Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF‐3 and CBP/p300
Open accessAbstract
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 measuredClinical 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).”
From The airway epithelium: soldier in the fight against respiratory viruses (2011) · cites this paper as [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
- ORCID
- Yoneyama, Mitsutoshi
- Venue
- The EMBO Journal
- Published
- 1998-02-15
- Volume
- 17
- Issue
- 4
- Pages
- 1087-1095
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1170457
- 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
- bronze
- doi.org
- 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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