Opposite Orientations of a Transcription Factor Heterodimer Bind DNA Cooperatively with Interaction Partners but Have Different Effects on Interferon-β Gene Transcription

Burns, Veronica Elizabeth; Kerppola, Tom K.

doi:10.1074/jbc.m112.374462

Cited by 5 publications

(7 citation statements)

References 24 publications

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“…In mouse embryonic fibroblasts (MEFs), studies using p65/RelA knockout mice suggested that NF-κB was rate limiting for IFN transcription only under conditions of low IRF3 activation (68). Interestingly, IRF3 recruitment has been proposed to be more efficient when c-jun/ATF2 are already bound adjacent to the IRF binding site (66, 69). …”

Section: Discussionmentioning

confidence: 99%

Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways

McGuire

Rosner

Ananieva

et al. 2017

Molecular and Cellular Biology

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Autocrine or paracrine signaling by beta interferon (IFN-β) is essential for many of the responses of macrophages to pathogen-associated molecular patterns. This feedback loop contributes to pathological responses to infectious agents and is therefore tightly regulated. We demonstrate here that macrophage expression of IFN-β is negatively regulated by mitogen- and stress-activated kinases 1 and 2 (MSK1/2). Lipopolysaccharide (LPS)-induced expression of IFN-β was elevated in both MSK1/2 knockout mice and macrophages. Although MSK1 and -2 promote the expression of the anti-inflammatory cytokine interleukin 10, it did not strongly contribute to the ability of MSKs to regulate IFN-β expression. Instead, MSK1 and -2 inhibit IFN-β expression via the induction of dual-specificity phosphatase 1 (DUSP1), which dephosphorylates and inactivates the mitogen-activated protein kinases p38 and Jun N-terminal protein kinase (JNK). Prolonged LPS-induced activation of p38 and JNK, phosphorylation of downstream transcription factors, and overexpression of IFN-β mRNA and protein were similar in MSK1/2 and DUSP1 knockout macrophages. Two distinct mechanisms were implicated in the overexpression of IFN-β: first, JNK-mediated activation of c-jun, which binds to the IFN-β promoter, and second, p38-mediated inactivation of the mRNA-destabilizing factor tristetraprolin, which we show is able to target the IFN-β mRNA.

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Section: Discussionmentioning

confidence: 99%

Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways

McGuire

Rosner

Ananieva

et al. 2017

Molecular and Cellular Biology

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“…Studies using different experimental approaches in different model systems have focused on different mechanisms of combinatorial transcriptional regulation (Arnosti et al, 1996;Burns and Kerppola, 2012;Takaya et al, 2012). BiFC analysis of protein interactions on polytene chromosomes combines various aspects of these approaches by providing information about molecular interactions in genetically modified animals at high spatial resolution.…”

Section: Visualization Of Combinatorial Transcription Complex Bindingmentioning

confidence: 99%

Visualization of the Drosophila dKeap1-CncC interaction on chromatin illumines cooperative, xenobiotic-specific gene activation

Huai

Kerppola

2014

Development

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Interactions among transcription factors control their physiological functions by regulating their binding specificities and transcriptional activities. We implement a strategy to visualize directly the genomic loci that are bound by multi-protein complexes in single cells in Drosophila. This method is based on bimolecular fluorescence complementation (BiFC) analysis of protein interactions on polytene chromosomes. Drosophila Keap1 (dKeap1)-CncC complexes localized to the nucleus and bound chromatin loci that were not bound preferentially by dKeap1 or CncC when they were expressed separately. dKeap1 and CncC binding at these loci was enhanced by phenobarbital, but not by tert-butylhydroquinone (tBHQ) or paraquat. Endogenous dKeap1 and CncC activated transcription of the Jheh (Jheh1, Jheh2, Jheh3) and dKeap1 genes at these loci, whereas CncC alone activated other xenobiotic response genes. Ectopic dKeap1 expression increased CncC binding at the Jheh and dKeap1 gene loci and activated their transcription, whereas dKeap1 inhibited CncC binding at other xenobiotic response gene loci and suppressed their transcription. The combinatorial chromatin-binding specificities and transcriptional activities of dKeap1-CncC complexes mediated the selective activation of different sets of genes by different xenobiotic compounds, in part through feed-forward activation of dKeap1 transcription.

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“…were classified in different categories based on previous studies of their activation (52)(53)(54). The Cdkn1a and Ccng1 transcripts were chosen for analysis because of the evidence for a role of Keap1 in the cell cycle (41).…”

Section: Discussionmentioning

confidence: 99%

“…Chromatin binding by Keap1 and by other regulators of virus induced gene transcription, and H3K9me2 deposition, were measured by ChIP analyses at virus induced genes and cell cycle associated genes in multiple independent MEFs of each genotype. The binding proteins and H3K9me2 were chyosen for analysis because of previous studies of proteins and histone modifications that correlated with the activation or inhibition of cytokine transcription (22, 23, 53).…”

Section: Methodsmentioning

confidence: 99%

Keap1 moderates the transcription of virus induced genes through G9a-GLP and NFкB p50 recruitment, and H3K9me2 deposition

Burns

Kerppola

2022

Preprint

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Cells must moderate transcription that is induced by virus infection to mitigate deleterious consequences of inflammation. We investigated the mechanisms whereby Keap1 moderates the transcription of genes that are induced by Sendai virus infection in mouse embryo fibroblasts (MEFs). Virus infection induced Keap1 to bind Ifnb1, Tnf and Il6, and reduced Keap1 binding at Cdkn1a and Ccng1. Keap1 was required for G9a and GLP to bind and to deposit H3K9me2 at these genes upon virus infection. Keap1 moderated the transcription of genes that were induced by virus infection in concert with G9a, GLP, and NFκB p50 recruitment. G9a-GLP lysine methyltransferase activity was required for Keap1 to moderate the transcription of virus induced genes. G9a-GLP inhibitors enhanced the transcription of virus induced genes, and they augmented Keap1 and NFκB p50 recruitment, in parallel with the inhibition of H3K9me2 deposition. The interdependent effects of Keap1 and G9a-GLP on transcription and on the recruitment of each other constitute a feedback circuit that moderates the transcription of virus induced genes. G9a-GLP inhibitors augmented Keap1 binding to different genes in virus infected and in uninfected MEFs, whereas they inhibited H3K9me2 deposition that was induced by virus infection selectively. G9a-GLP inhibitors stabilized Keap1 retention in permeabilized MEFs and augmented Keap1 binding to specific genes in parallel. Keap1 was required for NFκB p50 recruitment, and for the augmentation of NFκB binding by G9a-GLP inhibitors. Keap1 and the electrophile tBHQ attenuated virus induced gene transcription through independent mechanisms, and they regulated the recruitment of different NFκB subunits.

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Opposite Orientations of a Transcription Factor Heterodimer Bind DNA Cooperatively with Interaction Partners but Have Different Effects on Interferon-β Gene Transcription

Cited by 5 publications

References 24 publications

Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways

Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways

Visualization of the Drosophila dKeap1-CncC interaction on chromatin illumines cooperative, xenobiotic-specific gene activation

Keap1 moderates the transcription of virus induced genes through G9a-GLP and NFкB p50 recruitment, and H3K9me2 deposition

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