The Activation of IL-1-Induced Enhancers Depends on TAK1 Kinase Activity and NF-κB p65

Jurida, Liane; Soelch, Johanna; Bartkuhn, Marek; Handschick, Katja; Müller, H.‐Arno J.; Newel, Doris; Weber, Axel; Dittrich–Breiholz, Oliver; Schneider, Heike; Bhuju, Sabin; Saul, V.; Schmitz, M. Lienhard; Kracht, Michael

doi:10.1016/j.celrep.2015.01.001

Cited by 42 publications

(63 citation statements)

References 47 publications

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“…Here, we identify a TNF␣-inducible c-Jun binding region flanking a cluster of four highly TNF␣-regulated chemokine genes. This region has been found to harbor p65 binding sites induced by interleukin-1 (IL-1) in KB cells (40). By quantitative ChIP-PCR, we confirmed the binding of both AP-1 and p65 at this CXC locus.…”

Section: Discussionsupporting

confidence: 56%

AP-1 Is a Key Regulator of Proinflammatory Cytokine TNFα-mediated Triple-negative Breast Cancer Progression

Qiao

Jonsson

et al. 2016

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 56%

AP-1 Is a Key Regulator of Proinflammatory Cytokine TNFα-mediated Triple-negative Breast Cancer Progression

Qiao

Jonsson

et al. 2016

Journal of Biological Chemistry

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“…Most of the inducible p65 binding sites (3750 sites) are found outside from promoter regions that are only occupied at 635 sites (Fig. 5 C ), a distribution consistent with other studies (15, 36). …”

Section: Resultssupporting

confidence: 89%

“…Direct binding of p65 has been described for the AP-1 family members c-Fos and c-Jun (49). Accordingly, a previous study showed that IL-1–inducible corecruitment of p65 and the AP-1 subunits c-Fos and JunD to the promoters of the NF-κB target genes IL-8 and CXCL2 was dependent on the presence of the p65 protein (15). The auxiliary function of AP-1 binding for strictly NF-κB–dependent expression of the IL-8 gene was also found in this study after mutation of the AP-1 binding site.…”

Section: Discussionmentioning

confidence: 99%

NF‐κB p65 dimerization and DNA‐binding is important for inflammatory gene expression

et al. 2018

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Increasing evidence shows that many transcription factors execute important biologic functions independent from their DNA-binding capacity. The NF-κB p65 (RELA) subunit is a central regulator of innate immunity. Here, we investigated the relative functional contribution of p65 DNA-binding and dimerization in p65-deficient human and murine cells reconstituted with single amino acid mutants preventing either DNA-binding (p65 E/I) or dimerization (p65 FL/DD). DNA-binding of p65 was required for RelB-dependent stabilization of the NF-κB p100 protein. The antiapoptotic function of p65 and expression of the majority of TNF-α–induced genes were dependent on p65’s ability to bind DNA and to dimerize. Chromatin immunoprecipitation with massively parallel DNA sequencing experiments revealed that impaired DNA-binding and dimerization strongly diminish the chromatin association of p65. However, there were also p65-independent TNF-α–inducible genes and a subgroup of p65 binding sites still allowed some residual chromatin association of the mutants. These sites were enriched in activator protein 1 (AP-1) binding motifs and showed increased chromatin accessibility and basal transcription. This suggests a mechanism of assisted p65 chromatin association that can be in part facilitated by chromatin priming and cooperativity with other transcription factors such as AP-1.—Riedlinger, T., Liefke, R., Meier-Soelch, J., Jurida, L., Nist, A., Stiewe, T., Kracht, M., Schmitz, M. L. NF-κB p65 dimerization and DNA-binding is important for inflammatory gene expression.

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“…Next, we analyzed the amounts of NF-κB subunits in soluble (N1) and chromatin (N2) nuclear fractions in response to HCoV-229E infection or IL-1. Consistent with previously published data, IL-1 strongly increased the concentrations of p50, p52, p65 and c-Rel NF-κB subunits by 5 to 10-fold in the soluble N1 fraction, whereas p65 was the most prominently increased subunit stably associated with the N2 chromatin fraction ( Fig 5A and 5B, S6A Fig) [24,25]. In HCoV-229E-infected cells, a modest 1.5 to 3-fold increase of p65 was observed in the N1 fractions, but also of p50 and p52 which are characteristic for the activation of the non-canonical pathway (Fig 5A and 5B).…”

Section: Modulation Of Nf-κb Signaling By Hcov-229e and Functional Resupporting

confidence: 92%

The NF-κB-dependent and -independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells

et al. 2017

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Coronavirus replication takes place in the host cell cytoplasm and triggers inflammatory gene expression by poorly characterized mechanisms. To obtain more insight into the signals and molecular events that coordinate global host responses in the nucleus of coronavirus-infected cells, first, transcriptome dynamics was studied in human coronavirus 229E (HCoV-229E)-infected A549 and HuH7 cells, respectively, revealing a core signature of upregulated genes in these cells. Compared to treatment with the prototypical inflammatory cytokine interleukin(IL)-1, HCoV-229E replication was found to attenuate the inducible activity of the transcription factor (TF) NF-κB and to restrict the nuclear concentration of NF-κB subunits by (i) an unusual mechanism involving partial degradation of IKKβ, NEMO and IκBα and (ii) upregulation of TNFAIP3 (A20), although constitutive IKK activity and basal TNFAIP3 expression levels were shown to be required for efficient virus replication. Second, we characterized actively transcribed genomic regions and enhancers in HCoV-229E-infected cells and systematically correlated the genome-wide gene expression changes with the recruitment of Ser5-phosphorylated RNA polymerase II and prototypical histone modifications (H3K9ac, H3K36ac, H4K5ac, H3K27ac, H3K4me1). The data revealed that, in HCoV-infected (but not IL-1-treated) cells, an extensive set of genes was activated without inducible p65 NF-κB being recruited. Furthermore, both HCoV-229E replication and IL-1 were shown to upregulate a small set of genes encoding immunomodulatory factors that bind p65 at promoters and require IKKβ activity and p65 for expression. Also, HCoV-229E and IL-1 activated a common set of 440 p65-bound enhancers that differed from another 992 HCoV-229E-specific enhancer regions by distinct TF-binding motif combinations. Taken together, the study shows that cytoplasmic RNA viruses fine-tune NF-κB signaling at multiple levels and profoundly reprogram the host cellular chromatin landscape, thereby orchestrating the timely coordinated expression of genes involved in multiple signaling, immunoregulatory and metabolic processes.

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The Activation of IL-1-Induced Enhancers Depends on TAK1 Kinase Activity and NF-κB p65

Cited by 42 publications

References 47 publications

AP-1 Is a Key Regulator of Proinflammatory Cytokine TNFα-mediated Triple-negative Breast Cancer Progression

AP-1 Is a Key Regulator of Proinflammatory Cytokine TNFα-mediated Triple-negative Breast Cancer Progression

NF‐κB p65 dimerization and DNA‐binding is important for inflammatory gene expression

The NF-κB-dependent and -independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells

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