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Histone deacetylase 3 facilitates TNF α -mediated NF-κB activation through suppressing CTSB induced RIP1 degradation and is required for host defense against bacterial infection

ABSTRACT: Histone deacetylase 3 facilitates TNF α -mediated NF-κB activation through suppressing CTSB induced RIP1 degradation and is required for host defense against bacterial infection

PROVIDER: PRJNA813301 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18248236_1.fastq.gz	Fastqsanger.gz
	SRR18248236_2.fastq.gz	Fastqsanger.gz
	SRR18248237_1.fastq.gz	Fastqsanger.gz
	SRR18248237_2.fastq.gz	Fastqsanger.gz
	SRR18248238_1.fastq.gz	Fastqsanger.gz

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Histone deacetylase 3 facilitates TNF α -mediated NF-κB activation through suppressing CTSB induced RIP1 degradation and is required for host defense against bacterial infection

Project description:Histone deacetylases (HDACs), as important enzymes regulating acetylation, participate in a series of cell physiological process. Here we reported that HDAC3-deficient macrophages had elevated expression of multiple cathepsins and over-expressed cathepsins such as cathepsin B (CTSB) caused remarkable degradation of receptor (TNFRSF)-interacting serine-threonine kinase 1 (RIP1), which resulted in reduced TNFα mediated NF-κB activation and inflammatory response. Consistent with these findings, mice with macrophage specific knockout of HDAC3 were impaired in inflammatory response and susceptible to pseudomonas aeruginosa infection. Thus, our studies uncovered important roles of HDAC3 in the regulation of cathepsin-mediated lysosomal degradation and RIP1-mediated inflammatory response in macrophages as well as in host defense against bacterial infection.

2022-05-12 | GSE197989 | GEO

Histone deacetylase 3 facilitates TNF α -mediated NF-κB activation through suppressing CTSB induced RIP1 degradation and is required for host defense against bacterial infection [ChIP-seq]

2022-05-12 | GSE198218 | GEO

Histone deacetylase 3 facilitates TNF α -mediated NF-κB activation through suppressing CTSB induced RIP1 degradation and is required for host defense against bacterial infection [ChIP-seq]

Project description:Histone deacetylase 3 facilitates TNF α -mediated NF-κB activation through suppressing CTSB induced RIP1 degradation and is required for host defense against bacterial infection [ChIP-seq]

| PRJNA814237 | ENA

Histone deacetylase 3 facilitates TNFα-mediated NF-κB activation through suppressing CTSB induced RIP1 degradation and is required for host defense against bacterial infection.

Project description:BackgroundAs important enzymes regulating acetylation, histone deacetylases (HDACs) participate in a series of cell physiological process. However, the mechanisms responsible for individual HDAC family members in regulating innate immunity remained to be elucidated. Here we sought to reveal the mechanism of HDAC3 in regulating the inflammatory response of macrophages.MethodsRNAseq was done to detect the transcriptional influence of HDAC3 on macrophages. Kyoto Encyclopedia of Genes and Genomes was used to reveal the change of signaling pathways after HDAC3 knockout. CHIPseq was done to detect the deacetylation modification of HDAC3 on chromosome. Western blot, immunofluorescence, and real-time quantitative PCR were used to measure the change of genes and proteins' levels. Mice were intratracheal instillation with lipopolysaccharide or Pseudomonas aeruginosa to determine the influence of HDAC3 on inflammatory response in vivo.ResultsHDAC3-deficient macrophages had increased expression of cathepsins resulting from elevated histone acetylation. Over-expressed cathepsins such as cathepsin B (CTSB) caused remarkable degradation of receptor (TNFRSF)-interacting serine-threonine kinase 1 (RIP1), which reduced TNFα mediated NF-κB activation and inflammatory response. Consistently, mice with macrophage specific knockout of HDAC3 were impaired in inflammatory response and thereby susceptible to Pseudomonas aeruginosa infection.ConclusionHDAC3 was required for protecting RIP1 from degrading by CTSB in macrophages. Decreased RIP1 in HDAC3 knockout macrophages impaired TNFα mediated NF-κB activation. Our studies uncovered important roles of HDAC3 in the regulation of cathepsin-mediated lysosomal degradation and RIP1-mediated inflammatory response in macrophages as well as in host defense against bacterial infection.

| S-EPMC9164478 | biostudies-literature

RIP1 perturbation induces chondrocyte necroptosis and promotes osteoarthritis pathogenesis

Project description:Receptor-interacting protein kinase 1 (RIP1)-mediated necroptosis plays a vital role in various diseases, but the involvement of RIP1 and its functional mechanism in osteoarthritis pathogenesis remains largely unknown. To identify molecular targets of RIP1 in chondrocytes, RNA sequencing was performed in chondrocytes treated with adenovirus expressing RIP1 or vector control. We found that 9857 genes were differentially expressed in chondrocytes after RIP1 overexpression. GO analysis indicated that DNA replication, chromosome segregation and regulation of cell cycle process were upregulated, while terms including cartilage development, skeletal system development, extracellular matrix organization, skeletal system morphogenesis, chondrocyte differentiation, collagen fibril organization and limb development were downregulated. Pathway analysis revealed that IL-17 signaling pathway, cell cycle, DNA replication, proteasome, TNF signaling pathway, cellular senescence and p53 signaling pathway were significantly upregulated by RIP1, meanwhile, ECM-receptor interaction, other glycan degradation and glycosaminoglycan degradation were downregulated. These results underscore the importance of RIP1 in OA by perturbing a series of essential events during disease progression such like cell cycle regulation, chondrocyte differentiation, inflammation and ECM remodeling.

2021-01-22 | GSE165219 | GEO

Role of RelB in Suppressing NF-κB Pro-Inflammatory Gene Expression

Project description:Role of RelB in Suppressing NF-κB Pro-Inflammatory Gene Expression

| PRJNA991535 | ENA

The response of WT, ∆rip1, and ∆sigL strains of Mycobacterium tuberculosis to dipyridyl treatment

Project description:Mycobacterium tuberculosis is exposed to a variety of stresses during a chronic infection, as the immune system simultaneously produces bactericidal compounds and starves the pathogen for essential nutrients. The intramembrane protease, Rip1, plays an important role in the adaptation to these stresses, at least partially by the cleavage of membrane bound transcriptional regulators. Although Rip1 is known to be critical for surviving copper intoxication and nitric oxide exposure, these stresses do not fully account the regulatory protein’s essentiality during infection. In this work, we demonstrate that Rip1 is also necessary for growth in low iron and zinc conditions, similar to those imposed by the immune system. Using a newly generated library of sigma factor mutants, we show that the known regulatory target of Rip1, SigL, shares this defect. Transcriptional profiling under iron limiting conditions supported the coordinated activity of Rip1 and SigL and demonstrated that the loss of these proteins produces an exaggerated iron starvation response. These observations demonstrate that Rip1 coordinates several aspects of metal homeostasis and suggest that a Rip1- and SigL-dependent pathway is involved in the adaptation to the iron deficient environments encountered during infection.

2023-05-23 | GSE229446 | GEO

An autoregulatory RelB:p50 NF-κB pathway perpetuates pro-survival TNF response in multiple myeloma

Project description:Pro-inflammatory cytokines were shown to promote growth and survival of cancerous cells. TNF induced RelA:p50 NF-κB dimer via the canonical pathway is thought to link inflammation with cancer. Integrating biochemical and computational studies we identify that deficiency of non-canonical signal transducer p100 triggers a positive autoregulatory loop, which instead perpetuates an alternate RelB:p50 containing NF-κB activity upon TNF treatment. TNF stimulated RelB:p50 dimer is sufficient for mediating NF-κB target gene-expressions and suppressing apoptotic cellular death independent of principal NF-κB subunit RelA. We further demonstrate that activating mutations in non-canonical NF-κB module deplete multiple myeloma cells of p100, thereby, provoking autoregulatory RelB:p50 activation. Finally, autoregulatory control reinforces protracted pro-survival NF-κB response, albeit comprising of RelB:p50, upon TNF priming that protects myeloma cells with dysfunctional p100 from subsequent apoptotic insults. In sum, we present evidence for positive autoregulation mediated through the NF-κB system and its potential involvement in human neoplasm.

2017-06-12 | GSE68615 | GEO

Polystyrene MiPolystyrene Microplastics Induce Radiotherapy Resistance in Lung Cancer by Suppressing Ferroptosis through NF-κB Activationcroplastics Induce Radiotherapy Resistance in Lung Cancer by Suppressing Ferroptosis through NF-κB Activation

Project description:Aims: Polystyrene microplastics (PS-MPs) are emerging environmental pollutants, but their impact on lung cancer treatment remains unclear. This study investigates how PS-MPs affect radiotherapy efficacy in lung cancer, focusing on their role in ferroptosis regulation and NF-κB pathway activation. Results: PS-MPs were rapidly internalized by lung cancer cells and remained detectable across multiple passages. Exposure to PS-MPs promoted lung cancer cell proliferation, increased mitochondrial length, and elevated Ki67 and c-Myc expression. Following ionizing radiation, PS-MPs significantly attenuated radiation-induced ferroptosis, as evidenced by reduced mitochondrial damage, lipid peroxidation, and GSH depletion. Transcriptomic analysis revealed that PS-MPs activated the NF-κB pathway, leading to increased phosphorylation of IKKβ, IκBα degradation, and enhanced nuclear translocation of NF-κB. In vivo, PS-MPs accumulated in lung tumor-bearing mice, reducing radiotherapy efficacy by increasing tumor volume and weight while decreasing survival rates. Knockdown of NF-κB restored ferroptosis sensitivity and mitigated PS-MPs-induced radioresistance, confirming the NF-κB-dependent inhibition of ferroptosis. Innovation and Conclusion: This study provides the first evidence that PS-MPs impair radiotherapy efficacy in lung cancer by suppressing ferroptosis via NF-κB activation. Unlike previous research focusing on microplastic toxicity in normal tissues, our findings highlight their oncological impact and potential role as an environmental factor influencing cancer therapy resistance. These results emphasize the need for further investigation into microplastics as emerging disruptors of redox homeostasis in oncology and their broader implications for environmental and cancer research.

2025-09-08 | GSE307179 | GEO

Serratia bockelmannii strain:Rip1

Project description:Serratia bockelmannii strain:Rip1 Genome sequencing

| PRJNA674496 | ENA