Acetylation of Interferon Regulatory Factor-7 by p300/CREB-binding Protein (CBP)-associated Factor (PCAF) Impairs its DNA Binding

Caillaud, Alexandre; Prakash, Arun; Smith, Eric; Masumi, Atsuko; Hovanessian, Ara G.; Levy, David E.; Marié, Isabelle

doi:10.1074/jbc.m207484200

Cited by 72 publications

(67 citation statements)

References 31 publications

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“…Although previous studies have indicated that several IRF family members are acetylated and that acetylation inhibits their ability to bind DNA (21,22), our results do not support the notion that treatment of cells with TSA affects the ability of IRF9 to form an ISRE-binding complex with tyrosine-phosphorylated Stat1 and Stat2 (see Fig. 1).…”

Section: Resultscontrasting

confidence: 56%

Histone Deacetylase Activity Is Required to Recruit RNA Polymerase II to the Promoters of Selected Interferon-stimulated Early Response Genes

Sakamoto

Potla

Larner

2004

Journal of Biological Chemistry

120

119

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The biological actions of interferons (IFNs) 1 require the activation of immediate early genes, which are mediated by the Stat family of transcription factors (1). Type 1 interferons (IFN␣/␤) binding to their cell surface receptors initiate a set of events that leads to tyrosine phosphorylation of Stat1 and Stat2. Tyrosine-phosphorylated Stat1 and Stat2 heterodimerize through their Src homology 2 domains and translocate to the nucleus where they bind to interferon regulatory factor 9 (IRF9) to form the transcription complex ISGF3. ISGF3 binds to an interferon-stimulated response element (ISRE) that is present in many IFN␣/␤-stimulated genes. Alternatively, tyrosine-phosphorylated Stat1 can form homodimers and bind to a ␥ interferon activation sequence (GAS), an enhancer in the promoter of genes that do not require the participation of Stat2 or IRF9.Binding of ISGF3 to cellular genes containing ISREs is accompanied by changes in the chromatin structure of interferonstimulated genes (ISGs) (2). Cells incubated with IFN␣ show altered DNase I sensitivity surrounding the TATA box region as well as the ISRE of ISGs, suggesting that gene activation occurs as a result of chromatin remodeling (2). Consistent with this observation, both Stat1 and Stat2 have been shown to interact with the histone acetylases CBP/p300 and GCN5 resulting in increased association of the acetylated histone H3 with the promoter of the IFN␣/␤-stimulated gene ISG54 (3-6).From these observations one would predict that incubation of cells with HDAC inhibitors would increase IFN-activated gene expression, and this is indeed the case when one examines IFN␥-stimulated expression of the MHC-II (7). However, in contrast to IFN␥, interleukin-3-activated Stat5-dependent genes are inhibited in cells exposed to TSA (8), suggesting that in certain contexts HDAC activity may be required for Stat-dependent gene activation. Interestingly, other genes in which expression is activated by interleukin-3 in a Stat5-independent manner are unaffected by TSA. To examine the role of HDAC activity in the expression of genes regulated by Stat1 and Stat2, we have assayed for the expression of several RNAs in which genes are controlled by these transcription factors. To our surprise the actions of TSA on IFN␣/␤-stimulated gene expression were relatively selective. Whereas some IFN␣/␤-stimulated genes in which expression is regulated by an ISRE were strongly suppressed by TSA, others showed a more modest inhibition. Furthermore, genes in which activation required a GAS element, such as IRF-1, were not altered by TSA treatment. HDAC activity appears to be required to recruit RNA polymerase II (Pol II), but not Stat1 or Stat2, to the promoter of TSA-sensitive genes. The effects of TSA seem to be mediated either directly or indirectly by IRF9. Interestingly, if Pol II is already bound to the promoter and there is basal expression of the gene in the absence of IFN␣/␤ (i.e. IRF-1), then the suppressive actions of TSA are not observed. These data suggest a novel function for IRF9 ...

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Section: Resultscontrasting

confidence: 56%

Histone Deacetylase Activity Is Required to Recruit RNA Polymerase II to the Promoters of Selected Interferon-stimulated Early Response Genes

Sakamoto

Potla

Larner

2004

Journal of Biological Chemistry

120

119

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“…Alternatively, the ability of IRF-7 to bind to DNA after nuclear translocation and act as a transcription factor may be affected. It is known that acetylation of the DNA-binding domain of IRF-7 inhibits its ability to bind DNA (47). It is also possible that while cross-linking CD123 does not affect IRF-7 in PDC, it might have an impact on another IRF important for IFN-␣ production.…”

Section: Discussionmentioning

confidence: 96%

Receptor Cross-Linking on Human Plasmacytoid Dendritic Cells Leads to the Regulation of IFN-α Production

Fanning

George²,

Feng

et al. 2006

The Journal of Immunology

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Plasmacytoid dendritic cells (PDC) are the natural type I IFN-producing cells that produce large amounts of IFN-α in response to viral stimulation. During attempts to isolate PDC from human PBMC, we observed that cross-linking a variety of cell surface receptors, including blood DC Ag (BDCA)-2, BDCA-4, CD4, or CD123 with Abs and immunobeads on PDC leads to inhibition of IFN-α production in response to HSV. To understand the mechanisms involved, a number of parameters were investigated. Cross-linking did not inhibit endocytosis of soluble Ag by PDC. Flow cytometry for annexin V and activated caspase-3 indicated that PDC are not undergoing apoptosis after receptor cross-linking. Cross-linking of CD123, but not the other receptors, caused the up-regulation of costimulatory molecules CD80 and CD86, as well as the down-regulation of CD62L, indicating PDC maturation. Thus, anti-CD123 Ab may be acting similar to the natural ligand, IL-3. Anti-phosphotyrosine Ab, as well as Ab to the IFN regulatory factor, IRF-7, was used in intracellular flow cytometry to elucidate the signaling pathways involved. Tyrosine phosphorylation occurred after cross-linking BDCA-2 and BDCA-4, but not CD4. Cross-linking did not affect IRF-7 levels in PDC, however, cross-linking BDCA-2, BDCA-4, and CD4, but not CD123, inhibited the ability of IRF-7 to translocate to the nucleus. Taken together, these results suggest that cross-linking BDCA-2, BDCA-4, and CD4 on PDC regulates IFN-α production at the level of IRF-7, while the decrease in IFN-α production after CD123 cross-linking is due to stimulation of the IL-3R and induction of PDC maturation.

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“…Several transcription factors show increased DNA binding and subsequent transcriptional activity when acetylated, which correlates with the hyper-acetylation of histones in target chromatin (see references in Supplementary information S1 (table)). Perhaps more surprisingly, in some cases acetylation impairs the binding of transcriptional activators to the DNA, indicating that HATs and HDACs might work in an orchestrated way to achieve the same cellular effect 31 . Interestingly, general transcription factor 2B (GTF2B, also known as TFIIB) has been reported to behave as an auto-acetyltransferase, and acetylation regulates its activity 32 .…”

Section: At a Glancementioning

confidence: 99%

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

2006

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| Histone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully understood. Investigating these aspects in the context of what we now understand about HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols.Histone deacetylases (HDACs) have been intensively scrutinized over the past few years for two main reasons. First, they have been linked mechanistically to the pathogenesis of cancer, as well as several other diseases. Second, small-molecule HDAC inhibitors (HDACi) exist that have the capacity to interfere with HDAC activity and can therefore achieve significant biological effects in preclinical models of cancer. These findings justified the introduction of HDACi into clinical trials. These initial clinical trials have just ended and show encouraging results. At this stage it is crucial to evaluate whether our current knowledge on the mechanisms of tumorigenesis that are linked to HDACs, and on the mechanisms of tumour sensitivity to HDACi, is firm enough to improve the design of further clinical trials. Recent structural and chemical data have emerged that will help in the design of novel HDACi with more desirable properties than the existing ones. However, key areas of investigation that might help to further illuminate the design of successful HDACi-based cancer therapy remain poorly explored. Novel findings indicate that our understanding of how HDACi work will probably change significantly, establishing a new paradigm in the field of intelligent drug design with broad implications for the design of targeted therapies in cancer and possibly other diseases.HDACs: enzymes looking for substrate(s) Four HDAC classes have been identified (FIG. 1a). One of them (class 3 or the so-called sirtuins, from the yeast protein Sir2) constitutes a structurally unrelated, NADdependent subfamily, and will not be considered here; neither will the class 3-specific HDACi, which are less characterized than those for the other classes 1 .An extensive phylogenetic analysis of HDACs has been performed 2,3 . HDACs are members of an ancient enzyme family found in animals, plants, fungi and bacteria. It is thought that HDACs evolved in the absence of histone proteins. Indeed, eukaryotic HDACs can deacetylate non-histone as well as histone substrates, and some HDACs reside in the cytoplasm (where histones are synthesized and acetylated for proper assembly, without the intervention of HDACs) and in mitochondria (where histones are absent).Are HDACs, then, truly HDACs 4 ? We postulate that key HDAC substrates might not be histones, but instead belong to the growing list of acetylated non-histone proteins (FIG. 1b and Supplementary information S1 ...

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Acetylation of Interferon Regulatory Factor-7 by p300/CREB-binding Protein (CBP)-associated Factor (PCAF) Impairs its DNA Binding

Cited by 72 publications

References 31 publications

Histone Deacetylase Activity Is Required to Recruit RNA Polymerase II to the Promoters of Selected Interferon-stimulated Early Response Genes

Histone Deacetylase Activity Is Required to Recruit RNA Polymerase II to the Promoters of Selected Interferon-stimulated Early Response Genes

Receptor Cross-Linking on Human Plasmacytoid Dendritic Cells Leads to the Regulation of IFN-α Production

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

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