SUMOylation of ROR-γt inhibits IL-17 expression and inflammation via HDAC2

Singh, Amir Kumar; Khare, Prashant; Obaid, Abeer; Conlon, Kevin; Basrur, Venkatesha; DePinho, Ronald A.; Venuprasad, K.

doi:10.1038/s41467-018-06924-5

Cited by 50 publications

(33 citation statements)

References 38 publications

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“…These findings are supported by the essential role of class I HDACs, especially HDAC2, in inflammation: in the context of LPS induced inflammation, HDAC2 has been observed to down-regulate expression of IL-6 by recruitment to its promoter and subsequent deacetylation of H4 and H3 in myeloid cells (66). Similar regulatory functions were detected in chronic inflammatory disorders like rheumatoid arthritis or multiple sclerosis, in which dysregulation of the transcription factor RAR-related orphan receptor g has been described to result in HDAC2 recruitment to IL-17 promoter and its subsequent repression (67). Besides that, HDAC2 also exerts a particular role in the context of vascular inflammation.…”

Section: Discussionmentioning

confidence: 82%

Inflammation‐mediated deacetylation of the ribonuclease 1 promoterviahistone deacetylase 2 in endothelial cells

et al. 2019

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Ribonuclease 1 (RNase1) is a circulating extracellular endonuclease that regulates the vascular homeostasis of extracellular RNA and acts as a vessel‐ and tissue‐protective enzyme. Upon long‐term inflammation, high amounts of proinflammatory cytokines affect endothelial cell (EC) function by down‐regulation of RNase1. Here, we investigated the transcriptional regulation of RNase1 upon inflammation in HUVECs. TNF‐α or IL‐1β stimulation reduced the expression of RNase1 relative to the acetylation state of histone 3 at lysine 27 and histone 4 of the RNASE1 promoter. Inhibition of histone deacetylase (HDAC) 1, 2, and 3 by the specific class I HDAC inhibitor MS275 abolished the TNF‐α‐ or IL‐1β–mediated effect on the mRNA and chromatin levels of RNase1. Moreover, chromatin immunoprecipitation kinetics revealed that HDAC2 accumulates at the RNASE1 promoter upon TNF‐β stimulation, indicating an essential role for HDAC2 in regulating RNase1 expression. Thus, proinflammatory stimulation induced recruitment of HDAC2 to attenuate histone acetylation at the RNASE1 promoter site. Consequently, treatment with HDAC inhibitors may provide a new therapeutic strategy to stabilize vascular homeostasis in the context of inflammation by preventing RNase1 down‐regulation in ECs.—Bedenbender, K., Scheller, N., Fischer, S., Leiting, S., Preissner, K. T., Schmeck, B. T., Vollmeister, E. Inflammation‐mediated deacetylation of the ribonuclease 1 promoter via histone deacetylase 2 in endothelial cells. FASEB J. 33, 9017–9029 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 82%

Inflammation‐mediated deacetylation of the ribonuclease 1 promoterviahistone deacetylase 2 in endothelial cells

et al. 2019

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“…Several studies have revealed that RORγt-de cient T cells show suppressed differentiation of Th17 cells and downregulate IL-17A, while overexpression of RORγt induces IL-17A expression, conversely [47]. In addition, Amir Kumar Singh et al elaborated a detailed mechanism that SUMOylation of RORγt promotes HDAC2 interaction with the IL-17 promoter and suppresses IL-17A transcription [33]. Furthermore, a research demonstrated RORγt acetylation in Th17 cells, with a signi cant enhancement by HDAC2 inhibitors [47], consistent with a recent study which revealed elevated RORγt acetylation in cultured CSEinduced HBE cells with HDAC2 silencing [22].…”

Section: Discussionmentioning

confidence: 99%

“…Decreased RORγt expression and Th17 response under CS and OVA challenge after CpG-ODN and BUD treatment HDAC2 is important in Th-17 cell differentiation from naive CD4 + T cells, and RORγt involvement attracts increasing attention [32,33]. The catalytic activity of HDAC2 is important in inhibiting RORγt's transcriptional activity, and SUMOylated RORγt recruits HDAC2 to the IL-17 promoter for gene downregulation [34].…”

Section: Alteration Of Th2/th17 Polarization and Reduction Of Pro-in mentioning

confidence: 99%

CpG oligodeoxynucleotides attenuate RORγt-mediated Th17 response by restoring histone deacetylase-2 in cigarette smoke-exposure asthma

Lin

et al. 2020

Preprint

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Background: Cigarette smoke (CS) exposure increases corticosteroid insensitive asthma related to increased Th17 phenotype, and new treatment strategies are needed for CS-associated asthma. Histone deacetylase 2 (HDAC2), found in airway epithelium, is critical in improving glucocorticoids insensitivity. We recently demonstrated the anti-inflammatory properties of CpG oligodeoxynucleotides (CpG-ODN) in CS-exposure asthma. However, CpG-ODN’s effects on HDAC2 expression and enzyme activity remain unstudied. This study aimed to assess whether CpG-ODN protect against excessive Th17 immune responses in CS-induced asthma through HDAC2-dependent mechanisms, comparing their effects with corticosteroids’. Methods: The effects of CpG-ODN alone and in combination with budesonide (BUD) on airway inflammation and Th2/Th17 related airway immune responses were determined using the in vivo model of CS-associated asthma and in cultured bronchial epithelial (HBE) cells administered ovalbumin (OVA) and/or cigarette smoke extract (CSE). HDAC2 and retinoid-related orphan nuclear receptor γt (RORγt) were also assessed in mouse lung specimens and HBE cells. Results: CpG-ODN and BUD in vivo synergistically attenuated CS-exposure asthmatic responses at various levels such as immune cell influx with mixed eosinophils and neutrophils, airway remodeling, Th2/Th17 associated cytokine and chemokine production, and airway hyperresponsiveness, along with blockade of RORγt-mediated Th17 inflammation through induced HDAC2 expression/activity. In vitro, CpG-ODN synergized with BUD to inhibit Th17 cytokine production in OVA- and CSE-challenged HBE cells while suppressing RORγt and increasing epithelial HDAC2 expression/activity. Conclusions：CpG-ODN reversed CS-induced HDAC2 downregulation and enhances the sensitivity of CS-exposure asthma and CSE induced HBE cells to glucocorticoid treatment. This may be related to HDAC2 recovery via RORγt/IL-17 pathway regulation, suggesting CpG-ODN as a potential corticosteroid-sparing agent in CS-induced asthma with Th17-biased immune conditions.

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“…The silver stained gel slice was destained according to the manufacturer's protocol (PROTSIL2-1KT, Sigma). The digestion for gel slice, whole lysates and IPed beads were done according to previously published protocols (Singh et al 2018).…”

Section: Sample Digestion For Msmentioning

confidence: 99%

“…For DDA mode, the MS was set to collect one high-resolution MS1 scan (60,000 FWHM @200 m/z; scan range 400-1500 m/z) followed by data-dependent High-energy C-trap Dissociation MS/MS (HCD) spectra on the 20 most abundant ions observed in MS1. Other MS parameters were as previously published (Singh et al 2018).…”

Section: Liquid Chromatography Mass Spectrometry (Lc-ms/ms)mentioning

confidence: 99%

Near-cognate initiation generates FMRpolyG from CGG repeats in Fragile X associated Tremor Ataxia Syndrome

Zhang

Glineburg

Basrur

et al. 2020

Preprint

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Repeat associated non-AUG (RAN) translation of FMR1 5' UTR CGG repeats produces toxic homo-polymeric proteins that accumulate within ubiquitinated inclusions in Fragile X-associated tremor/ataxia syndrome (FXTAS) patient brains and model systems. The most abundant RAN product, FMRpolyG, initiates predominantly at an ACG codon located just 5' to the repeat. Methods to accurately measure FMRpolyG in FXTAS patients are lacking. Here we used data dependent acquisition (DDA) and parallel reaction monitoring (PRM) mass spectrometry coupled with stable isotope labeled standard peptides (SIS) to identify potential signature FMRpolyG fragments in patient cells and tissues. Following immunoprecipitation (IP) enrichment, we detected FMRpolyG signature peptides by PRM in transfected cells, FXTAS human samples and patient derived stem cells, but not in controls. Surprisingly, we identified two amino-terminal peptides: one beginning with methionine (Ac-MEAPLPGGVR) initiating at an ACG, and a second beginning with threonine (Ac-TEAPLPGGVR), initiating at a GUG. Abundance of the threonine peptide was enhanced relative to the methionine peptide upon activation of the integrated stress response. In addition, loss of the eIF2 alternative factor, eIF2A, or enhanced expression of initiation factor eIF1, preferentially suppressed GUG initiated FMRpolyG synthesis. These data demonstrate that FMRpolyG is quantifiable in human samples and that RAN translation on FMR1 initiates at specific near cognate codons dependent on available initiation factors and cellular environment.

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SUMOylation of ROR-γt inhibits IL-17 expression and inflammation via HDAC2

Cited by 50 publications

References 38 publications

Inflammation‐mediated deacetylation of the ribonuclease 1 promoterviahistone deacetylase 2 in endothelial cells

Inflammation‐mediated deacetylation of the ribonuclease 1 promoterviahistone deacetylase 2 in endothelial cells

CpG oligodeoxynucleotides attenuate RORγt-mediated Th17 response by restoring histone deacetylase-2 in cigarette smoke-exposure asthma

Near-cognate initiation generates FMRpolyG from CGG repeats in Fragile X associated Tremor Ataxia Syndrome

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