. 1999; HSV gene functions: what have we learned that could be generally applicable to its near and distant cousins?. Acta Virol 43:75–80
     [Google Scholar]
  40. Romano P. R., Garcia-Barrio M. T., Zhang X. & 7 other authors 1998; Autophosphorylation in the activation loop is required for full kinase activity in vivo of human and yeast eukaryotic initiation factor 2 α kinases PKR and GCN2. Mol Cell Biol 18:2282–2297
     [Google Scholar]
  41. Ronco L. V., Karpova A. Y., Vidal M., Howley P. M. 1998; Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Genes Dev 12:2061–2072 [CrossRef]
     [Google Scholar]
  42. Ruesch M. N., Laimins L. A. 1998; Human papillomavirus oncoproteins alter differentiation-dependent cell cycle exit on suspension in semisolid medium. Virology 250:19–29 [CrossRef]
     [Google Scholar]
  43. Scheffner M., Werness B. A., Huibregtse J. M., Levine A. J., Howley P. M. 1990; The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63:1129–1136 [CrossRef]
     [Google Scholar]
  44. Scheffner M., Huibregtse J. M., Vierstra R. D., Howley P. M. 1993; The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75:495–505 [CrossRef]
     [Google Scholar]
  45. Stark G. R., Kerr I. M., Williams B. R. G., Silverman R. H., Schreiber R. D. 1998; How cells respond to interferons. Annu Rev Biochem 67:227–264 [CrossRef]
     [Google Scholar]
  46. Taylor D. R., Lee S. B., Romano P. R., Marshak D. R., Hinnebusch A. G., Esteban M., Mathews M. B. 1996; Autophosphorylation sites participate in the activation of the double-stranded-RNA-activated protein kinase PKR. Mol Cell Biol 16:6295–6302
     [Google Scholar]
  47. Thomas M. C., Chiang C.-M. 2005; E6 oncoprotein represses p53-dependent gene activation via inhibition of protein acetylation independently of inducing p53 degradation. Mol Cell 17:251–264 [CrossRef]
     [Google Scholar]
  48. Um S.-J., Rhyu J.-W., Kim E.-J., Jeon K.-C., Hwang E.-S., Park J.-S. 2002; Abrogation of IRF-1 response by high-risk HPV E7 protein in vivo. Cancer Lett 179:205–212 [CrossRef]
     [Google Scholar]
  49. Werness B. A., Levine A. J., Howley P. M. 1990; Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248:76–79 [CrossRef]
     [Google Scholar]
  50. Williams B. R. 1999; PKR; a sentinel kinase for cellular stress. Oncogene 18:6112–6120 [CrossRef]
     [Google Scholar]
  51. Wilson R., Fehrmann F., Laimins L. A. 2005; Role of the E1^E4 protein in the differentiation-dependent life cycle of human papillomavirus type 31. J Virol 79:6732–6740 [CrossRef]
     [Google Scholar]
  52. zur Hausen H. 1996; Papillomavirus infections – a major cause of human cancers. Biochim Biophys Acta 1288F55–F78
     [Google Scholar]
  53. zur Hausen H. 2002; Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2:342–350 [CrossRef]
     [Google Scholar]
  54. zur Hausen H., de Villiers E.-M. 1994; Human papillomaviruses. Annu Rev Microbiol 48:427–447 [CrossRef]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.82098-0
Loading
Human papillomaviruses target the double-stranded RNA protein kinase pathway
J. Gen. Virol. 87, 3183 (2006); https://doi.org/10.1099/vir.0.82098-0
/content/journal/jgv/10.1099/vir.0.82098-0
/content/journal/jgv/10.1099/vir.0.82098-0
Loading

Data & Media loading...

Most cited 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