METTL3-dependent m6A RNA methylation regulates activation of the NLRP3 inflammasome
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ABSTRACT:
PROVIDER: PRJNA893677 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR22025159_1.fastq.gz | Fastqsanger.gz | |||
| SRR22025159_2.fastq.gz | Fastqsanger.gz | |||
| SRR22025160_1.fastq.gz | Fastqsanger.gz | |||
| SRR22025160_2.fastq.gz | Fastqsanger.gz |
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Project description:Inflammasomes are signalling complexes that are activated in response to infection, cellular stress and other cues to initiate an inflammatory response. The NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome is a cytosolic sensor that mediates caspase-1-dependent maturation and release of the pro-inflammatory cytokines IL-1β and IL-18, and Gasdermin D-induced pyroptotic cell death. While a broad range of pathogens can activate the NLRP3 inflammasome, in most cases, it appears to be dispensable to fight infection. In recent work, m6A has emerged as a key regulator of the immune response. However, the specific role played by METTL3 and RNA m6A methylation during inflammasome activation is still unknown. Using genetic manipulation and pharmacological inhibition, we demonstrate that METTL3 is essential for activation of the NLRP3 inflammasome in vitro and in vivo. We show that pharmacological inhibition of METTL3 attenuates NLRP3 hyperactivation in PBMCs isolated from patients affected by Cryopyrin Associated Periodic Syndrome (CAPS).
2025-05-28 | GSE216482 | GEO
Project description:Inflammasomes are signalling complexes that are activated in response to infection, cellular stress and other cues to initiate an inflammatory response. The NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome is a cytosolic sensor that mediates caspase-1-dependent maturation and release of the pro-inflammatory cytokines IL-1β and IL-18, and Gasdermin D-induced pyroptotic cell death. While a broad range of pathogens can activate the NLRP3 inflammasome, in most cases, it appears to be dispensable to fight infection. In recent work, m6A has emerged as a key regulator of the immune response. However, the specific role played by METTL3 and RNA m6A methylation during inflammasome activation is still unknown. Using genetic manipulation and pharmacological inhibition, we demonstrate that METTL3 is essential for activation of the NLRP3 inflammasome in vitro and in vivo. We show that pharmacological inhibition of METTL3 attenuates NLRP3 hyperactivation in PBMCs isolated from patients affected by Cryopyrin Associated Periodic Syndrome (CAPS).
2025-05-28 | GSE216441 | GEO
Project description:N6-methyladenosine (m6A), the most abundant RNA modification, plays the essential role in the immune disorders. Yet, the role of m6A and its master regulator, methyltransferase-like 3 (METTL3) in asthma remain ambiguous. Here, we found that macrophage deficient in METTL3 aggravates the ovalbumin/lipopolysaccharide (OVA/LPS)-induced neutrophilic asthma. Subsequently, we observed that METTL3 deficiency facilitates NLRP3 but not AIM2 and NLRC4-dependent inflammasome activation and IL-1β secretion. Mechanistically, METTL3 deficiency enhanced NLRP3 inflammasome activation were dependent on upregulation of ZBP1 and TRAF1. Lastly, we elucidated that METTL3 negatively regulates ZBP1 expression through m6A modification dependence. In summary, the study unveils the function of m6A in regulating NLRP3 inflammasome activation in macrophage and identifies potential targets in therapeutic intervention of neutrophilic asthma.
2025-02-09 | GSE283939 | GEO
Project description:METTL3-dependent m6A RNA methylation regulates activation of the NLRP3 inflammasome [RIP-Seq]
| PRJNA893686 | ENA
Project description:METTL3-dependent m6A RNA methylation regulates activation of the NLRP3 inflammasome [RNA-Seq]
| PRJNA893624 | ENA
Project description:Inflammasome, activated by pathogen-derived and host-derived danger signals, constitutes a multimolecular signaling complex that serves as a platform for caspase-1 (CASP1) activation and interleukin-1beta (IL1B) maturation. The activation of NLRP3 inflammasome requires two-step signals. The first “priming” signal (Signal 1) enhances gene expression of inflammasome components. The second “activation” signal (Signal 2) promotes the assembly of inflammasome components. Deregulated activation of NLRP3 inflammasome contributes to the pathological processes of Alzheimer’s disease (AD) and multiple sclerosis (MS). However, at present, the precise mechanism regulating NLRP3 inflammasome activation and deactivation remains largely unknown. By genome-wide gene expression profiling, we studied the molecular network of NLRP3 inflammasome activation-responsive genes in a human monocyte cell line THP-1 sequentially given two-step signals. We identified the set of 83 NLRP3 inflammasome activation-responsive genes. Among them, we found the NR4A nuclear receptor family NR4A1, NR4A2, and NR4A3, the EGR family EGR1, EGR2, and EGR3, the IkappaB family NFKBIZ, NFKBID, and NFKBIA as a key group of the genes that possibly constitute a negative feedback loop for shutting down inflammation following NLRP3 inflammasome activation. By molecular network analysis, we identified a complex network of NLRP3 inflammasome activation-responsive genes involved in cellular development and death, and immune and inflammatory responses, where transcription factors AP-1, NR4A, and EGR serve as a hub. Thus, NLRP3 inflammasome activation-responsive genes constitute the molecular network composed of a set of negative feedback regulators for prompt resolution of inflammation. To load the Signal 1 (S1), THP-1 cells were incubated for 3 hours in the culture medium with or without inclusion of 0.2 microgram/ml lipopolysaccharide (LPS). To load the Signal 2 (S2), they were incubated further for 2 hours in the culture medium with inclusion of 10 microM nigericin sodium salt dissolved in ethanol or the equal v/v% concentration of ethanol (vehicle), followed by processing for microarray analysis on Human Gene 1.0 ST Array (Affymetrix).
2014-07-01 | E-GEOD-58959 | biostudies-arrayexpress
Project description:This experiment was performed to analyze the contribution of NLRP3 inflammasome activation to age-related changes in hippocampal RNA. The hypothesis was that decreased inflammasome activation would reduce hippocampal inflammation. Results indicate that inflammasome knockout animals are protected from age-related changes in hippocampal gene expression Gene expression profiles of young (1 month) and old (21-23 month) wild type, CIAS -/- and ASC -/- mouse hippocampal tissue were compared. Total mRNA was extracted using Trizol.
2013-09-05 | E-GEOD-43034 | biostudies-arrayexpress
Project description:The immune system may respond to engineered nanomaterials (ENM) through inflammatory reactions. The NLRP3 inflammasome responds to a wide range of ENM, and its activation is associated with various inflammatory diseases. The objective of the study was to compare the effects of gold ENM of different shapes on NLRP3 inflammasome activation and related signalling pathways. Differentiated THP-1 cells (wildtype, ASC- or NLRP3-deficient), were exposed to PEGylated gold nanorods, nanostars, and nanospheres. Exposed cells were subjected to gene expression analysis. Nanorods, but not nanostars or nanospheres, showed NLRP3 inflammasome activation. ASC- or NLRP3-deficient cells did not show this effect. Gold nanorod-induced NLRP3 inflammasome activation was accompanied by downregulated sterol/cholesterol biosynthesis, oxidative phosphorylation, and purinergic receptor signalling. In conclusion, the shape and surface chemistry of gold nanoparticles determine NLRP3 inflammasome activation.
2023-05-29 | GSE233641 | GEO
Project description:This study investigates the role of DDX3X SUMOylation in the activation of the NLRP3 inflammasome during sepsis. We demonstrate that SUMOylation of DDX3X, regulated by the SUMO protease SENP1, is a crucial trigger for NLRP3 inflammasome activation. In endotoxemia and sepsis models, the absence of SENP1 in macrophages and mice led to increased NLRP3 inflammasome activation. Mechanistically, DDX3X SUMOylation promoted the interaction of NLRP3 at lysine 118, inhibiting K48-conjugated ubiquitination and subsequent degradation of NLRP3 by the deubiquitinase OTUD6A, resulting in enhanced oligomerization of NLRP3. In murine adoptive transfer experiments, macrophages expressing the SUMOylation-inhibiting mutation DDX3X-K118R suppressed NLRP3 inflammasome activation, providing protection against LPS-induced inflammatory lung injury. These findings suggest that SENP1-mediated DDX3X deSUMOylation regulates NLRP3 inflammasome activation, offering a potential therapeutic avenue to mitigate NLRP3-induced inflammation.
2025-03-06 | PXD060598 | Pride
Project description:The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of NLRP3 inflammasome through multiple mechanisms including generation of mitochondrial ROS. Here we report that mitochondrial electron transport chain (ETC) complexes I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase (AOX), which can respectively complement the functional loss of mitochondrial complex I or III, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP but a ROS independent mechanism.
2022-03-09 | GSE197606 | GEO