1887

Abstract

Herpesvirus saimiri (HVS), a T-lymphotropic monkey herpesvirus, induces fulminant T-cell lymphoma in non-natural primate hosts. In addition, it can immortalize human T-cells . HVS tyrosine kinase-interacting protein (Tip) is an essential viral gene required for T-cell transformation both and . In this study, we found that Tip interacts with the STAT6 transcription factor and induces phosphorylation of STAT6 in T-cells. The interaction with STAT6 requires the Tyr residue and Lck-binding domain of Tip, which are indispensable for interleukin (IL)-2-independent T-cell transformation by HVS. It was also demonstrated that Tip induces nuclear translocation of STAT6, as well as activation of STAT6-dependent transcription in Jurkat T-cells. Interestingly, the phosphorylated STAT6 mainly colocalized with vesicles containing Tip within T-cells, but was barely detectable in the nucleus. However, nuclear translocation of phospho-STAT6 and transcriptional activation of STAT6 by IL-4 stimulation were not affected significantly in T-cells expressing Tip. Collectively, these findings suggest that the constitutive activation of STAT6 by Tip in T-cells may contribute to IL-2-independent T-cell transformation by HVS.

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2012-02-01
2024-03-28
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References

  1. Benekli M., Baer M. R., Baumann H., Wetzler M. 2003; Signal transducer and activator of transcription proteins in leukemias. Blood 101:2940–2954 [View Article][PubMed]
    [Google Scholar]
  2. Biesinger B., Müller-Fleckenstein I., Simmer B., Lang G., Wittmann S., Platzer E., Desrosiers R. C., Fleckenstein B. 1992; Stable growth transformation of human T lymphocytes by herpesvirus saimiri. Proc Natl Acad Sci U S A 89:3116–3119 [View Article][PubMed]
    [Google Scholar]
  3. Biesinger B., Tsygankov A. Y., Fickenscher H., Emmrich F., Fleckenstein B., Bolen J. B., Bröker B. M. 1995; The product of the Herpesvirus saimiri open reading frame 1 (Tip) interacts with T cell-specific kinase p56lck in transformed cells. J Biol Chem 270:4729–4734 [View Article][PubMed]
    [Google Scholar]
  4. Bild A. H., Turkson J., Jove R. 2002; Cytoplasmic transport of Stat3 by receptor-mediated endocytosis. EMBO J 21:3255–3263 [View Article][PubMed]
    [Google Scholar]
  5. Bowman T., Garcia R., Turkson J., Jove R. 2000; STATs in oncogenesis. Oncogene 19:2474–2488 [View Article][PubMed]
    [Google Scholar]
  6. Bromberg J., Darnell J. E. Jr 2000; The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19:2468–2473 [View Article][PubMed]
    [Google Scholar]
  7. Brown S., Zeidler M. P. 2008; Unphosphorylated STATs go nuclear. Curr Opin Genet Dev 18:455–460 [View Article][PubMed]
    [Google Scholar]
  8. Cai Q., Verma S. C., Choi J. Y., Ma M., Robertson E. S. 2010; Kaposi’s sarcoma-associated herpesvirus inhibits interleukin-4-mediated STAT6 phosphorylation to regulate apoptosis and maintain latency. J Virol 84:11134–11144 [View Article][PubMed]
    [Google Scholar]
  9. Chatterjee-Kishore M., Kishore R., Hicklin D. J., Marincola F. M., Ferrone S. 1998; Different requirements for signal transducer and activator of transcription 1alpha and interferon regulatory factor 1 in the regulation of low molecular mass polypeptide 2 and transporter associated with antigen processing 1 gene expression. J Biol Chem 273:16177–16183 [View Article][PubMed]
    [Google Scholar]
  10. Cho N. H., Feng P., Lee S. H., Lee B. S., Liang X., Chang H., Jung J. U. 2004; Inhibition of T cell receptor signal transduction by tyrosine kinase-interacting protein of Herpesvirus saimiri. J Exp Med 200:681–687 [View Article][PubMed]
    [Google Scholar]
  11. Cho N. H., Kingston D., Chang H., Kwon E. K., Kim J. M., Lee J. H., Chu H., Choi M. S., Kim I. S., Jung J. U. 2006; Association of herpesvirus saimiri Tip with lipid raft is essential for downregulation of T-cell receptor and CD4 coreceptor. J Virol 80:108–118 [View Article][PubMed]
    [Google Scholar]
  12. Choi J. K., Ishido S., Jung J. U. 2000; The collagen repeat sequence is a determinant of the degree of herpesvirus saimiri STP transforming activity. J Virol 74:8102–8110 [View Article][PubMed]
    [Google Scholar]
  13. Cui X., Zhang L., Luo J., Rajasekaran A., Hazra S., Cacalano N., Dubinett S. M. 2007; Unphosphorylated STAT6 contributes to constitutive cyclooxygenase-2 expression in human non-small cell lung cancer. Oncogene 26:4253–4260 [View Article][PubMed]
    [Google Scholar]
  14. Deutsch H. H. J., Koettnitz K., Chung J., Kalthoff F. S. 1995; Distinct sequence motifs within the cytoplasmic domain of the human IL-4 receptor differentially regulate apoptosis inhibition and cell growth. J Immunol 154:3696–3703[PubMed]
    [Google Scholar]
  15. Duboise S. M., Guo J., Czajak S., Desrosiers R. C., Jung J. U. 1998; STP and Tip are essential for herpesvirus saimiri oncogenicity. J Virol 72:1308–1313[PubMed]
    [Google Scholar]
  16. Ensser A., Thurau M., Wittmann S., Fickenscher H. 2003; The genome of herpesvirus saimiri C488 which is capable of transforming human T cells. Virology 314:471–487 [View Article][PubMed]
    [Google Scholar]
  17. Guiter C., Dusanter-Fourt I., Copie-Bergman C., Boulland M. L., Le Gouvello S., Gaulard P., Leroy K., Castellano F. 2004; Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma. Blood 104:543–549 [View Article][PubMed]
    [Google Scholar]
  18. Hartley D. A., Cooper G. M. 2000; Direct binding and activation of STAT transcription factors by the herpesvirus saimiri protein Tip. J Biol Chem 275:16925–16932 [View Article][PubMed]
    [Google Scholar]
  19. Hartley D. A., Amdjadi K., Hurley T. R., Lund T. C., Medveczky P. G., Sefton B. M. 2000; Activation of the Lck tyrosine protein kinase by the herpesvirus saimiri tip protein involves two binding interactions. Virology 276:339–348 [View Article][PubMed]
    [Google Scholar]
  20. Haura E. B., Turkson J., Jove R. 2005; Mechanisms of disease: insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Pract Oncol 2:315–324 [View Article][PubMed]
    [Google Scholar]
  21. Heck E., Lengenfelder D., Schmidt M., Müller-Fleckenstein I., Fleckenstein B., Biesinger B., Ensser A. 2005; T-cell growth transformation by herpesvirus saimiri is independent of STAT3 activation. J Virol 79:5713–5720 [View Article][PubMed]
    [Google Scholar]
  22. Heck E., Friedrich U., Gack M. U., Lengenfelder D., Schmidt M., Müller-Fleckenstein I., Fleckenstein B., Ensser A., Biesinger B. 2006; Growth transformation of human T cells by herpesvirus saimiri requires multiple Tip–Lck interaction motifs. J Virol 80:9934–9942 [View Article][PubMed]
    [Google Scholar]
  23. Hou J., Schindler U., Henzel W. J., Ho T. C., Brasseur M., McKnight S. L. 1994; An interleukin-4-induced transcription factor: IL-4 Stat. Science 265:1701–1706 [View Article][PubMed]
    [Google Scholar]
  24. Ilaria R. L. Jr, Van Etten R. A. 1996; P210 and P190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J Biol Chem 271:31704–31710 [View Article][PubMed]
    [Google Scholar]
  25. Johnston J. A., Kawamura M., Kirken R. A., Chen Y. Q., Blake T. B., Shibuya K., Ortaldo J. R., McVicar D. W., O’Shea J. J. 1994; Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature 370:151–153 [View Article][PubMed]
    [Google Scholar]
  26. Jung J. U., Lang S. M., Friedrich U., Jun T., Roberts T. M., Desrosiers R. C., Biesinger B. 1995; Identification of Lck-binding elements in Tip of herpesvirus saimiri. J Biol Chem 270:20660–20667 [View Article][PubMed]
    [Google Scholar]
  27. Jung J. U., Choi J. K., Ensser A., Biesinger B. 1999; Herpesvirus saimiri as a model for gammaherpesvirus oncogenesis. Semin Cancer Biol 9:231–239 [View Article][PubMed]
    [Google Scholar]
  28. Keegan A. D., Nelms K., White M., Wang L. M., Pierce J. H., Paul W. E. 1994; An IL-4 receptor region containing an insulin receptor motif is important for IL-4-mediated IRS-1 phosphorylation and cell growth. Cell 76:811–820 [View Article][PubMed]
    [Google Scholar]
  29. Kjellen P., Amdjadi K., Lund T. C., Medveczky P. G., Sefton B. M. 2002; The herpesvirus saimiri Tip484 and Tip488 proteins both stimulate lck tyrosine protein kinase activity in vivo and in vitro . Virology 297:281–288 [View Article][PubMed]
    [Google Scholar]
  30. Lee H., Choi J. K., Li M., Kaye K., Kieff E., Jung J. U. 1999; Role of cellular tumor necrosis factor receptor-associated factors in NF-κB activation and lymphocyte transformation by herpesvirus saimiri STP. J Virol 73:3913–3919[PubMed]
    [Google Scholar]
  31. Lee B. S., Lee S. H., Feng P., Chang H., Cho N. H., Jung J. U. 2005; Characterization of the Kaposi’s sarcoma-associated herpesvirus K1 signalosome. J Virol 79:12173–12184 [View Article][PubMed]
    [Google Scholar]
  32. Levy D. E., Darnell J. E. Jr 2002; Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3:651–662 [View Article][PubMed]
    [Google Scholar]
  33. Li W. X. 2008; Canonical and non-canonical JAK-STAT signaling. Trends Cell Biol 18:545–551 [View Article][PubMed]
    [Google Scholar]
  34. Lund T. C., Garcia R., Medveczky M. M., Jove R., Medveczky P. G. 1997; Activation of STAT transcription factors by herpesvirus saimiri Tip-484 requires p56lck. J Virol 71:6677–6682[PubMed]
    [Google Scholar]
  35. Lund T. C., Prator P. C., Medveczky M. M., Medveczky P. G. 1999; The Lck binding domain of herpesvirus saimiri Tip-484 constitutively activates Lck and STAT3 in T cells. J Virol 73:1689–1694[PubMed]
    [Google Scholar]
  36. Min C. K., Bang S. Y., Cho B. A., Choi Y. H., Yang J. S., Lee S. H., Seong S. Y., Kim K. W., Kim S. other authors 2008; Role of amphipathic helix of a herpesviral protein in membrane deformation and T cell receptor downregulation. PLoS Pathog 4:e1000209 [View Article][PubMed]
    [Google Scholar]
  37. Murata T., Noguchi P. D., Puri R. K. 1996; IL-13 induces phosphorylation and activation of JAK2 Janus kinase in human colon carcinoma cell lines: similarities between IL-4 and IL-13 signaling. J Immunol 156:2972–2978[PubMed]
    [Google Scholar]
  38. Murphy C., Kretschmer C., Biesinger B., Beckers J., Jung J., Desrosiers R. C., Müller-Hermelink H. K., Fleckenstein B. W., Rüther U. 1994; Epithelial tumours induced by a herpesvirus oncogene in transgenic mice. Oncogene 9:221–226[PubMed]
    [Google Scholar]
  39. Park J., Lee B. S., Choi J. K., Means R. E., Choe J., Jung J. U. 2002; Herpesviral protein targets a cellular WD repeat endosomal protein to downregulate T lymphocyte receptor expression. Immunity 17:221–233 [View Article][PubMed]
    [Google Scholar]
  40. Park J., Cho N. H., Choi J. K., Feng P., Choe J., Jung J. U. 2003; Distinct roles of cellular Lck and p80 proteins in herpesvirus saimiri Tip function on lipid rafts. J Virol 77:9041–9051 [View Article][PubMed]
    [Google Scholar]
  41. Qin J. Z., Kamarashev J., Zhang C. L., Dummer R., Burg G., Döbbeling U. 2001; Constitutive and interleukin-7- and interleukin-15-stimulated DNA binding of STAT and novel factors in cutaneous T cell lymphoma cells. J Invest Dermatol 117:583–589 [View Article][PubMed]
    [Google Scholar]
  42. Reichel M., Nelson B. H., Greenberg P. D., Rothman P. B. 1997; The IL-4 receptor alpha-chain cytoplasmic domain is sufficient for activation of JAK-1 and STAT6 and the induction of IL-4-specific gene expression. J Immunol 158:5860–5867[PubMed]
    [Google Scholar]
  43. Ritz O., Guiter C., Castellano F., Dorsch K., Melzner J., Jais J. P., Dubois G., Gaulard P., Möller P., Leroy K. 2009; Recurrent mutations of the STAT6 DNA binding domain in primary mediastinal B-cell lymphoma. Blood 114:1236–1242 [View Article][PubMed]
    [Google Scholar]
  44. Ryan J. J., McReynolds L. J., Keegan A., Wang L. H., Garfein E., Rothman P., Nelms K., Paul W. E. 1996; Growth and gene expression are predominantly controlled by distinct regions of the human IL-4 receptor. Immunity 4:123–132 [View Article][PubMed]
    [Google Scholar]
  45. Shao H., Xu X., Mastrangelo M. A., Jing N., Cook R. G., Legge G. B., Tweardy D. J. 2004; Structural requirements for signal transducer and activator of transcription 3 binding to phosphotyrosine ligands containing the YXXQ motif. J Biol Chem 279:18967–18973 [View Article][PubMed]
    [Google Scholar]
  46. Sheng H., Shao J., Morrow J. D., Beauchamp R. D., DuBois R. N. 1998; Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res 58:362–366[PubMed]
    [Google Scholar]
  47. Shi S., Larson K., Guo D., Lim S. J., Dutta P., Yan S. J., Li W. X. 2008; Drosophila STAT is required for directly maintaining HP1 localization and heterochromatin stability. Nat Cell Biol 10:489–496 [View Article][PubMed]
    [Google Scholar]
  48. Skinnider B. F., Elia A. J., Gascoyne R. D., Patterson B., Trumper L., Kapp U., Mak T. W. 2002; Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed–Sternberg cells of Hodgkin lymphoma. Blood 99:618–626 [View Article][PubMed]
    [Google Scholar]
  49. Stolina M., Sharma S., Lin Y., Dohadwala M., Gardner B., Luo J., Zhu L., Kronenberg M., Miller P. W. other authors 2000; Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J Immunol 164:361–370[PubMed] [CrossRef]
    [Google Scholar]
  50. Wehner L. E., Schröder N., Kamino K., Friedrich U., Biesinger B., Rüther U. 2001; Herpesvirus saimiri Tip gene causes T-cell lymphomas in transgenic mice. DNA Cell Biol 20:81–88 [View Article][PubMed]
    [Google Scholar]
  51. Witthuhn B. A., Silvennoinen O., Miura O., Lai K. S., Cwik C., Liu E. T., Ihle J. N. 1994; Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature 370:153–157 [View Article][PubMed]
    [Google Scholar]
  52. Xu F., Mukhopadhyay S., Sehgal P. B. 2007; Live cell imaging of interleukin-6-induced targeting of ‘transcription factor’ STAT3 to sequestering endosomes in the cytoplasm. Am J Physiol Cell Physiol 293:C1374–C1382 [View Article][PubMed]
    [Google Scholar]
  53. Yan S. J., Lim S. J., Shi S., Dutta P., Li W. X. 2011; Unphosphorylated STAT and heterochromatin protect genome stability. FASEB J 25:232–241 [View Article][PubMed]
    [Google Scholar]
  54. Yang J., Stark G. R. 2008; Roles of unphosphorylated STATs in signaling. Cell Res 18:443–451 [View Article][PubMed]
    [Google Scholar]
  55. Yang J., Liao X., Agarwal M. K., Barnes L., Auron P. E., Stark G. R. 2007; Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFκB. Genes Dev 21:1396–1408 [View Article][PubMed]
    [Google Scholar]
  56. Yu H., Pardoll D., Jove R. 2009; STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809 [View Article][PubMed]
    [Google Scholar]
  57. Zhou S., Shoelson S. E., Chaudhuri M., Gish G., Pawson T., Haser W. G., King F., Roberts T., Ratnofsky S. other authors 1993; SH2 domains recognize specific phosphopeptide sequences. Cell 72:767–778 [View Article][PubMed]
    [Google Scholar]
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