S-glutathionylation of IRF3 regulates IRF3–CBP interaction and activation of the IFNβ pathway
Open Access
- 28 February 2008
- journal article
- research article
- Published by Springer Nature in The EMBO Journal
- Vol. 27 (6) , 865-875
- https://doi.org/10.1038/emboj.2008.28
Abstract
Interferon regulatory factor 3 (IRF3) is an essential transcriptional regulator of the interferon genes. IRF3 is constitutively present in a latent conformation in the cell cytoplasm. In cells infected by Sendai virus, IRF3 becomes phosphorylated, homodimerizes, translocates to the nucleus, binds to target genes and activates transcription by interacting with CBP/p300 co‐activators. In this study, we report that in non‐infected cells IRF3 is post‐translationally modified by S ‐glutathionylation. Upon viral‐infection, it undergoes a deglutathionylation step that is controlled by the cytoplasmic enzyme glutaredoxin‐1 (GRX‐1). In virus‐infected GRX‐1 knockdown cells, phosphorylation, homodimerization and nuclear translocation of IRF3 were not affected, but the transcriptional activity of IRF3 and the expression of interferon‐β (IFNβ), were severely reduced. We show that deglutathionylation of IRF3 is necessary for efficient interaction of IRF3 with CBP, an event essential for transcriptional activation of the interferon genes. Taken together, these findings reveal a crucial role for S ‐glutathionylation and GRX‐1 in controlling the activation of IRF3 and IFNβ gene expression.Keywords
This publication has 49 references indexed in Scilit:
- Epigenetic determination of a cell-specific gene expression program by ATF-2 and the histone variant macroH2AThe EMBO Journal, 2006
- Dynamic redox control of NF-κB through glutaredoxin-regulated S-glutathionylation of inhibitory κB kinase βProceedings of the National Academy of Sciences, 2006
- Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein that Activates NF-κB and IRF3Cell, 2005
- Innate Cellular Response to Virus Particle Entry Requires IRF3 but Not Virus ReplicationJournal of Virology, 2004
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001
- Studies on the Mechanism of Oxidative Modification of Human Glyceraldehyde-3-phosphate Dehydrogenase by Glutathione: Catalysis by GlutaredoxinBiochemical and Biophysical Research Communications, 1998
- Involvement of the IRF family transcription factor IRF‐3 in virus‐induced activation of the IFN‐β geneFEBS Letters, 1998
- Recruitment of CBP/p300 by the IFNβ Enhanceosome Is Required for Synergistic Activation of TranscriptionMolecular Cell, 1998
- Recent Trends in Glutathione Biochemistry—Glutathione–Protein Interactions: A Molecular Link between Oxidative Stress and Cell Proliferation?Biochemical and Biophysical Research Communications, 1998
- Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-β gene regulatory elementsCell, 1988