LPS-induced NFκB enhanceosome requires TonEBP/NFAT5 without DNA binding

Lee, Hwan Hee; Sanada, Satoshi; An, Seung Min; Ye, Byeong Jin; Lee, Jun Ho; Seo, Young‐Kyo; Lee, Chang-Wook; Lee-Kwon, Whaseon; Küper, Christoph; Neuhofer, Wolfgang; Choi, Soo Youn; Kwon, Hyug Moo

doi:10.1038/srep24921

Cited by 49 publications

(92 citation statements)

References 44 publications

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“…Originally described to be transcriptionally regulated by NFAT5 in renal epithelial cells upon hypertonic stimulation (22), COX2 expression in mechanoactivated cells is thought to be controlled by the transcription factor NF-kB (54). Interestingly, recent reports suggest that NFAT5 is capable of forming an enhanceosome with NF-kB, which is required to recruit p300 (55). Although the microarray data did not implicate that genetic ablation of Nfat5 significantly affects expression of gene sets associated with NF-kB signaling, an influence of NFAT5 on the activity and target specificity of NF-kB in the context of hypertension cannot be fully excluded.…”

Section: Discussionmentioning

confidence: 99%

Genetic ablation of NFAT5/TonEBP in smooth muscle cells impairs flow‐ and pressure‐induced arterial remodeling in mice

et al. 2018

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The arterial wall adapts to alterations in blood flow and pressure by remodeling the cellular and extracellular architecture. Biomechanical stress of vascular smooth muscle cells (VSMCs) in the media is thought to precede this process and promote their activation and subsequent proliferation. However, molecular determinants orchestrating the transcriptional phenotype under these conditions have been insufficiently studied. We identified the transcription factor, nuclear factor of activated T cells 5 (NFAT5; or tonicity enhancer‐binding protein) as a crucial regulatory element of mechanical stress responses of VSMCs. Here, the relevance of NFAT5 for arterial growth and thickening is investigated in mice upon inducible smooth muscle cell (SMC)‐specific genetic ablation of Nfat5. In cultured mouse VSMCs, loss of Nfat5 inhibits the expression of gene sets involved in the control of the cell cycle and the interaction with the extracellular matrix and cytoskeletal dynamics. In vivo, SMC‐specific knockout of Nfat5 did not affect the general vascular architecture and blood pressure levels under baseline conditions. However, proliferation of VSMCs and the thickening of the arterial wall were inhibited during both flow‐induced collateral remodeling and hypertension‐mediated arterial hypertrophy. Whereas originally described as a hypertonicity‐responsive transcription factor, these findings identify NFAT5 as a novel molecular determinant of biomechanically induced phenotype changes of VSMCs and wall stress‐induced arterial remodeling processes.—Arnold, C., Feldner, A., Zappe, M., Komljenovic, D., De La Torre, C., Ruzicka, P., Hecker, M., Neuhofer, W., Korff, T. Genetic ablation of NFAT5/TonEBP in smooth muscle cells impairs flow‐ and pressure‐induced arterial remodeling in mice. FASEB J. 33, 3364–3377 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Genetic ablation of NFAT5/TonEBP in smooth muscle cells impairs flow‐ and pressure‐induced arterial remodeling in mice

et al. 2018

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“…However, the lack of TonEBP immunoprecipitation with p65 showed TonEBP Regulates Pro-inflammatory Genes DECEMBER 23, 2016 • VOLUME 291 • NUMBER 52 that cross-talk does not involve physical interaction. Interestingly, in other cells, these proteins have been shown to interact at the immediate onset of hypertonic stimulation (26) and in response to LPS treatment (28). Interestingly, NF-B activity was required for hypertonic induction of only a subset of the studied targets; TauT and CCL2 were refractory to inhibition.…”

Section: Discussionmentioning

confidence: 99%

RNA Sequencing Reveals a Role of TonEBP Transcription Factor in Regulation of Pro-inflammatory Genes in Response to Hyperosmolarity in Healthy Nucleus Pulposus Cells

Johnson

Shapiro

Risbud

2016

Journal of Biological Chemistry

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Edited by Dennis VoelkerTranscription factor tonicity-responsive enhancer-binding protein (TonEBP/NFAT5) is critical for osmo-adaptation and extracellular matrix homeostasis of nucleus pulposus (NP) cells in their hypertonic tissue niche. Recent studies implicate TonEBP signaling in inflammatory disease and rheumatoid arthritis pathogenesis. However, broader functions of TonEBP in the disc remain unknown. RNA sequencing was performed on NP cells with TonEBP knockdown under hypertonic conditions. 1140 TonEBP-dependent genes were identified and categorized using Ingenuity Pathway Analysis. Bioinformatic analysis showed enrichment of matrix homeostasis and cytokine/ chemokine signaling pathways. C-C motif chemokine ligand 2 (CCL2), interleukin 6 (IL6), tumor necrosis factor (TNF), and nitric oxide synthase 2 (NOS2) were studied further. Knockdown experiments showed that TonEBP was necessary to maintain expression levels of these genes. Gain-and loss-of-function experiments and site-directed mutagenesis demonstrated that TonEBP binding to a specific site in the CCL2 promoter is required for hypertonic inducibility. Despite inhibition by dominant-negative TonEBP, IL6 and NOS2 promoters were not hypertonicity-inducible. Whole-disc response to hypertonicity was studied in an ex vivo organ culture model, using wild-type and haploinsufficient TonEBP mice. Pro-inflammatory targets were induced by hypertonicity in discs from wild-type but not TonEBP-haploinsufficient mice. Mechanistically, NF-B activity increased with hypertonicity and was necessary for hypertonic induction of target genes IL6, TNF, and NOS2 but not CCL2. Although TonEBP maintains transcription of genes traditionally considered pro-inflammatory, it is important to note that some of these genes also serve anabolic and pro-survival roles. Therefore, in NP cells, this phenomenon may reflect a physiological adaptation to diurnal osmotic loading of the intervertebral disc.The intervertebral disc is well suited to fulfill its mechanical role in the human spine, where it permits flexion and rotation, and absorbs compressive loads (1). The matrix-rich nucleus pulposus (NP) 2 at the center of the disc gives the tissue its ability to resist compression through high osmotic swelling pressure (2-4), loss of which correlates with degeneration and back pain (5). Although the high fixed charge density of the aggrecan-rich matrix allows the nucleus pulposus its water-imbibing properties, it also results in a hypertonic environment for NP cells. Importantly, tonicity of the extracellular environment fluctuates widely with diurnal cycle: water is forced out of the disc during the day when the spine is loaded and imbibed during the unloaded phase at night (6).In mammalian cells, a key transcription factor TonEBP (NFAT5) is activated by elevated hypertonicity and promotes transcription of genes that produce or transport organic osmolytes (7). In addition, TonEBP controls transcription of several genes that are important for cell survival under hypertonic conditions independ...

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“…Moreover, the POMC promoter was also activated by a mutant TonEBP (TonEBP-DIPT) that is unable to form a homodimer and thus cannot bind and act through TonEBP response elements [25]. Moreover, the POMC promoter was also activated by a mutant TonEBP (TonEBP-DIPT) that is unable to form a homodimer and thus cannot bind and act through TonEBP response elements [25].…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies in peripheral inflammatory conditions have reported that TonEBP is critical to the recruitment of an acetyltransferase p300 to p65 subunit of NF-jB, which results in assembly of NF-jB enhancesome and leads to p300 action on opening/remodeling of chromatin and binding of proximal factors such as Sp1 and RNA polymerase II [25,31]. Our results revealed that TonEBP haploinsufficiency resulted in half the levels of TNF-a-induced COX2, IL-1b, and IL-6 as compared to the levels observed in wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

Tonicity‐responsive enhancer binding protein (TonEBP) regulates TNF‐α‐induced hypothalamic inflammation

Kim

et al. 2019

FEBS Letters

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Tonicity‐responsive enhancer binding protein (TonEBP) is a widely expressed transcription factor and is important in the regulation of inflammatory cytokines. Here, we have identified TonEBP expression in the hypothalamus, which is particularly high in proopiomelanocortin (POMC) neurons. TonEBP overexpression stimulates POMC transcription, and TonEBP haploinsufficiency in TonEBP (+/−) mice results in a decrease in hypothalamic POMC expression. TonEBP (+/−) mice show reduced sickness responses, which include anorexia and hyperthermia, that are initially induced by tumor necrosis factor (TNF)‐α. TonEBP (+/−) mice also show lower levels of TNF‐α‐induced hypothalamic expression of POMC and pro‐inflammatory cytokines. These results suggest that TonEBP is an important molecular regulator in the development of inflammatory sickness responses through the control of POMC and pro‐inflammatory cytokine expression in the hypothalamus.

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LPS-induced NFκB enhanceosome requires TonEBP/NFAT5 without DNA binding

Cited by 49 publications

References 44 publications

Genetic ablation of NFAT5/TonEBP in smooth muscle cells impairs flow‐ and pressure‐induced arterial remodeling in mice

Genetic ablation of NFAT5/TonEBP in smooth muscle cells impairs flow‐ and pressure‐induced arterial remodeling in mice

RNA Sequencing Reveals a Role of TonEBP Transcription Factor in Regulation of Pro-inflammatory Genes in Response to Hyperosmolarity in Healthy Nucleus Pulposus Cells

Tonicity‐responsive enhancer binding protein (TonEBP) regulates TNF‐α‐induced hypothalamic inflammation

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