Cited by 841interferon and immune responsesImmune Response and InflammationCytokine Signaling Pathways and Interactions

Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF‐3 and CBP/p300

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Yoneyama, Mitsutoshi, Suhara, Wakako, Fukuhara, Yukiko, Fukuda, Makoto, Nishida, Eisuke, Fujita, Takashi·1998·The EMBO Journal

Abstract

It has been hypothesized that certain viral infections directly activate a transcription factor(s) which is responsible for the activation of genes encoding type I interferons (IFNs) and interferon-stimulated genes (ISGs) via interferon regulatory factor (IRF) motifs present in their respective promoters. These events trigger the activation of defense machinery against viruses. Here we demonstrate that IRF-3 transmits a virus-induced signal from the cytoplasm to the nucleus. In unstimulated cells, IRF-3 is present in its inactive form, restricted to the cytoplasm due to a continuous nuclear export mediated by nuclear export signal, and it exhibits few DNA-binding properties. Virus infection but not IFN treatment induces phosphorylation of IRF-3 on specific serine residues, thereby allowing it to complex with the co-activator CBP/p300 with simultaneous nuclear translocation and its specific DNA binding. We also show that a dominant-negative mutant of IRF-3 could inhibit virus-induced activation of chromosomal type I IFN genes and ISGs. These findings suggest that IRF-3 plays an important role in the virus-inducible primary activation of type I IFN and IFN-responsive genes.

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  • IRF-3 has a C-terminal autoinhibitory region, and regulated phosphorylation upon viral infection stimulates DNA binding.

    “IRF-3 possesses a C-terminal autoinhibitory region.Regulated phosphorylation of this region upon viral infection stimulates DNA binding”

    From Assembly requirements of PU.1–Pip (IRF‐4) activator complexes: inhibiting function in vivo using fused dimers (1999) · cites this paper as Yoneyama et al., 1998

    The Discussion reports that viral stimulation induces IRF-3 phosphorylation and sequence-specific DNA-binding activity; the Functional domains of IRF-3 section implicates C-terminal serines 385 and 386 in the virus-induced response. Our copy does not identify a C-terminal autoinhibitory region, and the Discussion says the order of phosphorylation and DNA-binding activation could not be determined. (LLM, conf=0.85)

    Experimental — accuracy not yet measured
  • Clinical studies have shown that respiratory viruses increase the incidence and severity of severe secondary bacterial complications.

    “Clinical studies have shown that respiratory viruses increase the incidence and severity of severe secondary bacterial complications (130, 207, 330).”

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Authors
Yoneyama, M., Suhara, W., Fukuhara, Y., Fukuda, M., Nishida, E., & Fujita, T.
Affiliations
  • Tokyo Metropolitan Institute of Medical Science (JP)
  • Kyoto University (JP)
Corresponding author
Fujita, Takashi
Venue
The EMBO Journal
Published
1998-02-15
Volume
17
Issue
4
Pages
1087-1095
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
OpenAlex
W2002301799
Cited by
841
References
54
Citations by year
2026: 14 · 2025: 21 · 2024: 15 · 2023: 20 · 2022: 19 · 2021: 16 · 2020: 26 · 2019: 17 · 2018: 18 · 2017: 15 · 2016: 24 · 2015: 18 · 2014: 27 · 2013: 40 · 2012: 32
FWCI
12.56
Type
journal article
Language
en
Open access
Locations
  • The EMBO Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Boehringer Ingelheim Japan
  • Toray Industries
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
type I interferon, IRF3, CBP/p300, interferon-stimulated genes, transcription factor activation, IRF3 phosphorylation, nuclear export, nuclear translocation, dominant-negative mutant, antiviral signaling, virus-induced gene expression
MeSH terms
Amino Acid Sequence, Animals, Biological Transport, Cell Line, Cell Nucleus, DNA-Binding Proteins, Gene Expression Regulation, Humans, Interferon Type I, Molecular Sequence Data, Newcastle disease virus, Phosphorylation, Promoter Regions, Genetic, Transcription Factors, Tumor Cells, Cultured, Transcriptional Activation, Trans-Activators, Protein Structure, Tertiary, Interferon Regulatory Factor-3, Mice, Histone Acetyltransferases, Nuclear Receptor Coactivator 3

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