The GRIP1:IRF3 interaction as a target for glucocorticoid receptor-mediated immunosuppression
Open accessAbstract
Glucocorticoids dramatically inhibit cytokine and chemokine production. They act through the glucocorticoid receptor (GR), a ligand-dependent transcription factor that binds to and represses activities of other DNA-bound regulators, activator protein 1 and nuclear factor kappaB, utilizing a p160 GRIP1 as a corepressor. A yeast two-hybrid screen with the GRIP1 corepression domain (RD) yielded interferon (IFN) regulatory factor (IRF)3-a downstream effector of Toll-like receptors (TLR) 3/4 and an essential activator of several IFN and chemokine genes. We defined the GRIP1:IRF3 interface and showed that endogenous GRIP1 and IRF3 interact in mammalian cells. Interestingly, GR and IRF3 competed for GRIP1 binding; GR activation or GRIP1 knockdown in macrophages blocked whereas GRIP1 overexpression rescued IRF3-dependent gene expression. GR interference persisted in MyD88- and IFNA receptor-deficient mice, suggesting a specific disruption of TLR3-IRF3 pathway, not of autocrine IFN signaling. Finally, IRF3-stimulated response elements were necessary and sufficient for TLR3-dependent induction and glucocorticoid inhibition. Thus, GRIP1 plays a cofactor role in innate immunity. Competition with GR for GRIP1 antagonizes IRF3-mediated transcription, identifying the GRIP1:IRF3 interaction as a novel target for glucocorticoid immunosuppression.
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The liganded GR prevents the recruitment of IRF3 to p65 on NF-kappaB target genes upon TLR4 stimulation by LPS.
“The liganded GR was also found to prevent the recruitment of IRF3 (which then acts as a co-activator) to p65 on NF-κB target genes upon TLR4 stimulation by LPS (94, 123).”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [94]
Liganded GRs impact gene transcription through non-genomic mechanisms that do not require de novo protein synthesis and underlie the more rapid actions of GCs.
“In addition to their genomic actions, liganded GRs also impact on gene transcription through various non-genomic mechanisms. These mechanisms do not require de novo protein synthesis and thus underlie the more rapid actions of GCs.”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [94]
Prominent non-genomic examples include mRNA destabilization, competition for co-activators, and interference with the binding of transcription factors to DNA.
“Prominent examples include mRNA destabilization, competition for co-activators [e.g., CREB-binding protein (CBP), p300, and GRIP], and interference with the binding of transcription factors to DNA (91–94).”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [94]
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References 65 · Cited by 149
- Authors
- Reily, M. M., Pantoja, C., Hu, X., Chinenov, Y., & Rogatsky, I.
- Affiliations
- Hospital for Special Surgery (US)
- University of California, San Francisco (US)
- Corresponding author
- Rogatsky, Inez
- Venue
- The EMBO Journal
- Published
- 2005-12-15
- Volume
- 25
- Issue
- 1
- Pages
- 108-117
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1356362
- OpenAlex
- W2060944064
- Cited by
- 149
- References
- 65
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 5 · 2022: 7 · 2021: 8 · 2020: 6 · 2019: 7 · 2018: 3 · 2017: 7 · 2016: 8 · 2015: 6 · 2014: 6 · 2013: 10 · 2012: 9
- FWCI
- 3.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Leukemia and Lymphoma Society
- National Institutes of Health
- National Cancer Institute (CA20535, R01CA020535, R37CA020535)
- 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 › Genetics › Estrogen and related hormone effects
- Keywords
- GRIP1, IRF3, glucocorticoid receptor, glucocorticoid-induced immunosuppression, protein-protein interaction, corepressors, TLR3 signaling, MyD88, interferon-alpha, innate immunity, transcriptional repression, chemokine expression, macrophages
- MeSH terms
- Animals, Binding, Competitive, Cells, Cultured, Glucocorticoids, Immunosuppression Therapy, Macrophages, Mice, Mutant Strains, Receptors, Glucocorticoid, Gene Expression, Interferon-beta, Receptors, Interferon, Response Elements, Two-Hybrid System Techniques, Adaptor Proteins, Signal Transducing, Interferon Regulatory Factor-3, Mice, Nuclear Receptor Coactivator 2, Myeloid Differentiation Factor 88, Receptor, Interferon alpha-beta
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