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. 1996 Jun;70(6):3599–3605. doi: 10.1128/jvi.70.6.3599-3605.1996

The human T-cell leukemia/lymphotropic virus type 1 p12I proteins bind the interleukin-2 receptor beta and gammac chains and affects their expression on the cell surface.

J C Mulloy 1, R W Crownley 1, J Fullen 1, W J Leonard 1, G Franchini 1
PMCID: PMC190235  PMID: 8648694

Abstract

p12I is a small hydrophobic protein encoded by the human T-cell leukemia/lymphotropic virus type 1 (HTLV-1) that interacts with the 16-kDa component of the H+ vacuolar ATPase and cooperates with bovine papillomavirus 1 E5 oncoprotein in cell transformation. Just as an important step in E5 action appears to be its binding to the platelet-derived growth factor receptor, it was found that p12I binds specifically to both the beta and gamma(c) chains of the interleukin-2 receptor (IL-2R). The IL-2R beta and gamma(c) chains associated with p12I are endoglycosidase-H sensitive, suggesting that their interaction occurs in a pre-Golgi compartment. p12I stabilizes the immature forms of the IL-2R beta and gamma(c) chains and decreases their cell surface expression. The interactions of p12I with IL-2R beta and gamma(c) may have important implications in the immunosuppressive effect of HTLV-1 in vivo as well as in the ligand-independent HTLV-1-mediated T-cell proliferation.

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Selected References

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  1. Arya S. K., Wong-Staal F., Gallo R. C. T-cell growth factor gene: lack of expression in human T-cell leukemia-lymphoma virus-infected cells. Science. 1984 Mar 9;223(4640):1086–1087. doi: 10.1126/science.6320374. [DOI] [PubMed] [Google Scholar]
  2. Berneman Z. N., Gartenhaus R. B., Reitz M. S., Jr, Blattner W. A., Manns A., Hanchard B., Ikehara O., Gallo R. C., Klotman M. E. Expression of alternatively spliced human T-lymphotropic virus type I pX mRNA in infected cell lines and in primary uncultured cells from patients with adult T-cell leukemia/lymphoma and healthy carriers. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3005–3009. doi: 10.1073/pnas.89.7.3005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Broder S. T cell proliferation and ablation. A biologic spectrum of abnormalities induced by the human T cell lymphotropic virus group. Prog Allergy. 1986;37:224–243. [PubMed] [Google Scholar]
  4. Cesarman E., Chadburn A., Inghirami G., Gaidano G., Knowles D. M. Structural and functional analysis of oncogenes and tumor suppressor genes in adult T-cell leukemia/lymphoma shows frequent p53 mutations. Blood. 1992 Dec 15;80(12):3205–3216. [PubMed] [Google Scholar]
  5. Cohen B. D., Goldstein D. J., Rutledge L., Vass W. C., Lowy D. R., Schlegel R., Schiller J. T. Transformation-specific interaction of the bovine papillomavirus E5 oncoprotein with the platelet-derived growth factor receptor transmembrane domain and the epidermal growth factor receptor cytoplasmic domain. J Virol. 1993 Sep;67(9):5303–5311. doi: 10.1128/jvi.67.9.5303-5311.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cross S. L., Feinberg M. B., Wolf J. B., Holbrook N. J., Wong-Staal F., Leonard W. J. Regulation of the human interleukin-2 receptor alpha chain promoter: activation of a nonfunctional promoter by the transactivator gene of HTLV-I. Cell. 1987 Apr 10;49(1):47–56. doi: 10.1016/0092-8674(87)90754-9. [DOI] [PubMed] [Google Scholar]
  7. Danial N. N., Pernis A., Rothman P. B. Jak-STAT signaling induced by the v-abl oncogene. Science. 1995 Sep 29;269(5232):1875–1877. doi: 10.1126/science.7569929. [DOI] [PubMed] [Google Scholar]
  8. Finbow M. E., Eliopoulos E. E., Jackson P. J., Keen J. N., Meagher L., Thompson P., Jones P., Findlay J. B. Structure of a 16 kDa integral membrane protein that has identity to the putative proton channel of the vacuolar H(+)-ATPase. Protein Eng. 1992 Jan;5(1):7–15. doi: 10.1093/protein/5.1.7. [DOI] [PubMed] [Google Scholar]
  9. Franchini G. Molecular mechanisms of human T-cell leukemia/lymphotropic virus type I infection. Blood. 1995 Nov 15;86(10):3619–3639. [PubMed] [Google Scholar]
  10. Franchini G., Mulloy J. C., Koralnik I. J., Lo Monico A., Sparkowski J. J., Andresson T., Goldstein D. J., Schlegel R. The human T-cell leukemia/lymphotropic virus type I p12I protein cooperates with the E5 oncoprotein of bovine papillomavirus in cell transformation and binds the 16-kilodalton subunit of the vacuolar H+ ATPase. J Virol. 1993 Dec;67(12):7701–7704. doi: 10.1128/jvi.67.12.7701-7704.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fujii M., Sassone-Corsi P., Verma I. M. c-fos promoter trans-activation by the tax1 protein of human T-cell leukemia virus type I. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8526–8530. doi: 10.1073/pnas.85.22.8526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gallo R. C. The first human retrovirus. Sci Am. 1986 Dec;255(6):88–98. doi: 10.1038/scientificamerican1286-88. [DOI] [PubMed] [Google Scholar]
  13. Gessain A., Barin F., Vernant J. C., Gout O., Maurs L., Calender A., de Thé G. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet. 1985 Aug 24;2(8452):407–410. doi: 10.1016/s0140-6736(85)92734-5. [DOI] [PubMed] [Google Scholar]
  14. Goldstein D. J., Andresson T., Sparkowski J. J., Schlegel R. The BPV-1 E5 protein, the 16 kDa membrane pore-forming protein and the PDGF receptor exist in a complex that is dependent on hydrophobic transmembrane interactions. EMBO J. 1992 Dec;11(13):4851–4859. doi: 10.1002/j.1460-2075.1992.tb05591.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Goldstein D. J., Finbow M. E., Andresson T., McLean P., Smith K., Bubb V., Schlegel R. Bovine papillomavirus E5 oncoprotein binds to the 16K component of vacuolar H(+)-ATPases. Nature. 1991 Jul 25;352(6333):347–349. doi: 10.1038/352347a0. [DOI] [PubMed] [Google Scholar]
  16. Grabstein K. H., Eisenman J., Shanebeck K., Rauch C., Srinivasan S., Fung V., Beers C., Richardson J., Schoenborn M. A., Ahdieh M. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science. 1994 May 13;264(5161):965–968. doi: 10.1126/science.8178155. [DOI] [PubMed] [Google Scholar]
  17. Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
  18. Hinuma Y., Nagata K., Hanaoka M., Nakai M., Matsumoto T., Kinoshita K. I., Shirakawa S., Miyoshi I. Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6476–6480. doi: 10.1073/pnas.78.10.6476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Inoue J., Seiki M., Taniguchi T., Tsuru S., Yoshida M. Induction of interleukin 2 receptor gene expression by p40x encoded by human T-cell leukemia virus type 1. EMBO J. 1986 Nov;5(11):2883–2888. doi: 10.1002/j.1460-2075.1986.tb04583.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kanamori H., Suzuki N., Siomi H., Nosaka T., Sato A., Sabe H., Hatanaka M., Honjo T. HTLV-1 p27rex stabilizes human interleukin-2 receptor alpha chain mRNA. EMBO J. 1990 Dec;9(12):4161–4166. doi: 10.1002/j.1460-2075.1990.tb07639.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kimura Y., Takeshita T., Kondo M., Ishii N., Nakamura M., Van Snick J., Sugamura K. Sharing of the IL-2 receptor gamma chain with the functional IL-9 receptor complex. Int Immunol. 1995 Jan;7(1):115–120. doi: 10.1093/intimm/7.1.115. [DOI] [PubMed] [Google Scholar]
  22. Koga Y., Oh-Hori N., Sato H., Yamamoto N., Kimura G., Nomoto K. Absence of transcription of lck (lymphocyte specific protein tyrosine kinase) message in IL-2-independent, HTLV-I-transformed T cell lines. J Immunol. 1989 Jun 15;142(12):4493–4499. [PubMed] [Google Scholar]
  23. Kondo M., Takeshita T., Higuchi M., Nakamura M., Sudo T., Nishikawa S., Sugamura K. Functional participation of the IL-2 receptor gamma chain in IL-7 receptor complexes. Science. 1994 Mar 11;263(5152):1453–1454. doi: 10.1126/science.8128231. [DOI] [PubMed] [Google Scholar]
  24. Kondo M., Takeshita T., Ishii N., Nakamura M., Watanabe S., Arai K., Sugamura K. Sharing of the interleukin-2 (IL-2) receptor gamma chain between receptors for IL-2 and IL-4. Science. 1993 Dec 17;262(5141):1874–1877. doi: 10.1126/science.8266076. [DOI] [PubMed] [Google Scholar]
  25. Koralnik I. J., Fullen J., Franchini G. The p12I, p13II, and p30II proteins encoded by human T-cell leukemia/lymphotropic virus type I open reading frames I and II are localized in three different cellular compartments. J Virol. 1993 Apr;67(4):2360–2366. doi: 10.1128/jvi.67.4.2360-2366.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Koralnik I. J., Gessain A., Klotman M. E., Lo Monico A., Berneman Z. N., Franchini G. Protein isoforms encoded by the pX region of human T-cell leukemia/lymphotropic virus type I. Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8813–8817. doi: 10.1073/pnas.89.18.8813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Markham P. D., Salahuddin S. Z., Kalyanaraman V. S., Popovic M., Sarin P., Gallo R. C. Infection and transformation of fresh human umbilical cord blood cells by multiple sources of human T-cell leukemia-lymphoma virus (HTLV). Int J Cancer. 1983 Apr 15;31(4):413–420. doi: 10.1002/ijc.2910310404. [DOI] [PubMed] [Google Scholar]
  28. Maruyama M., Shibuya H., Harada H., Hatakeyama M., Seiki M., Fujita T., Inoue J., Yoshida M., Taniguchi T. Evidence for aberrant activation of the interleukin-2 autocrine loop by HTLV-1-encoded p40x and T3/Ti complex triggering. Cell. 1987 Jan 30;48(2):343–350. doi: 10.1016/0092-8674(87)90437-5. [DOI] [PubMed] [Google Scholar]
  29. Migone T. S., Lin J. X., Cereseto A., Mulloy J. C., O'Shea J. J., Franchini G., Leonard W. J. Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I. Science. 1995 Jul 7;269(5220):79–81. doi: 10.1126/science.7604283. [DOI] [PubMed] [Google Scholar]
  30. Mills G. B., Arima N., May C., Hill M., Schmandt R., Li J., Miyamoto N. G., Greene W. C. Neither the LCK nor the FYN kinases are obligatory for IL-2-mediated signal transduction in HTLV-I-infected human T cells. Int Immunol. 1992 Nov;4(11):1233–1243. doi: 10.1093/intimm/4.11.1233. [DOI] [PubMed] [Google Scholar]
  31. Miyoshi I., Kubonishi I., Yoshimoto S., Akagi T., Ohtsuki Y., Shiraishi Y., Nagata K., Hinuma Y. Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells. Nature. 1981 Dec 24;294(5843):770–771. doi: 10.1038/294770a0. [DOI] [PubMed] [Google Scholar]
  32. Nagata K., Ohtani K., Nakamura M., Sugamura K. Activation of endogenous c-fos proto-oncogene expression by human T-cell leukemia virus type I-encoded p40tax protein in the human T-cell line, Jurkat. J Virol. 1989 Aug;63(8):3220–3226. doi: 10.1128/jvi.63.8.3220-3226.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Nakamura Y., Russell S. M., Mess S. A., Friedmann M., Erdos M., Francois C., Jacques Y., Adelstein S., Leonard W. J. Heterodimerization of the IL-2 receptor beta- and gamma-chain cytoplasmic domains is required for signalling. Nature. 1994 May 26;369(6478):330–333. doi: 10.1038/369330a0. [DOI] [PubMed] [Google Scholar]
  34. Nelson B. H., Lord J. D., Greenberg P. D. Cytoplasmic domains of the interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation. Nature. 1994 May 26;369(6478):333–336. doi: 10.1038/369333a0. [DOI] [PubMed] [Google Scholar]
  35. Nilson L. A., DiMaio D. Platelet-derived growth factor receptor can mediate tumorigenic transformation by the bovine papillomavirus E5 protein. Mol Cell Biol. 1993 Jul;13(7):4137–4145. doi: 10.1128/mcb.13.7.4137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Noguchi M., Nakamura Y., Russell S. M., Ziegler S. F., Tsang M., Cao X., Leonard W. J. Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor. Science. 1993 Dec 17;262(5141):1877–1880. doi: 10.1126/science.8266077. [DOI] [PubMed] [Google Scholar]
  37. Noguchi M., Yi H., Rosenblatt H. M., Filipovich A. H., Adelstein S., Modi W. S., McBride O. W., Leonard W. J. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993 Apr 9;73(1):147–157. doi: 10.1016/0092-8674(93)90167-o. [DOI] [PubMed] [Google Scholar]
  38. Ohashi T., Masuda M., Ruscetti S. K. Induction of sequence-specific DNA-binding factors by erythropoietin and the spleen focus-forming virus. Blood. 1995 Mar 15;85(6):1454–1462. [PubMed] [Google Scholar]
  39. Osame M., Usuku K., Izumo S., Ijichi N., Amitani H., Igata A., Matsumoto M., Tara M. HTLV-I associated myelopathy, a new clinical entity. Lancet. 1986 May 3;1(8488):1031–1032. doi: 10.1016/s0140-6736(86)91298-5. [DOI] [PubMed] [Google Scholar]
  40. Petti L., DiMaio D. Stable association between the bovine papillomavirus E5 transforming protein and activated platelet-derived growth factor receptor in transformed mouse cells. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6736–6740. doi: 10.1073/pnas.89.15.6736. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Petti L., Nilson L. A., DiMaio D. Activation of the platelet-derived growth factor receptor by the bovine papillomavirus E5 transforming protein. EMBO J. 1991 Apr;10(4):845–855. doi: 10.1002/j.1460-2075.1991.tb08017.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Poiesz B. J., Ruscetti F. W., Gazdar A. F., Bunn P. A., Minna J. D., Gallo R. C. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7415–7419. doi: 10.1073/pnas.77.12.7415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Popovic M., Lange-Wantzin G., Sarin P. S., Mann D., Gallo R. C. Transformation of human umbilical cord blood T cells by human T-cell leukemia/lymphoma virus. Proc Natl Acad Sci U S A. 1983 Sep;80(17):5402–5406. doi: 10.1073/pnas.80.17.5402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Reid R. L., Lindholm P. F., Mireskandari A., Dittmer J., Brady J. N. Stabilization of wild-type p53 in human T-lymphocytes transformed by HTLV-I. Oncogene. 1993 Nov;8(11):3029–3036. [PubMed] [Google Scholar]
  45. Rodgers-Johnson P., Gajdusek D. C., Morgan O. S., Zaninovic V., Sarin P. S., Graham D. S. HTLV-I and HTLV-III antibodies and tropical spastic paraparesis. Lancet. 1985 Nov 30;2(8466):1247–1248. doi: 10.1016/s0140-6736(85)90778-0. [DOI] [PubMed] [Google Scholar]
  46. Russell S. M., Keegan A. D., Harada N., Nakamura Y., Noguchi M., Leland P., Friedmann M. C., Miyajima A., Puri R. K., Paul W. E. Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor. Science. 1993 Dec 17;262(5141):1880–1883. doi: 10.1126/science.8266078. [DOI] [PubMed] [Google Scholar]
  47. Siekevitz M., Feinberg M. B., Holbrook N., Wong-Staal F., Greene W. C. Activation of interleukin 2 and interleukin 2 receptor (Tac) promoter expression by the trans-activator (tat) gene product of human T-cell leukemia virus, type I. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5389–5393. doi: 10.1073/pnas.84.15.5389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Suzuki J., Takeshita T., Ohbo K., Asao H., Tada K., Sugamura K. IL-2 receptor subunit, p75: direct demonstration of its IL-2 binding ability by using a novel monoclonal antibody. Int Immunol. 1989;1(4):373–377. doi: 10.1093/intimm/1.4.373. [DOI] [PubMed] [Google Scholar]
  49. Taniguchi T., Minami Y. The IL-2/IL-2 receptor system: a current overview. Cell. 1993 Apr 9;73(1):5–8. doi: 10.1016/0092-8674(93)90152-g. [DOI] [PubMed] [Google Scholar]
  50. Tsudo M., Kitamura F., Miyasaka M. Characterization of the interleukin 2 receptor beta chain using three distinct monoclonal antibodies. Proc Natl Acad Sci U S A. 1989 Mar;86(6):1982–1986. doi: 10.1073/pnas.86.6.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Voss S. D., Sondel P. M., Robb R. J. Characterization of the interleukin 2 receptors (IL-2R) expressed on human natural killer cells activated in vivo by IL-2: association of the p64 IL-2R gamma chain with the IL-2R beta chain in functional intermediate-affinity IL-2R. J Exp Med. 1992 Aug 1;176(2):531–541. doi: 10.1084/jem.176.2.531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Waldmann T. A., White J. D., Goldman C. K., Top L., Grant A., Bamford R., Roessler E., Horak I. D., Zaknoen S., Kasten-Sportes C. The interleukin-2 receptor: a target for monoclonal antibody treatment of human T-cell lymphotrophic virus I-induced adult T-cell leukemia. Blood. 1993 Sep 15;82(6):1701–1712. [PubMed] [Google Scholar]
  53. Watowich S. S., Yoshimura A., Longmore G. D., Hilton D. J., Yoshimura Y., Lodish H. F. Homodimerization and constitutive activation of the erythropoietin receptor. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2140–2144. doi: 10.1073/pnas.89.6.2140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. White K. N., Nosaka T., Kanamori H., Hatanaka M., Honjo T. The nucleolar localisation signal of the HTLV-I protein p27rex is important for stabilisation of IL-2 receptor alpha subunit mRNA by p27rex. Biochem Biophys Res Commun. 1991 Feb 28;175(1):98–103. doi: 10.1016/s0006-291x(05)81205-7. [DOI] [PubMed] [Google Scholar]
  55. Xu X., Kang S. H., Heidenreich O., Okerholm M., O'Shea J. J., Nerenberg M. I. Constitutive activation of different Jak tyrosine kinases in human T cell leukemia virus type 1 (HTLV-1) tax protein or virus-transformed cells. J Clin Invest. 1995 Sep;96(3):1548–1555. doi: 10.1172/JCI118193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Yamaguchi K., Takatsuki K. Adult T cell leukaemia-lymphoma. Baillieres Clin Haematol. 1993 Dec;6(4):899–915. doi: 10.1016/s0950-3536(05)80183-0. [DOI] [PubMed] [Google Scholar]
  57. Yamamoto N., Okada M., Koyanagi Y., Kannagi M., Hinuma Y. Transformation of human leukocytes by cocultivation with an adult T cell leukemia virus producer cell line. Science. 1982 Aug 20;217(4561):737–739. doi: 10.1126/science.6980467. [DOI] [PubMed] [Google Scholar]
  58. Yamanashi Y., Mori S., Yoshida M., Kishimoto T., Inoue K., Yamamoto T., Toyoshima K. Selective expression of a protein-tyrosine kinase, p56lyn, in hematopoietic cells and association with production of human T-cell lymphotropic virus type I. Proc Natl Acad Sci U S A. 1989 Sep;86(17):6538–6542. doi: 10.1073/pnas.86.17.6538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Yoshimura A., D'Andrea A. D., Lodish H. F. Friend spleen focus-forming virus glycoprotein gp55 interacts with the erythropoietin receptor in the endoplasmic reticulum and affects receptor metabolism. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4139–4143. doi: 10.1073/pnas.87.11.4139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Youssoufian H., Longmore G., Neumann D., Yoshimura A., Lodish H. F. Structure, function, and activation of the erythropoietin receptor. Blood. 1993 May 1;81(9):2223–2236. [PubMed] [Google Scholar]
  61. Zambetti G. P., Levine A. J. A comparison of the biological activities of wild-type and mutant p53. FASEB J. 1993 Jul;7(10):855–865. doi: 10.1096/fasebj.7.10.8344485. [DOI] [PubMed] [Google Scholar]

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