Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1997 Jan;71(1):771–777. doi: 10.1128/jvi.71.1.771-777.1997

STAT1 pathway is involved in activation of caprine arthritis-encephalitis virus long terminal repeat in monocytes.

T Sepp 1, S E Tong-Starksen 1
PMCID: PMC191116  PMID: 8985415

Abstract

The caprine arthritis-encephalitis virus (CAEV) long terminal repeat (LTR) is activated by gamma interferon (IFN-gamma) in promonocytic cells. We have previously shown that a 70-bp element is necessary and sufficient for the response of the CAEV LTR to this cytokine. At the 5' end, this 70-bp IFN-gamma response element contains sequence similarity to the gamma activated site (GAS). Here we demonstrate that the putative GAS element in the CAEV LTR binds specifically to a cellular factor induced by IFN-gamma in promonocytic cells. Substitution mutations in this consensus sequence eliminate binding of the inducible factor. The GAS element from the 70-bp motif is sufficient to confer responsiveness to IFN-gamma using a heterologous minimal promoter. Consistent with the binding data, the same mutations in the GAS element eliminate responsiveness to IFN-gamma in the context of both a functional CAEV LTR and a heterologous promoter. The cellular factor that binds to the GAS element is present from 5 min to 14 h after stimulation with IFN-gamma. Binding of the nuclear factor to the GAS element in the CAEV LTR is inhibited by antibody directed against STAT1 (p91/84). Thus, the GAS sequence in the CAEV LTR is essential for the response to IFN-gamma and a STAT1-like factor binds to this site. The STAT-1 signaling pathway provides at least one mechanism for activation of the CAEV LTR by IFN-gamma in monocytes. These data are the first demonstration of a role for a STAT family member in the regulation of a viral promoter.

Full Text

The Full Text of this article is available as a PDF (352.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baron S., Dianzani F. The interferons: a biological system with therapeutic potential in viral infections. Antiviral Res. 1994 Jul;24(2-3):97–110. doi: 10.1016/0166-3542(94)90058-2. [DOI] [PubMed] [Google Scholar]
  2. Caldenhoven E., Coffer P., Yuan J., Van de Stolpe A., Horn F., Kruijer W., Van der Saag P. T. Stimulation of the human intercellular adhesion molecule-1 promoter by interleukin-6 and interferon-gamma involves binding of distinct factors to a palindromic response element. J Biol Chem. 1994 Aug 19;269(33):21146–21154. [PubMed] [Google Scholar]
  3. Crawford T. B., Adams D. S., Cheevers W. P., Cork L. C. Chronic arthritis in goats caused by a retrovirus. Science. 1980 Feb 29;207(4434):997–999. doi: 10.1126/science.6153243. [DOI] [PubMed] [Google Scholar]
  4. Dalton D. K., Pitts-Meek S., Keshav S., Figari I. S., Bradley A., Stewart T. A. Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science. 1993 Mar 19;259(5102):1739–1742. doi: 10.1126/science.8456300. [DOI] [PubMed] [Google Scholar]
  5. Darnell J. E., Jr, Kerr I. M., Stark G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. doi: 10.1126/science.8197455. [DOI] [PubMed] [Google Scholar]
  6. Durbin J. E., Hackenmiller R., Simon M. C., Levy D. E. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell. 1996 Feb 9;84(3):443–450. doi: 10.1016/s0092-8674(00)81289-1. [DOI] [PubMed] [Google Scholar]
  7. Eilers A., Baccarini M., Horn F., Hipskind R. A., Schindler C., Decker T. A factor induced by differentiation signals in cells of the macrophage lineage binds to the gamma interferon activation site. Mol Cell Biol. 1994 Feb;14(2):1364–1373. doi: 10.1128/mcb.14.2.1364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Greenlund A. C., Morales M. O., Viviano B. L., Yan H., Krolewski J., Schreiber R. D. Stat recruitment by tyrosine-phosphorylated cytokine receptors: an ordered reversible affinity-driven process. Immunity. 1995 Jun;2(6):677–687. doi: 10.1016/1074-7613(95)90012-8. [DOI] [PubMed] [Google Scholar]
  9. Griffin G. E., Leung K., Folks T. M., Kunkel S., Nabel G. J. Activation of HIV gene expression during monocyte differentiation by induction of NF-kappa B. Nature. 1989 May 4;339(6219):70–73. doi: 10.1038/339070a0. [DOI] [PubMed] [Google Scholar]
  10. Haagmans B. L., van der Meide P. H., Stals F. S., van den Eertwegh A. J., Claassen E., Bruggeman C. A., Horzinek M. C., Schijns V. E. Suppression of rat cytomegalovirus replication by antibodies against gamma interferon. J Virol. 1994 Apr;68(4):2305–2312. doi: 10.1128/jvi.68.4.2305-2312.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Haase A. T. Pathogenesis of lentivirus infections. Nature. 1986 Jul 10;322(6075):130–136. doi: 10.1038/322130a0. [DOI] [PubMed] [Google Scholar]
  12. Harms J. S., Splitter G. A. Interferon-gamma inhibits transgene expression driven by SV40 or CMV promoters but augments expression driven by the mammalian MHC I promoter. Hum Gene Ther. 1995 Oct;6(10):1291–1297. doi: 10.1089/hum.1995.6.10-1291. [DOI] [PubMed] [Google Scholar]
  13. Harris P., Ralph P. Human leukemic models of myelomonocytic development: a review of the HL-60 and U937 cell lines. J Leukoc Biol. 1985 Apr;37(4):407–422. doi: 10.1002/jlb.37.4.407. [DOI] [PubMed] [Google Scholar]
  14. Hess J. L., Pyper J. M., Clements J. E. Nucleotide sequence and transcriptional activity of the caprine arthritis-encephalitis virus long terminal repeat. J Virol. 1986 Nov;60(2):385–393. doi: 10.1128/jvi.60.2.385-393.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hilfinger J. M., Clark N., Smith M., Robinson K., Markovitz D. M. Differential regulation of the human immunodeficiency virus type 2 enhancer in monocytes at various stages of differentiation. J Virol. 1993 Jul;67(7):4448–4453. doi: 10.1128/jvi.67.7.4448-4453.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ihle J. N. STATs: signal transducers and activators of transcription. Cell. 1996 Feb 9;84(3):331–334. doi: 10.1016/s0092-8674(00)81277-5. [DOI] [PubMed] [Google Scholar]
  17. Lairmore M. D., Akita G. Y., Russell H. I., DeMartini J. C. Replication and cytopathic effects of ovine lentivirus strains in alveolar macrophages correlate with in vivo pathogenicity. J Virol. 1987 Dec;61(12):4038–4042. doi: 10.1128/jvi.61.12.4038-4042.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Meraz M. A., White J. M., Sheehan K. C., Bach E. A., Rodig S. J., Dighe A. S., Kaplan D. H., Riley J. K., Greenlund A. C., Campbell D. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell. 1996 Feb 9;84(3):431–442. doi: 10.1016/s0092-8674(00)81288-x. [DOI] [PubMed] [Google Scholar]
  19. Murray H. W. Interferon-gamma, the activated macrophage, and host defense against microbial challenge. Ann Intern Med. 1988 Apr;108(4):595–608. doi: 10.7326/0003-4819-108-4-595. [DOI] [PubMed] [Google Scholar]
  20. Prieto J., Eklund A., Patarroyo M. Regulated expression of integrins and other adhesion molecules during differentiation of monocytes into macrophages. Cell Immunol. 1994 Jun;156(1):191–211. doi: 10.1006/cimm.1994.1164. [DOI] [PubMed] [Google Scholar]
  21. Queen C., Baltimore D. Immunoglobulin gene transcription is activated by downstream sequence elements. Cell. 1983 Jul;33(3):741–748. doi: 10.1016/0092-8674(83)90016-8. [DOI] [PubMed] [Google Scholar]
  22. Schindler C., Darnell J. E., Jr Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu Rev Biochem. 1995;64:621–651. doi: 10.1146/annurev.bi.64.070195.003201. [DOI] [PubMed] [Google Scholar]
  23. Sherman L., Yaniv A., Lichtman-Pleban H., Tronick S. R., Gazit A. Analysis of regulatory elements of the equine infectious anemia virus and caprine arthritis-encephalitis virus long terminal repeats. J Virol. 1989 Nov;63(11):4925–4931. doi: 10.1128/jvi.63.11.4925-4931.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Shih D. S., Carruth L. M., Anderson M., Clements J. E. Involvement of FOS and JUN in the activation of visna virus gene expression in macrophages through an AP-1 site in the viral LTR. Virology. 1992 Sep;190(1):84–91. doi: 10.1016/0042-6822(92)91194-y. [DOI] [PubMed] [Google Scholar]
  25. Steimle V., Siegrist C. A., Mottet A., Lisowska-Grospierre B., Mach B. Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA. Science. 1994 Jul 1;265(5168):106–109. doi: 10.1126/science.8016643. [DOI] [PubMed] [Google Scholar]
  26. Tong-Starksen S. E., Sepp T., Pagtakhan A. S. Activation of caprine arthritis-encephalitis virus long terminal repeat by gamma interferon. J Virol. 1996 Jan;70(1):595–599. doi: 10.1128/jvi.70.1.595-599.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Tsukada J., Waterman W. R., Koyama Y., Webb A. C., Auron P. E. A novel STAT-like factor mediates lipopolysaccharide, interleukin 1 (IL-1), and IL-6 signaling and recognizes a gamma interferon activation site-like element in the IL1B gene. Mol Cell Biol. 1996 May;16(5):2183–2194. doi: 10.1128/mcb.16.5.2183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Uehara S., Hitoshi Y., Numata F., Makino M., Howard M., Mizuochi T., Takatsu K. An IFN-gamma-dependent pathway plays a critical role in the pathogenesis of murine immunodeficiency syndrome induced by LP-BM5 murine leukemia virus. Int Immunol. 1994 Dec;6(12):1937–1947. doi: 10.1093/intimm/6.12.1937. [DOI] [PubMed] [Google Scholar]
  29. Wen Z., Zhong Z., Darnell J. E., Jr Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995 Jul 28;82(2):241–250. doi: 10.1016/0092-8674(95)90311-9. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES