Suppression of interferon β gene transcription by inhibitors of bromodomain and extra-terminal (BET) family members
| Autor: | Malik, Nazma, Vollmer, Stefan, Nanda, Sambit Kumar, Lopez-Pelaez, Marta, Prescott, Alan, Gray, Nathanael, Cohen, Philip |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Transcription
Genetic Proto-Oncogene Proteins c-jun Cell Cycle Proteins histone Antimitotic Agents Ligands Mice BI-2536 Toll-like receptor Animals Humans Protein Isoforms Promoter Regions Genetic Research Articles Cell Line Transformed Polo-like kinase Macrophages Pteridines Nuclear Proteins interferon Dendritic Cells Interferon-beta Toll-Like Receptor 7 Toll-Like Receptor 9 Interferon Regulatory Factor-3 bromodomain and extra-terminal Research Article Signal Transduction Transcription Factors |
| Zdroj: | Biochemical Journal |
| ISSN: | 1470-8728 0264-6021 |
| Popis: | We have found that interferon production is suppressed by compounds that prevent bromodomains from interacting with acetylated histones at the interferon gene promoter. This is a new way in which interferon production is regulated to combat bacterial or viral infection. PLK (Polo-like kinase) inhibitors, such as BI-2536, have been reported to suppress IFNB (encoding IFNβ, interferon β) gene transcription induced by ligands that activate TLR3 (Toll-like receptor 3) and TLR4. In the present study, we found that BI-2536 is likely to exert this effect by preventing the interaction of the transcription factors IRF3 (interferon-regulatory factor 3) and c-Jun with the IFNB promoter, but without affecting the TBK1 {TANK [TRAF (tumour-necrosis-factor-receptor-associated factor)-associated nuclear factor κB activator]-binding kinase 1}-catalysed phosphorylation of IRF3 at Ser396, the dimerization and nuclear translocation of IRF3 or the phosphorylation of c-Jun and ATF2 (activating transcription factor 2). Although BI-2536 inhibits few other kinases tested, it interacts with BET (bromodomain and extra-terminal) family members and displaces them from acetylated lysine residues on histones. We found that BET inhibitors that do not inhibit PLKs phenocopied the effect of BI-2536 on IFNB gene transcription. Similarly, BET inhibitors blocked the interaction of IRF5 with the IFNB promoter and the secretion of IFNβ induced by TLR7 or TLR9 ligands in the human plasmacytoid dendritic cell line GEN2.2, but without affecting the nuclear translocation of IRF5. We found that the BET family member BRD4 (bromodomain-containing protein 4) was associated with the IFNB promoter and that this interaction was enhanced by TLR3- or TLR4-ligation and prevented by BI-2536 and other BET inhibitors. Our results establish that BET family members are essential for TLR-stimulated IFNB gene transcription by permitting transcription factors to interact with the IFNB promoter. They also show that the interaction of the IFNB promoter with BRD4 is regulated by TLR ligation and that BI-2536 is likely to suppress IFNB gene transcription by targeting BET family members. |
| Databáze: | OpenAIRE |
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