Interferon-alpha regulates nuclear translocation and DNA-binding affinity of ISGF3, a multimeric transcriptional activator.
10.1101/gad.4.10.1753
Crossref journal-article
Cold Spring Harbor Laboratory
Genes & Development (246)
Abstract

The interaction of interferon-alpha (IFN-alpha) with a specific cell-surface receptor elicits physiological changes that rely on rapid transcriptional activation of a group of IFN-alpha-stimulated genes (ISGs). The IFN-stimulated response element (ISRE), a conserved regulatory element of all ISGs, is the target for transcriptional activation by the positive regulator IFN-stimulated gene factor-3 (ISGF3). We reported previously that post-translational activation of ISGF3 in the cytoplasm of IFN-alpha-treated cells requires two cytoplasmic activities (ISGF3 alpha and ISGF3 gamma) to produce an ISRE-binding complex that accumulates in the nucleus. In this study, we show that these activities are actually distinct subunits of the ISGF3 complex, which associate through noncovalent interaction. Sedimentation analysis, protein renaturation, and photoaffinity cross-linking of enriched preparations of cytoplasmic ISGF3 alpha and ISGF3 gamma and of nuclear ISGF3 demonstrated that ISGF3 gamma was a 48-kD polypeptide with intrinsic, low-affinity DNA-binding activity. Four polypeptides of 48, 84, 91, and 113 kD bound to the ISRE in vitro; the larger three polypeptides most likely compose the ISGF3 alpha component. These ISGF3 alpha polypeptides were unable to bind DNA alone but formed a DNA-binding complex in conjunction with ISGF3 gamma. The resulting heteromeric complex had the same ISRE-binding specificity as the individual ISGF3 gamma polypeptide but approximately 25-fold higher affinity. Whereas ISGF3 gamma partitioned between the cytoplasm and nucleus in unstimulated cells, ISGF3 alpha was stimulated to translocate to the nucleus only following IFN-alpha treatment, resulting in preferential nuclear accumulation of both ISGF3 alpha and ISGF3 gamma as a stable ISGF3-ISRE complex. This regulated nuclear translocation of an activated transcription factor subunit maintained the specificity and rapidity of the IFN-alpha signaling pathway.

Bibliography

Kessler, D. S., Veals, S. A., Fu, X. Y., & Levy, D. E. (1990). Interferon-alpha regulates nuclear translocation and DNA-binding affinity of ISGF3, a multimeric transcriptional activator. Genes & Development, 4(10), 1753–1765.

Authors 4
  1. D S Kessler (first)
  2. S A Veals (additional)
  3. X Y Fu (additional)
  4. D E Levy (additional)
References 57 Referenced 241
  1. 10.1016/0092-8674(88)90382-0
  2. 10.1126/science.3140380
  3. 10.1126/science.3529394
  4. 10.1002/j.1460-2075.1985.tb04055.x / EMBO J. / The common 90-kd protein component of non-transformed “8S” steroid receptors is a heat-shock protein. (1985)
  5. 10.1016/0092-8674(88)90483-7
  6. 10.1002/j.1460-2075.1988.tb02958.x / EMBO J. / Enhancer-like interferon responsive sequences of the human and murine (2′–5′)oligoadenylate synthetase gene promoters. (1988)
  7. 10.1016/0092-8674(88)90024-4
  8. 10.1073/pnas.86.4.1203
  9. 10.1002/j.1460-2075.1989.tb03444.x / EMBO J. / Overlapping sites for constitutive and induced DNA-binding factors involved in interferon-stimulated transcription. (1989)
  10. De Maeyer, E. and J. De Maeyer-Guignard. 1988. Interferons and other regulatory cytokines. John Wiley & Sons, New York.
  11. 10.1021/bi00375a037
  12. 10.1073/pnas.83.15.5382
  13. 10.1126/science.3283939
  14. 10.1101/gad.3.8.1166
  15. 10.1038/314637a0
  16. 10.1016/0092-8674(84)90270-8
  17. 10.1002/j.1460-2075.1988.tb03213.x / EMBO J. / Evidence for a nuclear factor(s), IRF-1, mediating induction and silencing properties to human IFN-β gene regulatory elements. (1988)
  18. 10.1016/0014-4827(89)90106-7
  19. 10.1038/344678a0
  20. {'key': '2021111320121088000_4.10.1753.20', 'first-page': '4495', 'article-title': 'E2F from adenovirus-infected cells binds cooperatively to DNA containing two properly oriented and spaced recognition sites.', 'volume': '9', 'year': '1989', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / E2F from adenovirus-infected cells binds cooperatively to DNA containing two properly oriented and spaced recognition sites. (1989)
  21. 10.1101/gad.3.7.1062
  22. 10.1101/gad.3.11.1699
  23. 10.1016/0092-8674(89)90747-2
  24. 10.1038/322743a0
  25. 10.1073/pnas.85.22.8521
  26. 10.1002/j.1460-2075.1988.tb03262.x / EMBO J. / Cells resistant to interferon are defective in activation of a promoter-binding factor. (1988)
  27. 10.1038/227680a0
  28. 10.1016/S0021-9258(17)42492-6 / J. Biol. Chem. / Transcriptional induction by interferon. (1986)
  29. 10.1073/pnas.81.21.6733
  30. 10.1016/0092-8674(89)90966-5
  31. 10.1101/gad.3.9.1362
  32. {'key': '2021111320121088000_4.10.1753.32', 'first-page': '383', 'article-title': 'Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative control.', 'volume': '2', 'year': '1998', 'journal-title': 'Genes Dev.'} / Genes Dev. / Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative control. (1998)
  33. 10.1073/pnas.83.23.8929
  34. 10.1002/j.1460-2075.1990.tb08216.x / EMBO J. / Synergistic interaction between interferon-α and interferon-γ through induced synthesis of one subunit of the transcription factor ISGF3. (1990)
  35. {'key': '2021111320121088000_4.10.1753.35', 'first-page': '5404', 'article-title': 'α-interferon and γ interferon stimulate transcription of a single gene through different signal transduction pathways.', 'volume': '9', 'year': '1989', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / α-interferon and γ interferon stimulate transcription of a single gene through different signal transduction pathways. (1989)
  36. 10.1073/pnas.87.5.2008
  37. 10.1016/0092-8674(88)90122-5
  38. {'key': '2021111320121088000_4.10.1753.38', 'first-page': '2448', 'article-title': 'Purification and cloning of interferon-stimulated-gene factor 2: ISGF2 (IRF-1) can bind to the promoters of both interferon-β and interferon-stimulated genes but is not a primary transcriptional activator of either.', 'volume': '10', 'year': '1990', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / Purification and cloning of interferon-stimulated-gene factor 2: ISGF2 (IRF-1) can bind to the promoters of both interferon-β and interferon-stimulated genes but is not a primary transcriptional activator of either. (1990)
  39. 10.1002/j.1460-2075.1988.tb02786.x / EMBO J. / Interferon response element of the human gene 6–16. (1988)
  40. 10.1093/nar/17.9.3415
  41. 10.1073/pnas.84.18.6394
  42. 10.1016/0092-8674(89)90774-5
  43. 10.1016/0092-8674(89)90772-1
  44. 10.1002/j.1460-2075.1988.tb02872.x / EMBO J. / Interferon-induced binding of nuclear factors to promoter elements of the 2–5A synthetase gene. (1988)
  45. 10.1016/S0021-9258(17)38886-5 / J. Biol. Chem. / Evidence that the 90-kDa phosphoprotein associated with the untransformed L-cell glucocorticoid receptor is a murine heat shock protein. (1985)
  46. 10.1002/j.1460-2075.1990.tb08218.x / EMBO J. / Synergism in ternary complex formation between the dimeric glycoprotein p67SRF, polypeptide p62TCF and the c-fos serum response element. (1990)
  47. {'key': '2021111320121088000_4.10.1753.47', 'first-page': '2424', 'article-title': 'In vitro activation and nuclear translocation of NF-γB catalyzed by cyclic AMP-dependent protein kinase and protein kinase C.', 'volume': '9', 'year': '1989', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / In vitro activation and nuclear translocation of NF-γB catalyzed by cyclic AMP-dependent protein kinase and protein kinase C. (1989)
  48. 10.1073/pnas.85.16.5884
  49. 10.1016/0092-8674(89)90773-3
  50. {'key': '2021111320121088000_4.10.1753.50', 'first-page': '2625', 'article-title': 'Interferons increase transcription of a major histocompatibility class I gene via a 5′ interferon consensus sequence.', 'volume': '7', 'year': '1987', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / Interferons increase transcription of a major histocompatibility class I gene via a 5′ interferon consensus sequence. (1987)
  51. 10.1021/bi00366a043
  52. {'key': '2021111320121088000_4.10.1753.52', 'first-page': '13', 'article-title': 'Interferons alpha and beta as cellular regulatory molecules.', 'volume': '9', 'year': '1987', 'journal-title': 'Interferon'} / Interferon / Interferons alpha and beta as cellular regulatory molecules. (1987)
  53. 10.1016/0092-8674(87)90328-X
  54. 10.1016/0092-8674(90)90738-Z
  55. {'key': '2021111320121088000_4.10.1753.55', 'first-page': '3550', 'article-title': 'A transcriptional enhancer and an interferon-responsive sequence in major histocompatibility complex class I genes.', 'volume': '6', 'year': '1986', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / A transcriptional enhancer and an interferon-responsive sequence in major histocompatibility complex class I genes. (1986)
  56. 10.1111/j.1432-1033.1987.tb13614.x / Eur. J. Biochem. / New inducers revealed by the promoter sequence analysis of two interferon-activated human genes. (1987)
  57. 10.1016/0003-2697(81)90179-2
Dates
Type When
Created 18 years, 2 months ago (June 5, 2007, 5:15 p.m.)
Deposited 3 years, 9 months ago (Nov. 13, 2021, 11:15 p.m.)
Indexed 3 months, 1 week ago (May 20, 2025, 10:30 a.m.)
Issued 34 years, 10 months ago (Oct. 1, 1990)
Published 34 years, 10 months ago (Oct. 1, 1990)
Published Online 34 years, 10 months ago (Oct. 1, 1990)
Published Print 34 years, 10 months ago (Oct. 1, 1990)
Funders 0

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@article{Kessler_1990, title={Interferon-alpha regulates nuclear translocation and DNA-binding affinity of ISGF3, a multimeric transcriptional activator.}, volume={4}, ISSN={1549-5477}, url={http://dx.doi.org/10.1101/gad.4.10.1753}, DOI={10.1101/gad.4.10.1753}, number={10}, journal={Genes & Development}, publisher={Cold Spring Harbor Laboratory}, author={Kessler, D S and Veals, S A and Fu, X Y and Levy, D E}, year={1990}, month=oct, pages={1753–1765} }