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
2019-10-19
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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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [PubMed]
    [Google Scholar]
  5. Bowman T. , Garcia R. , Turkson J. , Jove R. . ( 2000; ). STATs in oncogenesis. . Oncogene 19:, 2474–2488. [CrossRef] [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. [CrossRef] [PubMed]
    [Google Scholar]
  7. Brown S. , Zeidler M. P. . ( 2008; ). Unphosphorylated STATs go nuclear. . Curr Opin Genet Dev 18:, 455–460. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [PubMed]
    [Google Scholar]
  33. Li W. X. . ( 2008; ). Canonical and non-canonical JAK-STAT signaling. . Trends Cell Biol 18:, 545–551. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [PubMed]
    [Google Scholar]
  54. Yang J. , Stark G. R. . ( 2008; ). Roles of unphosphorylated STATs in signaling. . Cell Res 18:, 443–451. [CrossRef] [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. [CrossRef] [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. [CrossRef] [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. [CrossRef] [PubMed]
    [Google Scholar]
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