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WSB1/2 target chromatin-bound lysine-methylated RelA for proteasomal degradation and NF-κB termination

ABSTRACT: WSB1/2 target chromatin-bound lysine-methylated RelA for proteasomal degradation and NF-κB termination

PROVIDER: PRJNA975809 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24724933_1.fastq.gz	Fastqsanger.gz
	SRR24724933_2.fastq.gz	Fastqsanger.gz
	SRR24724934_1.fastq.gz	Fastqsanger.gz
	SRR24724934_2.fastq.gz	Fastqsanger.gz
	SRR24724935_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

WSB1/2 target chromatin-bound lysine-methylated RelA for proteasomal degradation and NF-κB termination

Project description:Proteasome-mediated degradation of chromatin-bound NF-κB is critical in terminating the transcription of pro-inflammatory genes and can be triggered by Set9-mediated lysine methylation of RelA subunit. However, the E3 ligase targeting methylated RelA remains unknown. Here, we identified two structurally similar WD-40 repeat (WDR) proteins, WSB1 and WSB2, as the E3s that recognize chromatin-bound methylated RelA for polyubiquitination and proteasomal degradation. WSB1/2 specifically recognized methylated lysines (K) 314 and 315 of RelA via their WDR domains. Deletion of WRD in WSB1/2 or mutation of K314/315 of RelA to arginines abolished the interaction between WSB1/2 and RelA. RNA-sequencing of TNF--stimulated WSB1/2 knockdown cells revealed that WSB1/2 negatively regulated a subset of NF-B target genes with reduced polyubiquitination of chromatin-bound RelA. TNF- stimulated the methylation of RelA and the subsequent recruitment of WSB1/2 to the promoters of these NF-B target genes to terminate the transcription. Computational modeling demonstrated that a highly conserved Asp within repeat 3 of WDR domains of WSB1/2 coordinated its interaction with K314/K315 of RelA, with a higher pKa when either of the lysines is methylated. Together, these findings identify novel E3 ligases that target chromatin-bound methylated RelA for proteolysis to prevent sustained NF-κB activation, providing new targets for therapeutic intervention of NF-κB-mediated inflammatory diseases.

2024-05-29 | GSE233286 | GEO

Monoubiquitination of nuclear RelA negatively regulates NF-κB activity independent of proteasomal degradation.

Project description:Termination and resolution of inflammation are tightly linked to the inactivation of one of its strongest inducers, NF-κB. While canonical post-stimulus inactivation is achieved by upregulation of inhibitory molecules that relocate NF-κB complexes to the cytoplasm, termination of the NF-κB response can also be accomplished directly in the nucleus by posttranslational modifications, e.g., ubiquitination of the RelA subunit. Here we reveal a functional role for RelA monoubiquitination in regulating NF-κB activity. By employing serine-to-alanine mutants, we found that hypo-phosphorylated nuclear RelA is monoubiquitinated on multiple lysine residues. Ubiquitination was reversed by IκBα expression and was reduced when nuclear translocation was inhibited. RelA monoubiquitination decreased NF-κB transcriptional activity despite prolonged nuclear presence and independently of RelA degradation, possibly through decreased CREB-binding protein (CBP) co-activator binding. Polyubiquitin-triggered proteasomal degradation has been proposed as a model for RelA inactivation. However, here we show that proteasomal inhibition, similar to RelA hypo-phosphorylation, resulted in nuclear translocation and monoubiquitination of RelA. These findings indicate a degradation-independent mechanism for regulating the activity of nuclear RelA by ubiquitination.

| S-EPMC3621033 | biostudies-literature

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.

2015-11-30 | E-MTAB-3596 | biostudies-arrayexpress

Role of RelA:CBP/p300 interaction on RelA-activated genes

Project description:A structure-function study of NF-kB subunit RelA and coactivator CBP/p300 interaction reveals the critical role of CBP/p300 in recruitment of RelA to its target promoter site. mRNA profiles of unstimulated or stimulated with TNFa rela-/- MEF reconstituted with RelA wild type or mutants were generated by deep sequencing, in duplicate

2013-09-09 | E-GEOD-46213 | biostudies-arrayexpress

Reconstituted Rela-/- MEF

Project description:Reconstituted Rela-/- MEF

| PRJNA549298 | ENA

Reconstituted Rela-/- MEF

Project description:Protein deamidation is emerging as a post-translational modification that regulates protein function. The general role of protein deamidation is emerging asn fundamental to biological processes, yet remains is poorly understood. Here, we report that the rate-limiting enzyme of pyrimidine synthesis, a trifunctional enzyme containing activity of carbamoyl phosphate synthetase, aspartyl transcarbamoylase and dihydroorotase (CAD), deamidates the RelA subunit to inactivate NF-κB and promote glycolysis. Functional screening and identified CAD as a negative regulator of NF-κB activation, and biochemical analysis demonstrated that CAD deamidatesd RelA in vitro and in cellsto negate NF-κB activation. D eamidated RelA, though failed to activate the expression of NF-κB-dependent genes, thoughbut it up-regulated that of key glycolytic enzymes to promote glycolysis and cell proliferation. In proliferating cells, CAD is activated and catalyzes de novo pyrimidine synthesis to meet the metabolic need during S phase. CAD-mediated RelA deamidation and NF-κB inactivation and glycolytic gene expression paralleled in a cell cycle-dependent mannerdriven by CAD-mediated RelA deamidation are necessary for cell proliferation. In addition, CAD promoted glycolysis via deamidated RelA that up-regulated the expression of key glycolytic enzymes. Stratification of cancer cell lines by CAD-mediated RelA deamidation predicted their sensitivity to inhibitors of glycolytic enzymes, while a subset of mutations predisposed RelA to deamidation and promoted glycolysis to enable cell proliferation. This work describes a process of metabolic reprogramming enabled by CAD-mediated RelA deamidation that underpins cell proliferation and tumorigenesis.

2019-11-01 | GSE132871 | GEO

HDXMS comparison of NFkB (p50(39-350)/RelA(19-321) vs NFkB (p50(39-350)/RelA(19-549)

Project description:HDXMS comparison of NFkB (p50(39-350)/RelA(19-321) vs NFkB (p50(39-350)/RelA(19-549)

2022-04-12 | MSV000089247 | MassIVE

Identification of genes responsible for RelA-dependent proliferation arrest in HMEC conditionally expressing RelA

Project description:Immuno-histochemistry for RelA in breast tumors revealed a range of staining intensity and negative correlation between RelA levels and proliferation-index in estrogen receptor-positive tumors. Conditional expression of RelA arrested proliferation in primary mammary and fallopian tube epithelial cells. RelA dependent CDK4 downregulation was responsible for activating the G1/S checkpoint and cell cycle arrest. RelA target genes, including Interferon Response Factors (IRF), were up-regulated in the arrested cells. Among the IRFs, IRF1 expression correlates with RelA expression. Suppressing IRF1 restored CDK4 levels and rescued RelA-dependent proliferation arrest analogous to abrogating the G1/S checkpoint or restoring CDK4 levels. Apart from cyclins, regulation of CDK4 by the RelA-IRF1 transcriptional network controls proliferation of breast tumors and predicts sensitivity to a CDK4/6 inhibitor.

2015-09-26 | GSE65040 | GEO

Role of RelA:CBP/p300 interaction on RelA-activated genes

Project description:A structure-function study of NF-kB subunit RelA and coactivator CBP/p300 interaction reveals the critical role of CBP/p300 in recruitment of RelA to its target promoter site.

2013-09-09 | GSE46213 | GEO

CLIP-Seq experiment of Escherichia coli RelA wild type and RelA::C289Y mutant strains to identify specific RNAs that bind RelA

Project description:In this experiment, we carried out a global analysis of specific RNAs that are bound to the RelA protein. CLIP-Seq experiment was carried out with E. coli RelA wild type and RelA::C289Y mutant strains. Libraries were prepared and high throughput sequencing was done.

2021-09-16 | E-MTAB-10884 | biostudies-arrayexpress

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