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Cited by 312interferon and immune responsesCytokine Signaling Pathways and InteractionsGenomics and Chromatin Dynamics

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Interferon-alpha regulates nuclear translocation and DNA-binding affinity of ISGF3, a multimeric transcriptional activator.

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Kessler, D S, Veals, S A, Fu, X Y, Levy, D E·1990·Genes & Development
DOI 10.1101/gad.4.10.1753
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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.

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Metadata

Authors
Kessler, D. S., Veals, S. A., Fu, X. Y., & Levy, D. E.
Affiliations
New York University (US)
ORCID
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
1990-10
Volume
4
Issue
10
Pages
1753-1765
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
DOI
10.1101/gad.4.10.1753
OpenAlex
W2136690547
Cited by
312
References
0
Citations by year
2026: 4 · 2025: 2 · 2024: 7 · 2023: 7 · 2022: 6 · 2021: 5 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 5 · 2016: 6 · 2015: 5 · 2014: 3 · 2013: 4 · 2012: 8
Type
posted content
Language
en
Open access
Locations
  • Genes & Development (publishedVersion)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • American Cancer Society
  • Cancer Research Institute
  • Amgen
  • National Institutes of Health (2s07rr005399-30)
  • National Cancer Institute (CA16087, P30CA016087)
  • National Institute of Allergy and Infectious Diseases (R01-AI28900-01, R01AI028900)
  • National Center for Research Resources (S07RR05399-28)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
interferon-alpha, ISGF3, interferon-stimulated response element, interferon-stimulated genes, transcriptional activation, nuclear translocation, DNA binding affinity, transcription factor complex, heteromeric complexes, interferon signaling
MeSH terms
Base Sequence, Biological Transport, Biopolymers, Cell Nucleus, Centrifugation, Density Gradient, Cytoplasm, DNA-Binding Proteins, Electrophoresis, Polyacrylamide Gel, Humans, Interferon Type I, Molecular Sequence Data, Transcription Factors

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