IFN-Stimulated Gene 15 Is Synergistically Activated Through Interactions Between the Myelocyte/Lymphocyte-Specific Transcription Factors, PU.1, IFN Regulatory Factor-8/IFN Consensus Sequence Binding Protein, and IFN Regulatory Factor-4: Characterization of a New Subtype of IFN-Stimulated Response Element
Open accessAbstract
Type I IFNs cause the induction of a subset of genes termed IFN-stimulated genes (ISGs), which harbor a specific DNA element, IFN-stimulated response element (ISRE). This ISRE confers the responsiveness to the IFN signal through the binding of a family of transcription factors designated IFN regulatory factors (IRFs). Some IRFs can bind to the DNA alone, such as IRF-1, which elicits transcriptional activation, or IRF-2, which leads to transcriptional repression. In addition, these factors associate with IRF-8/IFN consensus sequence binding protein (ICSBP), an immune cell-restricted IRF, and the assembled heterocomplexes lead to synergistic repression of ISRE elements. ISG15 is a prototype ISG that contains a well-characterized ISRE. Here we show that PU.1, an ETS member essential for myeloid/lymphoid cell differentiation, forms heterocomplexes with the immune-restricted IRFs, IRF-8\/ICSBP and IRF-4, which lead to transcriptional activation of ISG15. These data allowed the characterization of a subset of ISREs designated ETS/IRF response element (EIRE), which are differentially regulated in immune cells. EIREs are unique in their ability to recruit different factors to an assembled enhanceosomes. In nonimmune cells the factors will mainly include IRF members, while cell type-restricted factors, such as PU.1, IRF-8\/ICSBP, and IRF-4, will be recruited in immune cells. IRF heterocomplex formation leads to transcriptional repression, and conversely, PU.1/IRFs heterocomplex formation leads to transcriptional activation. The fact that IRF-8\/ICSBP is an IFN-γ-induced factor explains why some of the EIREs are also induced by type II IFN. Our results lay the molecular basis for the unique regulation of ISGs, harboring EIRE, in immune cells.
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Irf8 cooperatively regulates the expression of target genes together with PU.1.
“As Irf8 cooperatively regulates the expression of target genes together with PU.130–32”
From Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia (2015) · cites this paper as [32]
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- Authors
- Meraro, D., Gleit-Kielmanowicz, M., Hauser, H., & Levi, B.-Z.
- Affiliations
- Technion – Israel Institute of Technology (IL)
- Department of Gene Regulation and Differentiation, Gesellschaft für Biotechnologische Forschung , Braunschweig ,
- Corresponding author
- Meraro, David
- ORCID
- Levi, Ben-Zion
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2002-06
- Volume
- 168
- Issue
- 12
- Pages
- 6224-6231
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1786654010
- Cited by
- 105
- References
- 12
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 1 · 2020: 5 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 3 · 2015: 1 · 2014: 1 · 2013: 5 · 2012: 5
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The Journal of Immunology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- German-Israeli Foundation for Scientific Research and Development
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- ISG15, IFN-stimulated response element, PU.1, IRF4, type I interferon, transcriptional activation, transcriptional repression, heterocomplexes, enhanceosome, interferon-gamma
- MeSH terms
- Interferon Regulatory Factor-8, Interferon Regulatory Factor-4, Proto-Oncogene Protein Spi-1, Animals, DNA-Binding Proteins, Drug Synergism, Gene Expression Regulation, Hematopoietic Stem Cells, Humans, Interferon Type I, Interferons, Phosphoproteins, Proto-Oncogene Proteins, Repressor Proteins, Transcription Factors, Ubiquitins, Transcriptional Activation, Trans-Activators, Cytokines, Consensus Sequence, 3T3 Cells, K562 Cells, Response Elements, U937 Cells, Interferon Regulatory Factors, Interferon Regulatory Factor-1, Mice
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