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PKCα-LSD1-NF-κB Signaling Cascade Is Crucial for Epigenetic Control of the Inflammatory Response [RNA-Seq]

ABSTRACT: The inflammatory response mediated by NF-κB signaling is essential for host defense against pathogens. Although the components and regulatory mechanism of NF-κB signaling have been well-studied, molecular basis for the epigenetic regulation of the inflammatory response is poorly understood. Here, we identify a new signaling axis of PKCα- LSD1-NF-κB p65 which is critical for activation and amplification of the inflammatory response and triggering systemic inflammatory diseases. In response to excessive inflammatory stimuli, PKCα translocates to the nucleus and phosphorylates LSD1. Phosphorylation of LSD1 is required for its interaction with p65 and facilitates demethylation of p65 leading to enhanced protein stability. Genome-wide analysis reveals a critical role of LPS-induced LSD1 phosphorylation in the transcriptional activation of NF-κB target genes. Together, we demonstrate that PKCα-LSD1-NF-κB signaling cascade is crucial for epigenetic control of the inflammatory response.

ORGANISM(S): Mus musculus

PROVIDER: GSE100216 | GEO | 2018/01/31

REPOSITORIES: GEO

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PKCα-LSD1-NF-κB Signaling Cascade Is Crucial for Epigenetic Control of the Inflammatory Response [ChIP-Seq]

Project description:The inflammatory response mediated by NF-κB signaling is essential for host defense against pathogens. Although the components and regulatory mechanism of NF-κB signaling have been well-studied, molecular basis for the epigenetic regulation of the inflammatory response is poorly understood. Here, we identify a new signaling axis of PKCα- LSD1-NF-κB p65 which is critical for activation and amplification of the inflammatory response and triggering systemic inflammatory diseases. In response to excessive inflammatory stimuli, PKCα translocates to the nucleus and phosphorylates LSD1. Phosphorylation of LSD1 is required for its interaction with p65 and facilitates demethylation of p65 leading to enhanced protein stability. Genome-wide analysis reveals a critical role of LPS-induced LSD1 phosphorylation in the transcriptional activation of NF-κB target genes. Together, we demonstrate that PKCα-LSD1-NF-κB signaling cascade is crucial for epigenetic control of the inflammatory response.

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PKCα-LSD1-NF-κB Signaling Cascade Is Crucial for Epigenetic Control of the Inflammatory Response

Project description:PKCα-LSD1-NF-κB Signaling Cascade Is Crucial for Epigenetic Control of the Inflammatory Response

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Cyclin-dependent kinase 6 is a chromatin-bound cofactor for nuclear factor kappaB-dependent gene expression [Agilent]

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T Cell Receptor-Induced NF-kB Signaling and Transcriptional Activation Are Regulated by STIM1- and Orai1-Mediated Calcium Entry

Project description:T cell activation following antigen binding to the T cell receptor (TCR) involves the mobilization of intracellular calcium (Ca2+) to activate the key transcription factors NFAT and NF-κB. The mechanism of NFAT activation by Ca2+ has been determined; however, the role of Ca2+ in controlling NF-κB signaling is poorly understood and the source of Ca2+ required for NF-κB activation is unknown. We demonstrate that TCR- but not TNF- induced NF-κB signaling upstream of IκB kinase (IKK) activation absolutely requires the influx of extracellular Ca2+ via STIM1-dependent CRAC/Orai channels. We further show that Ca2+ influx controls phosphorylation of the NF-κB protein p65 on Ser536 and that this post- translational modification controls its nuclear localization and transcriptional activation. Notably our data reveal that this role for Ca2+ is entirely separate from its upstream control of IκBα degradation, thereby identifying a novel Ca2+- dependent distal step in TCR-induced NF-κB activation. Finally, we demonstrate that this control of distal signaling occurs via Ca2+-dependent PKCk-mediated phosphorylation of p65. Thus, we establish the source of Ca2+ required for TCR induced NF-kB activation and we define a new distal Ca2+-dependent checkpoint in TCR-induced NF-kB signaling that has broad implications for the control of immune cell development and T cell functional specificity.

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A single Thr505 phospho-site mutation reveals an important role for the RelA NF-κB subunit in liver regeneration and cancer

Project description:Post-translational modification of NF-κB subunits provides a mechanism to differentially regulate their activity in response to the many stimuli that can induce this pathway. However, the physiological significance of these modifications is largely unknown and it remains unclear if these have a critical role in the normal and pathological functions of NF-κB in vivo. Among these, phosphorylation of the RelA(p65) Thr505 residue has been described as an important regulator of NF-κB activity in cell lines but its physiological significance was not known. Therefore, to learn more about the role of this pathway in vivo, we generated a knockin mouse with a RelA T505A mutation. Unlike RelA knockout mice, the RelA T505A mice develop normally but exhibit aberrant hepatocyte proliferation following liver partial hepatectomy or damage resulting from carbon tetrachloride treatment. Consistent with these effects, RelA T505A mice exhibit earlier onset of cancer in the N-nitrosodiethylamine (DEN) model of hepatocellular carcinoma. This data reveals a critical pathway controlling NF-κB function in the liver that acts to suppress tumour-promoting activities of RelA.

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