ASK1 Inhibition Reduces Cell Death and Hepatic Fibrosis in an Nlrp3 Mutant Liver Injury Model
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PROVIDER: PRJNA590748 | ENA |
REPOSITORIES: ENA
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Project description:The aim of the current study was to investigate whether pharmacologic inhibition of ASK1 could attenuate hepatic fibrosis driven by inflammasome activation using gain-of-function NOD-like receptor protein 3 (Nlrp3) mutant mice.
2020-02-01 | GSE140742 | GEO
Project description:Hepatic inflammasome activation is considered a major contributor to liver fibrosis in NASH. Apoptosis signal-regulating kinase 1 (ASK1) is an apical mitogen-activated protein kinase that activates hepatic JNK and p38 to promote apoptosis, inflammation, and fibrosis. The aim of the current study was to investigate whether pharmacologic inhibition of ASK1 could attenuate hepatic fibrosis driven by inflammasome activation using gain-of-function NOD-like receptor protein 3 (Nlrp3) mutant mice. Tamoxifen-inducible Nlrp3 knock-in (Nlrp3A350V/+CreT-KI) mice and WT mice were administered either control chow diet or diet containing the selective ASK1 inhibitor GS-444217 for 6 weeks. Livers of Nlrp3-KI mice had increased inflammation, cell death, and fibrosis and increased phosphorylation of ASK1, p38, and c-Jun. GS-444217 reduced ASK1 pathway activation, liver cell death, and liver fibrosis. ASK1 inhibition resulted in a significant downregulation of genes involved in collagen production and extracellular matrix deposition, as well as in a reduced hepatic TNF-α expression. ASK1 inhibition also directly reduced LPS-induced gene expression of Collagen 1A1 (Col1a1) in hepatic stellate cells isolated from Nlrp3-KI mice. In conclusion, ASK1 inhibition reduced liver cell death and fibrosis downstream of inflammatory signaling induced by NLRP3. These data provide mechanistic insight into the antifibrotic mechanisms of ASK1 inhibition.
| S-EPMC7098717 | biostudies-literature
Project description:To elucidate the potential function of ASK1 in adipose tissues, microarray analysis was performed using iBAT and eWAT. Tissue samples were collected from 10-week-old male mice, and RNA samples derived from three individuals were pooled to analyze. These data provide novel insights into the physiological functions of ASK1. To elucidate the potential function of ASK1 in adipose tissues, microarray analysis was performed using iBAT and eWAT.
2016-01-08 | E-GEOD-76660 | biostudies-arrayexpress
Project description:ARABIDOPSIS SKP1-LIKE1 (ASK1) protein is involved in regulating flower development. We have compared ask1 mutant floral transcriptome with wild-type Ler to identify the role of ASK1-containing E3 ubiquitin ligases in regulating flower transcriptome. In this dataset, we include the expression data obtained from Arabidopsis thaliana Ler and ask1 mutant flower buds. We identified 42 genes and 74 genes that are down-regulated and up-regulated, respectively. Totally 5 samples were analyzed: 3 samples of ask1 and 2 samples of Ler. The average values were compared between ask1 and Ler.
2013-02-01 | E-GEOD-42841 | biostudies-arrayexpress
Project description:Innate immune sensing of influenza A virus (IAV) induces activation of various immune effector mechanisms including the NLRP3 inflammasome and programmed cell death pathways. Although type I IFNs are identified as key mediators of inflammatory and cell death responses during IAV infection, the involvement of various IFN-regulated effectors in facilitating these responses are less studied. Here, we demonstrate the role of interferon regulatory factor 1 (IRF1) in promoting NLRP3 inflammasome activation and cell death during IAV infection. IRF1 functions as a transcriptional regulator of Z-DNA binding protein 1 (ZBP1, also called as DLM1/DAI), a key molecule mediating IAV-induced inflammatory and cell death responses. Therefore, our study identified IRF1 as an upstream regulator of NLRP3 inflammasome and cell death during IAV infection and further highlights the complex and multilayered regulation of key molecules controlling inflammatory response and cell fate decisions during infections.
2017-12-07 | GSE103059 | GEO
Project description:To elucidate the potential function of ASK1 in adipose tissues, microarray analysis was performed using iBAT and eWAT. Tissue samples were collected from 10-week-old male mice, and RNA samples derived from three individuals were pooled to analyze. These data provide novel insights into the physiological functions of ASK1.
2016-01-08 | GSE76660 | GEO
Project description:Deubiquitinating enzymes have gained more and more attention in the field of pathological cardiac hypertrophy. In this study, we explored the role of a deubiquitinase, OTUD1, in the transverse aortic constriction (TAC) induced cardiac hypertrophy. We found the upregulation of OTUD1 in heart tissues of TAC mice. OTUD1 overexpression promoted cardiac hypertrophy, cardiac fibrosis and apoptosis. Conversely, OTUD1 depletion alleviated these pathological changes both in vivo and in vitro. Mechanistically, ASK1 was identified as one substrate of OTUD1 using co-immunoprecipitation followed with LC-MS/MS. Interestingly, OTUD1 didn’t deubiquitinate ASK1, but increased the phosphorylation level of ASK1 during the process of cardiac hypertrophy. We found that PGAM5, the upper stream regulator of ASK1, was stabilized by OTUD1 in a K63 ubiquitin chain dependent way, which reminded us OTUD1 increased the phosphorylation level of ASK1 by deubiquitinating PGAM5. This study identified the OTUD1-ASK1 axis as a potential therapeutic target for pathological cardiac hypertrophy.
2023-09-05 | GSE241809 | GEO
Project description:ARABIDOPSIS SKP1-LIKE1 (ASK1) protein is involved in regulating flower development. We have compared ask1 mutant floral transcriptome with wild-type Ler to identify the role of ASK1-containing E3 ubiquitin ligases in regulating flower transcriptome. In this dataset, we include the expression data obtained from Arabidopsis thaliana Ler and ask1 mutant flower buds. We identified 42 genes and 74 genes that are down-regulated and up-regulated, respectively.
2013-02-01 | GSE42841 | GEO
Project description:Purpose: Ubiquitin-mediated proteolysis by the 26S proteasome is a critical regulatory mechanism controlling many biological processes. The multi-subunit Skp1-Cullin1-F-box (SCF) complexes are designed to select substrates for ubiquitylation in all eukaryotes. Within these complexes, the Skp1 protein is defined as the bridge between the F-box and the Cullin1 proteins. In Arabidopsis thaliana, there are 19 Arabidopsis Skp1-Like (ASK) genes that encode Skp1 proteins. Our previous genomics and evolutionary studies suggest that ASK1 plays a predominant role in the ASK family. To demonstrate this hypothesis, we genetically introduced the same Ds insertion allele of ask1-1 in Ler into the Arabidopsis Col-0 reference genome. The ask1-1 allele was initially obtained from an ask1-1(+/-)ask2-1(+/-)/LerWs double heterozygous mutant (Liu et al., 2004). To identify the breadth and depth of SCF functions, we applied RNA-Seq sequencing to systematically analyze the perturbation of transcriptomes in both floral bud and open flower tissues in this novel ask1 mutant. Method: Two replicates of total RNA were extracted from 10-50 mg of floral buds or open flowers from Col-0, ask1, and ASK1 (WT allele) primary inflorescences five hours after dawn grown under a long-day photoperiod condition. The NucleoSpin® RNA kit (Macherey-Nagel) was used for RNA extraction following the manufacturer’s instructions. 1 μg each from the 12 RNA samples was used for pair end 150-mer deep sequencing using a NovaSeq 6000 platform (Novogene). Adapter and low-quality sequences in the raw FASTQ sequencing data were removed to produce valid sequences using Trimmomatic (phred=33, minimum length=36; (Bolger et al., 2014)), which were further aligned to the A. thaliana Col-0 reference genome (TAIR10; www.arabidopsis.org) via TOPHAT2 (Kim et al., 2013a) to identify accepted hits of each locus. HTSeq was then used to calculate an absolute expression level (counts) of each locus based on the accepted hits (Anders et al., 2015). The resulting counts per locus were normalized to counts per million reads (CPM) among all 12 libraries and used to identify groups of SDEGs in bud and open flower tissues in ask1 and ASK1 through comparing to the WT bud and open flower tissues, respectively, by edgeR (Log2FC ≥ 1; FDR < 0.01%; (Robinson et al., 2010)). Results: In total, 52 and 54 SDEGs were identified to be up-regulated and down-regulated, respectively, in ASK1 BC10F4 bud tissues; and 13 and 3 SDEGs were identified to be up-regulated and down-regulated, respectively, in ASK1 BC10F4 open flower tissues (2-fold change (FC) with a false discovery rate (FDR) < 0.01). However, 306 and 941 SDEGs (in total 1,247) in ask1 bud tissues and 392 and 1,137 SDEGs (in total 1,529) in ask1 open flower tissues were identified to be up-regulated and down-regulated, respectively (2-FC and FDR < 0.01). Conclusions: Compared to Col-0, 527 and 640 SDEGs were identified in Ler and Ws, respectively, which were greatly higher than the number of SDEGs identified in ASK1 floral bud (Fisher’s exact test, p = 6.0e-82 and 7.5e-112, respectively) and open flower tissues (Fisher’s exact test, p = 7.4e-150 and 1.2e-186, respectively). Therefore, we concluded that the genetic background of ASK1 and ask1 are isogenic to Col-0. The large array of SDEGs identified in both floral buds and open flower tissues in ask1 demonstrated a wide range of roles of ASK1-containing SCF complexes.
2020-08-20 | GSE132841 | GEO
Project description:Background and Aims: The activation of stimulator of interferon genes (STING) and NOD-like receptors protein 3 (NLRP3) inflammasomes-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnection between these two pathways and the epigenetic regulation of the STING-NLRP3 axis in hepatocyte pyroptosis during liver fibrosis remain unknown and is the focus of this study. Approach and Results: Liver fibrosis was induced in Sting knockout, Gasdermin D (Gsdmd) knockout mice, and in mice with hepatocyte-specific Nlrp3 deletion. RNA-sequencing, metabolomics, epigenetic compound screening system, and chromatin immunoprecipitation were utilized. STING and NLRP3 inflammasome signaling pathways were activated in cirrhotic livers but were suppressed by Sting knockout. Sting knockout also ameliorated hepatic pyroptosis, inflammation, and fibrosis in the murine cirrhotic model. In vitro, STING induced pyroptosis in primary murine hepatocytes via activating the NLRP3 inflammasome. H3K4-specific histone methyltransferase WD repeat-containing protein 5 (WDR5) and DOT1-like histone H3K79 methyltransferase (DOT1L) were identified to regulate NLRP3 expression in STING-overexpressed AML12 hepatocytes. WDR5/DOT1L-mediated histone methylation enhanced interferon regulatory transcription factor 3 (IRF3) binding to the Nlrp3 promoter and promoted STING-induced Nlrp3 transcription in hepatocytes. The RNA-sequencing and metabolomics analysis in murine livers and primary hepatocytes showed that metabolic reprogramming might participate in NLRP3-mediated hepatocyte pyroptosis and liver fibrosis. Moreover, hepatocyte-specific Nlrp3 deletion and downstream Gsdmd knockout attenuated hepatic pyroptosis, inflammation, and fibrosis in murine cirrhotic models. Conclusions: This study describes a novel epigenetic mechanism by which the STING-WDR5/DOT1L/IRF3-NLRP3 signaling pathway enhances hepatocyte pyroptosis and hepatic inflammation in liver fibrosis.
2023-09-18 | GSE217363 | GEO