The ketogenic diet increases Neuregulin 1 expression via elevating histone acetylation and its anti-seizure effect requires ErbB4 kinase activity

Abstract Background The ketogenic diet (KD)has been considered an effective treatment for epilepsy, whereas its underlying mechanisms remain obscure. We have previously reported that the KD feeding increased Neuregulin 1 (NRG1) expression in the hippocampus; disruption of NRG1 signaling by genetically deleting its receptor-ErbB4 abolished KD’s effects on inhibitory synaptic activity and seizures. However, it is still unclear about the mechanisms underlying the effect of KD on NRG1 expression and whether the effects of KD require ErbB4 kinase activity. Methods The effects of the KD on NRG1 expression were assessed via western blotting and real-time PCR. Acetylation level at the Nrg1 promoter locus was examined using the chromatin immunoprecipitation technique. Kainic acid (KA)-induced acute seizure model was utilized to examine the effects of KD and histone deacetylase inhibitor-TSA on seizures. Synaptic activities in the hippocampus were recorded with the technique of electrophysiology. The obligatory role of ErbB4 kinase activity in KD’s effects on seizures and inhibitory synaptic activity was evaluated by using ErbB kinase antagonist and transgenic mouse-T796G. Results We report that KD specifically increases Type I NRG1 expression in the hippocampus. Using the chromatin immunoprecipitation technique, we observe increased acetylated-histone occupancy at the Nrg1 promoter locus of KD-fed mice. Treatment of TSA dramatically elevates NRG1 expression and diminishes the difference between the effects of the control diet (CD) and KD. These data indicate that KD increases NRG1 expression via up-regulating histone acetylation. Moreover, both pharmacological and genetic inhibitions of ErbB4 kinase activity significantly block the KD’s effects on inhibitory synaptic activity and seizure, suggesting an essential role of ErbB4 kinase activity. Conclusion These results strengthen our understanding of the role of NRG1/ErbB4 signaling in KD and shed light on novel therapeutic interventions for epilepsy.

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Neuregulin 1/ErbB4 signaling contributes to the anti-epileptic effects of the ketogenic diet

Cell & Bioscience ◽

10.1186/s13578-021-00536-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jin Wang ◽

Jie Huang ◽

Yuan-Quan Li ◽

Shan Yao ◽

Cui-Hong Wu ◽

...

Keyword(s):

Ketogenic Diet ◽

Molecular Mechanisms ◽

Critical Role ◽

Therapeutic Interventions ◽

Seizure Threshold ◽

Neuregulin 1 ◽

Neuropsychiatric Diseases ◽

Seizure Models ◽

Gabaergic Activity

Abstract Background The ketogenic diet (KD) has been recognized as a potentially effective therapy to treat neuropsychiatric diseases, including epilepsy. Previous studies have indicated that KD treatment elevates γ-Amino butyric acid (GABA) levels in both human and murine brains, which presumably contributes to the KD’s anti-seizure effects. However, this has not been systematically investigated at the synaptic level, and the underlying molecular mechanisms remain to be elucidated. Methods Kainic acid (KA)-induced acute and chronic seizure models were utilized to examine the effects of KD treatment on seizure threshold and epileptogenesis. Synaptic activities in the hippocampus were recorded with the technique of electrophysiology. The effects of the KD on Neuregulin 1 (Nrg1) expression were assessed via RNA sequencing, real-time PCR and Western blotting. The obligatory role of Nrg1 in KD’s effects on seizures was evaluated through disruption of Nrg1 signaling in mice by genetically deleting its receptor-ErbB4. Results We found that KD treatment suppressed seizures in both acute and chronic seizure models and enhanced presynaptic GABA release probability in the hippocampus. By screening molecular targets linked to GABAergic activity with transcriptome analysis, we identified that KD treatment dramatically increased the Nrg1 gene expression in the hippocampus. Disruption of Nrg1 signaling by genetically deleting its receptor-ErbB4 abolished KD’s effects on GABAergic activity and seizures. Conclusion Our findings suggest a critical role of Nrg1/ErbB4 signaling in mediating KD’s effects on GABAergic activity and seizures, shedding light on developing new therapeutic interventions to seizure control.

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A critical role for IRAK4 kinase activity in Toll-like receptor–mediated innate immunity

Journal of Experimental Medicine ◽

10.1084/jem.20061825 ◽

2007 ◽

Vol 204 (5) ◽

pp. 1025-1036 ◽

Cited By ~ 174

Author(s):

Tae Whan Kim ◽

Kirk Staschke ◽

Katarzyna Bulek ◽

Jianhong Yao ◽

Kristi Peters ◽

...

Keyword(s):

Immune Responses ◽

Kinase Activity ◽

Critical Role ◽

Nuclear Factor Κb ◽

Type I ◽

Toll Like Receptor ◽

Chemokine Production ◽

Cytokines And Chemokines ◽

Plasmacytoid Dcs

IRAK4 is a member of IL-1 receptor (IL-1R)–associated kinase (IRAK) family and has been shown to play an essential role in Toll-like receptor (TLR)–mediated signaling. We recently generated IRAK4 kinase-inactive knock-in mice to examine the role of kinase activity of IRAK4 in TLR-mediated signaling pathways. The IRAK4 kinase–inactive knock-in mice were completely resistant to lipopolysaccharide (LPS)- and CpG-induced shock, due to impaired TLR-mediated induction of proinflammatory cytokines and chemokines. Although inactivation of IRAK4 kinase activity did not affect the levels of TLR/IL-1R–mediated nuclear factor κB activation, a reduction of LPS-, R848-, and IL-1–mediated mRNA stability contributed to the reduced cytokine and chemokine production in bone marrow–derived macrophages from IRAK4 kinase–inactive knock-in mice. Both TLR7- and TLR9-mediated type I interferon production was abolished in plasmacytoid dendritic cells isolated from IRAK4 knock-in mice. In addition, influenza virus–induced production of interferons in plasmacytoid DCs was also dependent on IRAK4 kinase activity. Collectively, our results indicate that IRAK4 kinase activity plays a critical role in TLR-dependent immune responses.

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Molecular Mechanisms of JAK2V617F Oncogenic Activation: The JAK2- V617F Mutant Utilizes the SH2 Domain for Constitutive Kinase Activity in the Presence of Unstimulated Heterodimeric Cytokine Receptor.

Blood ◽

10.1182/blood.v112.11.175.175 ◽

2008 ◽

Vol 112 (11) ◽

pp. 175-175

Author(s):

Sivahari P Gorantla ◽

Tobias Dechow ◽

Rebekka Grundler ◽

Christian Peschel ◽

Justus Duyster

Keyword(s):

Molecular Mechanisms ◽

Kinase Activity ◽

Jak2 V617f ◽

Sh2 Domain ◽

Cytokine Receptor ◽

Cytokine Receptors ◽

Type I ◽

Constitutive Activation ◽

Downstream Signaling

Abstract The JAK2-V617F mutation has been reported in the majority of MPDs including PV, ET, and IMF. This mutation leads to the constitutive activation of the JAK2 tyrosine kinase activity and overexpression of JAK2V617F renders hematopoietic cell lines growth factor-independent. However, the molecular mechanism leading to constitutive activation of JAK2V617F is largely unclear and the requirement of homodimeric or heterodimeric cytokine receptors needs to be determined. Here we show that oncogenic JAK2-V617F requires an intact SH2 domain for constitutive kinase activity. To this end we mutated the conserved arginine 426 within the SH2 domain to a lysine. Ba/F3 cells expressing JAK2V617F grew IL-3-independent and showed constitutive activation of JAK2, STAT5, and ERK1/2. In contrast, introduction of the SH2 mutation in JAK2V617F abrogated both transformation as well as constitutive activation of downstream signaling pathways. Accordingly, reconstitution of JAK2 mutants in a JAK2-negative cell line with IL-3R co-expression revealed reduced activation of JAK2 when the SH2 domain was mutated. It has been reported that JAK2 binding to homodimeric type I cytokine receptor may facilitate JAK2V617F-mediated transformation. Interestingly, co-expression of the homodomeric EpoR with SH2 mutated JAK2V617F rescues the phenotype indicating that the SH2 domain is required for JAK2 signaling in the presence of heterodimeric but not homodimeric cytokine receptors. Membrane localization studies showed equal membrane distribution of SH2-mutated and unmutated JAK2-V617F indicating that the SH2 domain mutation does not affect subcellular distribution of JAK2. However, co-IP experiments revealed a possible role for the SH2 domain in the dimerization and transphosphorylation of JAK2. Consequently, reduced transphosphorylation was seen in IL-3R- but not in EpoR-expressing cells. In a BM transplantation model we found that an intact SH2 domain in JAK2V617F was required for the induction of a MPD-like disease. Thus, our results points to an important role of the SH2 domain for the constitutive activation of JAK2V617F in cells expressing heterodimeric cytokine receptors.

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The Saccharomyces cerevisiae Srb8-Srb11 Complex Functions with the SAGA Complex during Gal4-Activated Transcription

Molecular and Cellular Biology ◽

10.1128/mcb.25.1.114-123.2005 ◽

2005 ◽

Vol 25 (1) ◽

pp. 114-123 ◽

Cited By ~ 61

Author(s):

Erica Larschan ◽

Fred Winston

Keyword(s):

Saccharomyces Cerevisiae ◽

Chromatin Immunoprecipitation ◽

Kinase Activity ◽

Saga Complex ◽

Functional Interaction ◽

Complex Functions ◽

Complementation Groups ◽

Stable Association ◽

Activation Sequence

ABSTRACT The Saccharomyces cerevisiae SAGA (Spt-Ada-Gcn5-acetyltransferase) complex functions as a coactivator during Gal4-activated transcription. A functional interaction between the SAGA component Spt3 and TATA-binding protein (TBP) is important for TBP binding at Gal4-activated promoters. To better understand the role of SAGA and other factors in Gal4-activated transcription, we selected for suppressors that bypass the requirement for SAGA. We obtained eight complementation groups and identified the genes corresponding to three of the groups as NHP10, HDA1, and SRB9. In contrast to the srb9 suppressor mutation that we identified, an srb9Δ mutation causes a strong defect in Gal4-activated transcription. Our studies have focused on this requirement for Srb9. Srb9 is part of the Srb8-Srb11 complex, associated with the Mediator coactivator. Srb8-Srb11 contains the Srb10 kinase, whose activity is important for GAL1 transcription. Our data suggest that Srb8-Srb11, including Srb10 kinase activity, is directly involved in Gal4 activation. By chromatin immunoprecipitation studies, Srb9 is present at the GAL1 promoter upon induction and facilitates the recruitment or stable association of TBP. Furthermore, the association of Srb9 with the GAL1 upstream activation sequence requires SAGA and specifically Spt3. Finally, Srb9 association also requires TBP. These results suggest that Srb8-Srb11 associates with the GAL1 promoter subsequent to SAGA binding, and that the binding of TBP and Srb8-Srb11 is interdependent.

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Epigenetic Modifications in Placenta are Associated with the Child’s Sensitization to Allergens

BioMed Research International ◽

10.1155/2019/1315257 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 7

Author(s):

Hani Harb ◽

Bilal Alashkar Alhamwe ◽

Nathalie Acevedo ◽

Paolo Frumento ◽

Catharina Johansson ◽

...

Keyword(s):

Histone Acetylation ◽

Chromatin Immunoprecipitation ◽

Allergic Sensitization ◽

Regulatory Genes ◽

Food Allergens ◽

Promoter Regions ◽

Chromatin Immunoprecipitation Assay ◽

H3 Acetylation ◽

Prospective Birth Cohort

Prenatal environmental exposures are considered to contribute to the development of allergic sensitization by epigenetic mechanisms. The role of histone acetylation in the placenta has not been examined yet. We hypothesized that placental histone acetylation at the promoter regions of allergy-related immune regulatory genes is associated with the development of sensitization to allergens in the child. Histones H3 and H4 acetylation at the promoter regions of 6 selected allergy-related immune regulatory genes was assessed by a chromatin immunoprecipitation assay in 173 term placentas collected in the prospective birth-cohort ALADDIN. The development of IgE sensitization to allergens in the children was followed from 6 months up to 5 years of age. We discovered significant associations of histone acetylation levels with decreased risk of allergic sensitization in 3 genes. Decreased risk of sensitization to food allergens was associated with higher H3 acetylation levels in placentas at the IFNG and SH2B3 genes, and for H4 acetylation in HDAC4. Higher HDAC4 H4 acetylation levels were also associated with a decreased risk of sensitization to aeroallergens. In conclusion, our results suggest that acetylation of histones in placenta has a potential to predict the development of sensitization to allergens in children.

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Role of prokaryotic type I and III pantothenate kinases in the coenzyme A biosynthetic pathway of Bacillus subtilis

Canadian Journal of Microbiology ◽

10.1139/cjm-2013-0793 ◽

2014 ◽

Vol 60 (5) ◽

pp. 297-305 ◽

Cited By ~ 5

Author(s):

Yuta Ogata ◽

Hiroki Katoh ◽

Munehiko Asayama ◽

Shigeru Chohnan

Keyword(s):

Bacillus Subtilis ◽

Recombinant Proteins ◽

Biosynthetic Pathway ◽

Kinase Activity ◽

Wild Type Strain ◽

Coenzyme A ◽

Monovalent Cation ◽

Type I ◽

Wild Type

Pantothenate kinases (CoaAs) catalyze the phosphorylation of pantothenate in the first step of the coenzyme A (CoA) biosynthetic pathway. These bacterial enzymes have been categorized into 3 types, the prokaryotic type I, II, and III CoaAs. Bacteria typically carry a single CoaA gene on their genome, but Bacillus subtilis possesses 2 proteins homologous to type I and III CoaAs, known as BsCoaA and BsCoaX, respectively. Both recombinant proteins exhibited the expected kinase activity and the characteristic properties of type I and III CoaAs, i.e., regulation by CoASH and acyl-CoAs in BsCoaA and the requirement of a monovalent cation in BsCoaX. Both gene disruptants appeared to grow in a manner similar to the wild-type strain. With the BsCoaX disruptant, the BsCoaA had the ability to completely fill the intracellular CoA pool, whereas the BsCoaA disruptant did not. These findings clearly indicate that these 2 CoaAs are employed together in the CoA biosynthetic pathway in B. subtilis and that the contribution of the type I CoaA (BsCoaA) to the formation of the intracellular CoA pool is larger than that of the type III CoaA (BsCoaX).

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