1887

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) uses several strategies to counteract the interferon (IFN) system. In this study, the relationship of the protein LANA2 from KSHV to the IFN-activated protein kinase (PKR) and 2-5A system was analysed. It was found that LANA2 could not abrogate apoptosis or RNA degradation mediated by the 2-5A system. However, expression of LANA2 inhibited apoptosis triggered by PKR. LANA2 also counteracted the PKR-mediated inhibition of protein synthesis and partially blocked PKR-induced phosphorylation of eIF-2. Analysis of PKR-induced activation of caspases 3 and 9 revealed that LANA2 abrogated activation of caspase 3 but not of caspase 9. These findings show that LANA2 is able to interfere with downstream events triggered by PKR. Hence, LANA2 should be considered as a KSHV defence protein against IFN.

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2003-06-01
2019-12-06
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References

  1. Baldwin, A. S., Jr ( 1996; ). The NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol 14, 649–681.[CrossRef]
    [Google Scholar]
  2. Black, T., Safer, B., Hovanessian, A. & Katze, M. G. ( 1989; ). The cellular 68,000 M r protein kinase is highly autophosphorylated and activated yet significantly degraded during poliovirus infection: implications for translational regulation. J Virol 63, 2244–2251.
    [Google Scholar]
  3. Burysek, L. & Pitha, P. M. ( 2001; ). Latently expressed human herpesvirus 8-encoded interferon regulatory factor 2 inhibits double-stranded RNA-activated protein kinase. J Virol 75, 2345–2352.[CrossRef]
    [Google Scholar]
  4. Burysek, L., Yeow, W. S., Lubyova, B., Kellum, M., Schafer, S. L., Huang, Y. Q. & Pitha, P. M. ( 1999; ). Functional analysis of the HHV-8 encoded vIRF-1 and its association with cellular IRFs and p300. J Virol 73, 7334–7342.
    [Google Scholar]
  5. Castelli, J. A., Hassel, B. A., Wood, K. A., Li, X.-L., Amemiya, K., Dalakas, M. C., Torrence, P. & Youle, R. J. ( 1997; ). A study of the interferon antiviral mechanism: apoptosis activation of the 2-5A system. J Exp Med 186, 967–972.[CrossRef]
    [Google Scholar]
  6. Chang, Y., Cesarman, E., Pessin, M. S., Lee, F., Culpepper, J., Knowles, D. M. & Moore, P. S. ( 1994; ). Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266, 1865–1869.[CrossRef]
    [Google Scholar]
  7. Chong, K. L., Feng, L., Schappert, K., Meurs, E., Donahue, T. F., Friesen, J. D., Hovanessian, A. G. & Williams, B. R. ( 1992; ). Human p68 kinase exhibits growth suppression in yeast and homology to the translational regulator GCN2. EMBO J 11, 1553–1562.
    [Google Scholar]
  8. Der, S. D., Yang, Y., Weissmann, C. & Williams, B. R. G. ( 1997; ). A double stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis. Proc Natl Acad Sci U S A 94, 3279–3283.[CrossRef]
    [Google Scholar]
  9. Dever, T. E., Sripriya, R., McLachlin, J. R., Lu, J., Fabian, J. R., Kimball, S. R. & Miller, L. K. ( 1998; ). Disruption of cellular translational control by a viral truncated eukaryotic translation initiation factor 2α kinase homolog. Proc Natl Acad Sci U S A 95, 4164–4169.[CrossRef]
    [Google Scholar]
  10. Díaz-Guerra, M., Rivas, C. & Esteban, M. ( 1997a; ). Inducible expression of the 2-5A-synthetase/RNaseL system results in inhibition of vaccinia virus replication. Virology 227, 220–228.[CrossRef]
    [Google Scholar]
  11. Díaz-Guerra, M., Rivas, C. & Esteban, M. ( 1997b; ). Activation of the IFN-inducible enzyme RNaseL causes apoptosis of animal cells. Virology 236, 354–363.[CrossRef]
    [Google Scholar]
  12. Gale, M., Jr & Katze, M. G. ( 1998; ). Molecular mechanisms of interferon resistance mediated by viral-directed inhibition of PKR, the interferon-induced protein kinase. Pharmacol Ther 78, 29–46.[CrossRef]
    [Google Scholar]
  13. Gale, M., Jr, Korth, M. J., Tang, N. M., Tan, S. L., Hopkins, D. A., Dever, T. E., Polyak, S. J., Gretch, D. R. & Katze, M. G. ( 1997; ). Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology 230, 217–227.[CrossRef]
    [Google Scholar]
  14. Gale, M., Jr, Blakely, C. M., Kwieciszewski, B. & 7 other authors ( 1998; ). Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. Mol Cell Biol 18, 5208–5218.
    [Google Scholar]
  15. Gao, S. J., Boshoff, C., Jayachandra, S., Weiss, R. A., Chang, Y. & Moore, P. S. ( 1997; ). KSHV ORFK9 (vIRF) is an oncogene which inhibits the interferon signaling pathway. Oncogene 15, 1979–1985.[CrossRef]
    [Google Scholar]
  16. Gil, J., Alcami, J. & Esteban, M. ( 1999; ). Induction of apoptosis by double-stranded-RNA dependent protein kinase (PKR) involves the α subunit of eukaryotic translation initiation factor 2 and NF-κB. Mol Cell Biol 19, 4653–4663.
    [Google Scholar]
  17. Gil, J., Alcami, J. & Esteban, M. ( 2000; ). Activation of NF-κB by the dsRNA dependent protein kinase, PKR involves the IκB kinase complex. Oncogene 19, 1369–1378.[CrossRef]
    [Google Scholar]
  18. Gil, J., Rullas, J., Alcami, J. & Esteban, M. ( 2001; ). MC159L protein from the poxvirus molluscum contagiosum virus inhibits NF-κB activation and apoptosis induced by PKR. J Gen Virol 82, 3027–3034.
    [Google Scholar]
  19. Gil, J., Garcia, M. A. & Esteban, M. ( 2002; ). Caspase 9 activation by the dsRNA-dependent protein kinase, PKR: molecular mechanism and relevance. FEBS Lett 529, 249–255.[CrossRef]
    [Google Scholar]
  20. Gonzalo, R. M., Rodríguez, J. R., Rodríguez, D., Gonzalez-Aseguinolaza, G., Larraga, V. & Esteban, M. ( 2001; ). Protective immune response against cutaneous leishmaniasis by prime-booster immunization regimens with vaccinia virus recombinants expressing Leishmania infantum p36/LACK and IL-12 in combination with purified p36. Microbes Infect 3, 701–711.[CrossRef]
    [Google Scholar]
  21. Goodbourn, S., Didcock, L. & Randall, R. E. ( 2000; ). Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. J Gen Virol 81, 2341–2364.
    [Google Scholar]
  22. Harada, H., Taniguchi, T. & Taneka, N. ( 1998; ). The role of interferon regulatory factors in the interferon system and cell growth control. Biochimie 88, 641–650.
    [Google Scholar]
  23. He, B., Gross, M. & Roizman, B. ( 1997; ). The γ134·5 protein of herpes simples virus 1 complexes with protein phosphatase 1 α to dephosphorylate the α subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase. Proc Natl Acad Sci U S A 94, 843–848.[CrossRef]
    [Google Scholar]
  24. Hirt, B. ( 1967; ). Selective extraction of polyoma DNA from infected mouse cell cultures. J Mol Biol 27, 365–369.
    [Google Scholar]
  25. Katze, M. G., Decorato, D., Safer, B., Galabru, J. & Hovanessian, A. G. ( 1987; ). Adenovirus VAI RNA complexes with the 68,000 M r protein kinase to regulate its autophosphorylation and activity. EMBO J 6, 689–697.
    [Google Scholar]
  26. Kumar, A., Haque, J., Lacoste, J., Hiscott, J. & Williams, B. R. G. ( 1994; ). Double-stranded RNA-dependent protein kinase activates transcription factor NF-κB by phosphorylating IκB. Proc Natl Acad Sci U S A 91, 6288–6292.[CrossRef]
    [Google Scholar]
  27. Kunzi, M. S. & Pitha, P. M. ( 1998; ). The role of cytokines in viral infections. In Topley and Wilson's Microbiology and Microbial Infections, 9th edn, vol. 1, p. 193. Edited by L. Collier, A. Balows & M. Sussman. London: Arnold.
  28. Lee, S. B. & Esteban, M. ( 1993; ). The interferon-induced double-stranded RNA-activated human p68 protein kinase inhibits the replication of vaccinia virus. Virology 193, 1037–1041.[CrossRef]
    [Google Scholar]
  29. Lee, S. B. & Esteban, M. ( 1994; ). The interferon-induced double-stranded RNA-activated protein kinase induces apoptosis. Virology 199, 491–496.[CrossRef]
    [Google Scholar]
  30. Lee, S. B., Bablaman, R. & Esteban, M. ( 1996; ). Regulated expression of the interferon-induced protein kinase p68 (PKR) by vaccinia virus recombinants inhibits the replication of vesicular stomatitis virus but not that of poliovirus. J Interferon Cytokine Res 16, 1073–1078.
    [Google Scholar]
  31. Li, M., Lee, H., Guo, J., Niepel, F., Fleckenstein, B., Ozato, K. & Jung, J. U. ( 1998; ). Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor. J Virol 72, 5433–5440.
    [Google Scholar]
  32. Lloyd, R. M. & Shatkin, A. J. ( 1993; ). Translational stimulation by reovirus polypeptide sigma substitution for VAI RNA and inhibition of phosphorylation of the alpha subunit of eukaryotic initiation factor 2. J Virol 66, 6878–6884.
    [Google Scholar]
  33. Lu, Y., Wambach, M., Katze, M. G. & Krug, R. M. ( 1995; ). Binding of the influenza virus NSI protein to double-stranded RNA inhibits the activation of the protein kinase that phosphorylates the eIF2α translation initiation factor. Virology 214, 222–228.[CrossRef]
    [Google Scholar]
  34. Lubyova, B. & Pitha, P. M. ( 2000; ). Characterization of a novel human herpesvirus 8-encoded protein vIRF3, that shows homology to viral and cellular interferon regulatory factors. J Virol 74, 8194–8201.[CrossRef]
    [Google Scholar]
  35. Mamane, Y., Heylbroeck, C., Genin, P. & 7 other authors ( 1999; ). Interferon regulatory factors: the next generation. Gene 237, 1–14.[CrossRef]
    [Google Scholar]
  36. Moore, P. S., Gao, S. J., Dominguez, G. & 7 other authors ( 1996; ). Primary characterization of a herpesvirus agent associated with Kaposi's sarcoma. J Virol 70, 549–558.
    [Google Scholar]
  37. Nguyen, H., Hiscott, J. & Pitha, P. M. ( 1997; ). The growing family of interferon regulatory factors. Cytokine Growth Factor Rev 8, 293–312.[CrossRef]
    [Google Scholar]
  38. Petryshyn, R., Chen, J. J. & London, I. M. ( 1984; ). Growth-related expression of a double-stranded RNA-dependent protein kinase in 3T3 cells. J Biol Chem 259, 14736–14742.
    [Google Scholar]
  39. Ploegh, H. L. ( 1998; ). Viral strategies of immune evasions. Science 280, 248–253.[CrossRef]
    [Google Scholar]
  40. Rivas, C., Thlick, A. E., Parravicini, C., Moore, P. S. & Chang, Y. ( 2001; ). Kaposi's sarcoma-associated herpesvirus LANA2 is a B-cell-specific latent viral protein that inhibits p53. J Virol 75, 429–438.[CrossRef]
    [Google Scholar]
  41. Rowlands, A. G., Panniers, R. & Henshaw, E. C. ( 1988; ). The catalytic mechanism of guanine nucleotide exchange factor action and competitive inhibition by phosphorylated eukaryotic initiation factor 2. J Biol Chem 263, 5526–5533.
    [Google Scholar]
  42. Samuel, C. E. ( 1991; ). Antiviral actions of interferon. Interferon-regulated cellular proteins and their surprisingly selective antiviral activities. Virology 183, 1–11.[CrossRef]
    [Google Scholar]
  43. Sarid, R., Olsen, S. J. & Moore, P. S. ( 1999; ). Kaposi's sarcoma-associated herpesvirus: epidemiology, virology, and molecular biology. Adv Virus Res 52, 139–232.
    [Google Scholar]
  44. Soulier, J., Grollet, L., Oksenhendler, E. & 7 other authors ( 1995; ). Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 86, 1275–1280.
    [Google Scholar]
  45. Stark, G. R., Kerr, I. M., Williams, B. R., Silverman, R. H. & Schreiber, R. D. ( 1998; ). How cells respond to interferons. Annu Rev Biochem 67, 227–264.[CrossRef]
    [Google Scholar]
  46. Taniguchi, T., Ogasawara, K., Takaoka, A. & Tanaka, N. ( 2001; ). IRF family of transcription factors as regulators of host defense. Annu Rev Immunol 19, 623–655.[CrossRef]
    [Google Scholar]
  47. Taylor, D. R., Shi, S. T., Romano, P. R., Barber, G. N. & Lai, M. M. ( 1999; ). Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science 285, 107–110.[CrossRef]
    [Google Scholar]
  48. Thornberry, N. A. & Lazebnik, Y. ( 1998; ). Caspases: enemies within. Science 281, 1312–1316.[CrossRef]
    [Google Scholar]
  49. Vazquez, M. I. & Esteban, M. ( 1999; ). Identification of the functional domains in the 14-kilodalton envelope protein (A27L) of vaccinia virus. J Virol 73, 9098–9109.
    [Google Scholar]
  50. Vilcek, J. & Sen, G. ( 1996; ). Interferons and other cytokines. In Fields Virology, 3rd edn, vol. 1, pp. 375–399. Edited by B. N. Fields, D. M. Knipe & P. M. Howley. Philadelphia: Lippincott–Raven.
  51. Zhou, A., Paranjape, J., Brown, T. L. & 8 other authors ( 1997; ). Interferon action and apoptosis are defective in mice devoid of 2′,5′-oligoadenylate-dependent RNase L. EMBO J 16, 6355–6363.[CrossRef]
    [Google Scholar]
  52. Zimring, J. C., Goodbourn, S. & Offermann, M. K. ( 1998; ). Human herpesvirus 8 encodes an interferon regulatory factor (IRF) homolog that represses IRF-1 mediated transcription. J Virol 72, 701–707.
    [Google Scholar]
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