Suppression of interferon β gene transcription by inhibitors of bromodomain and extra-terminal (BET) family members

Nazma Malik, Stefan Vollmer, Sambit Kumar Nanda, Marta Lopez-Pelaez, Alan Prescott, Nathanael Gray, Philip Cohen (Lead / Corresponding author)

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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 (interferonregulatory 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 andATF2 (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.

Original languageEnglish
Pages (from-to)363-372
Number of pages10
JournalBiochemical Journal
Volume468
Issue number3
DOIs
Publication statusPublished - 15 Jun 2015

Fingerprint

Transcription
Interferons
Genes
Toll-Like Receptor 3
Phosphorylation
Phosphotransferases
Ligation
Transcription Factors
Activating Transcription Factor 2
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Ligands
Gene Targeting
Dimerization
Histones
Dendritic Cells
Lysine
BI 2536
Proteins
Cell Line

Keywords

  • BI-2536
  • Bromodomain and extra-terminal
  • Histone
  • Interferon
  • Polo-like kinase
  • Toll-like receptor

Cite this

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title = "Suppression of interferon β gene transcription by inhibitors of bromodomain and extra-terminal (BET) family members",
abstract = "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 (interferonregulatory 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 andATF2 (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.",
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Suppression of interferon β gene transcription by inhibitors of bromodomain and extra-terminal (BET) family members. / Malik, Nazma; Vollmer, Stefan; Nanda, Sambit Kumar; Lopez-Pelaez, Marta; Prescott, Alan; Gray, Nathanael; Cohen, Philip (Lead / Corresponding author).

In: Biochemical Journal, Vol. 468, No. 3, 15.06.2015, p. 363-372.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Suppression of interferon β gene transcription by inhibitors of bromodomain and extra-terminal (BET) family members

AU - Malik, Nazma

AU - Vollmer, Stefan

AU - Nanda, Sambit Kumar

AU - Lopez-Pelaez, Marta

AU - Prescott, Alan

AU - Gray, Nathanael

AU - Cohen, Philip

PY - 2015/6/15

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N2 - 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 (interferonregulatory 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 andATF2 (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.

AB - 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 (interferonregulatory 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 andATF2 (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.

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KW - Interferon

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KW - Toll-like receptor

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