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

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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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The genomic structure of the murine ICSBP gene reveals the presence of the gamma interferon-responsive element, to which an ISGF3 alpha subunit (or similar) molecule binds
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“ISGF3 is believed to act as a transcriptional activator involved in the initial stage of type I IFN-induced transcription (5, 12, 13, 14, 26, 32, 56, 57).”
Background
IL-1-induced NFκB and c-Jun N-terminal kinase (JNK) activation diverge at IL-1 receptor-associated kinase (IRAK)
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The genomic structure of the murine ICSBP gene reveals the presence of the gamma interferon-responsive element, to which an ISGF3 alpha subunit (or similar) molecule binds.
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“Other heteromeric transcription factors consist of multiple polypeptides, such as the complexes that contain the herpes simplex virus protein VP16 (8, 24), the interferon-stimulated complex (14, 22 ), and GABP, the GA-binding protein complex (25, 41).”
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The Multiple Roles of Interferon Regulatory Factor family in Health and Disease
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Early events in signalling by interferons.
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Interferon Regulatory Factor-2 Is a Transcriptional Activator in Muscle Where It Regulates Expression of Vascular Cell Adhesion Molecule-1
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“a transcriptionally active complex (Kessler et al., 1990; Darnell et al., 1994).”
Phosphorylation-Induced Dimerization of Interferon Regulatory Factor 7 Unmasks DNA Binding and a Bipartite Transactivation Domain
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“Nuclear extracts were dialyzed against buffer containing 40 mM KCl, 20 mM HEPES (pH 7.6), 1 mM MgCl2, 0.1 mM EGTA, 0.5 mM dithiothreitol, and 10% glycerol and fractionated on 15 to 30% glycerol gradients by centrifugation, as described previously ( 18 ).”
MethodInfluentialSelf-citation
Avian Interferons and Their Antiviral Effectors
Santhakumar, D., Rubbenstroth, D., Martínez‐Sobrido, L., & Munir, M. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00049 · Cited by 157
“Upon nuclear translocation, ISGF3 and GAF bind to IFN-stimulated response elements (ISREs) (88) or GAS element, respectively (1).”
BackgroundInfluential
Weapons of STAT destruction
Horvath, C. M. (2004) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.2004.04425.x · Cited by 161
Stat2 Is a Transcriptional Activator That Requires Sequence-specific Contacts Provided by Stat1 and p48 for Stable Interaction with DNA
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Self-citation
The unique role of STAT2 in constitutive and IFN-induced transcription and antiviral responses
Błaszczyk, K., Nowicka, H., Kostyrko, K., Antonczyk, A., Wesoły, J., & Bluyssen, H. A. R. (2016) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2016.02.010 · Cited by 157
STAT6: its role in interleukin 4-mediated biological functions
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Cytokines and STAT Signaling
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Two distinct alpha-interferon-dependent signal transduction pathways may contribute to activation of transcription of the guanylate-binding protein gene
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“Such a speculation is especially tempting because of the multimeric composition of ISGF-3 (13, 17) and our preliminary biochemical results, which suggest that GAF might be composed of more than one protein (34a).”
Background
Mechanism of action of interferon-tau in the uterus during early pregnancy.
Hansen, T. R., Austin, K., Perry, D. J., Pru, J., Teixeira, M., & Johnson, G. (2019) · Journal of reproduction and fertility. Supplement · doi:10.1530/biosciprocs.4.025 · Cited by 138
“ISGF3 is composed of a 48 kDa DNA-binding protein termed p48, STAT-la (p91), STAT-lb (p84), and STAT-2 (p113) (Kessler et al., 1990).”
Background
Arginine/Lysine-rich Structural Element Is Involved in Interferon-induced Nuclear Import of STATs*
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Two Domains of ISGF3γ That Mediate Protein-DNA and Protein-Protein Interactions during Transcription Factor Assembly Contribute to DNA-Binding Specificity
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“1A and B, lanes 1) because the affinity of the ternary complex for DNA is much greater than that of ISGF3-y alone (23).”
BackgroundInfluentialSelf-citation
Restriction of interferon gamma responsiveness and basal expression of the myeloid human Fc gamma R1b gene is mediated by a functional PU.1 site and a transcription initiator consensus.
Eichbaum, Q. G., Iyer, R., Raveh, D. P., Mathieu, C., & Ezekowitz, R. A. (1994) · The Journal of experimental medicine · doi:10.1084/jem.179.6.1985 · Cited by 86
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Self-citation
New Function of Type I IFN: Induction of Autophagy
Schmeisser, H., Bekisz, J., & Zoon, K. C. (2014) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2013.0128 · Cited by 133
Cerulein Pancreatitis: Oxidative Stress, Inflammation, and Apoptosis
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“Stat signaling can account for various cellular responses to several cytokines, growth factors, and hormones.(60,61) The Jak/Stat pathway is well known to be activated by”
Background
STAT2 Is a Primary Target for Measles Virus V Protein-Mediated Alpha/Beta Interferon Signaling Inhibition
Ramachandran, A., Parisien, J.-P., & Horvath, C. (2008) · Journal of Virology · doi:10.1128/jvi.00831-08 · Cited by 124
“8330 signal transducer and activator of transcription (STAT) proteins, STAT1 and STAT2, and an IFN regulatory factor, IRF9 (12, 20).”
Background
Interferon regulatory factor subcellular localization is determined by a bipartite nuclear localization signal in the DNA-binding domain and interaction with cytoplasmic retention factors.
Lau, J. F., Parisien, J.-P., & Horvath, C. M. (2000) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.97.13.7278 · Cited by 120
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“, 1992b) and which has a 20 to 30-fold higher ISRE binding affinity than IRF9 allone (Levy et al., 1989; Kessler et al., 1990).”
Influential
Alternate interferon signaling pathways
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Background
A unique palindromic element mediates gamma interferon induction of mig gene expression
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Innate immune responses of salmonid fish to viral infections
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Growth hormone signaling pathways
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Type I interferons induce autophagy in certain human cancer cell lines
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Differential roles of STAT1α and STAT1β in fludarabine-induced cell cycle arrest and apoptosis in human B cells
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Acetylation of Interferon Regulatory Factor-7 by p300/CREB-binding Protein (CBP)-associated Factor (PCAF) Impairs its DNA Binding*
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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
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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Interferon-alpha regulates nuclear translocation and DNA-binding affinity of ISGF3, a multimeric transcriptional activator.

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