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

Kessler, D S; Veals, S A; Fu, X Y; Levy, D E

doi:10.1101/gad.4.10.1753

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

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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Despite the lack of reporter expression, TF footprints and nucleosome-free regions are present at ISREs pre-stimulation, consistent with the model of pre-bound but transcriptionally inactive IRF9.
“Despite the lack of reporter expression, TF footprints and nucleosome-free regions are present at ISREs pre-stimulation, consistent with the model of pre-bound but transcriptionally inactive IRF939 (Fig. 4C–D, Fig. S6C)”
From Single-molecule states link transcription factor binding to gene expression (2024) · cites this paper as [39]
The ISGF3γ DNA-binding and Discussion sections report an ISRE-binding protein in unstimulated cells, including nuclei, and show that its binding is much weaker than that of activated ISGF3. This is consistent with the proposed model, but the paper tests binding to ISRE probes in extracts; it does not establish that the protein is pre-bound at ISREs in intact cells before stimulation. The cited paper also does not report the citing authors’ reporter-expression or nucleosome-free-region observations. (LLM, conf=0.84)
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Self-citation

Authors: Kessler, D. S., Veals, S. A., Fu, X. Y., & Levy, D. E.
Affiliations: New York University (US)
ORCID: Kessler, D S
Fu, X Y
Levy, D E
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: bronze
doi.org
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
Health Sciences › Medicine › Oncology › 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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Interferon-alpha regulates nuclear translocation and DNA-binding affinity of ISGF3, a multimeric transcriptional activator.

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