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A20 attenuate oxidized self-DNA mediated inflammasome activation through promoting NEK7 ubiquitination in AKI

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE219189 | GEO | 2022/12/20

REPOSITORIES: GEO

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A20 attenuate oxidized self-DNA mediated inflammasome activation through promoting NEK7 ubiquitination in AKI [ox-dsDNA90]

Project description:To seek out the target of restricting the exaggerated inflammation results from ox-dsDNA90, we treated BMDMs with ox-dsDNA90 from kidney of acute kidney injury mice model. We then performed gene expression profiling analysis using data obtained from RNA-seq of 2 different groups of BMDMs.

2022-12-20 | GSE219188 | GEO

A20 attenuate oxidized self-DNA mediated inflammasome activation in AKI [AA-DNA]

Project description:To seek out the target of restricting the exaggerated inflammation results from ox-self-DNA, we treated BMDMs with self-dsDNA from kidney of acute kidney injury mice model. We then performed gene expression profiling analysis using data obtained from RNA-seq of 2 different groups of BMDMs.

2022-12-20 | GSE219187 | GEO

A20 attenuate oxidized self-DNA mediated inflammasome activation through promoting NEK7 ubiquitination in AKI

Project description:A20 attenuate oxidized self-DNA mediated inflammasome activation through promoting NEK7 ubiquitination in AKI

| PRJNA907366 | ENA

A20 attenuate oxidized self-DNA mediated inflammasome activation through promoting NEK7 ubiquitination in AKI [ox-dsDNA90]

Project description:A20 attenuate oxidized self-DNA mediated inflammasome activation through promoting NEK7 ubiquitination in AKI [ox-dsDNA90]

| PRJNA907369 | ENA

A20 attenuate oxidized self-DNA mediated inflammasome activation in AKI [AA-DNA]

Project description:A20 attenuate oxidized self-DNA mediated inflammasome activation in AKI [AA-DNA]

| PRJNA907368 | ENA

The E3 Ubiquitin Ligase TRIM65 Negatively Regulates Inflammasome Activation Through Promoting Ubiquitination of NLRP3.

Project description:The dysregulation of NLRP3 inflammasome plays a critical role in pathogenesis of various human inflammatory diseases, thus NLRP3 inflammasome activation must be tightly controlled at multiple levels. However, the underlying mechanism regulating NLRP3 inflammasome activation remains unclear. Herein, the effects of Tripartite motif-containing protein 65 (TRIM65) on NLRP3 inflammasome activation and the underlying molecular mechanism were investigated in vitro and in vivo. Inhibition or deletion of Trim65 could significantly strengthen agonist induced NLRP3 inflammasome activation in THP-1 cells and BMDMs, indicated by increased caspase-1 activation and interleukin-1β secretion. However, TRIM65 had no effect on poly (dA: dT)-induced AIM2 inflammasome activation or flagellin-induced IPAF inflammasome activation. Mechanistically, immunoprecipitation assays demonstrated that TRIM65 binds to NACHT domain of NLRP3, promotes lys48- and lys63- linked ubiquitination of NLRP3 and restrains the NEK7-NLRP3 interaction, thereby inhibiting NLRP3 inflammasome assembly, caspase-1 activation, and IL-1β secretion. In vivo, three models of inflammatory diseases were used to confirm the suppression role of TRIM65 in NLRP3 inflammasome activation. TRIM65-deficient mice had a higher production of IL-1β induced by lipopolysaccharide in sera, and more IL-1β secretion and neutrophil migration in the ascites, and more severity of joint swelling and associated IL-1β production induced by monosodium urate, suggesting that TRIM65 deficiency was susceptible to inflammation. Therefore, the data elucidate a TRIM65-dependent negative regulation mechanism of NLRP3 inflammasome activation and provide potential therapeutic strategies for the treatment of NLRP3 inflammasome-related diseases.

| S-EPMC8427430 | biostudies-literature

Inhibition of NLRP3 Inflammasome Activation by A20 through Modulation of NEK7

Project description:The NLRP3 inflammasome, a pivotal component of innate immunity, has been implicated in various inflammatory disorders. The ubiquitin-editing enzyme A20 is well known to regulate inflammation and maintain homeostasis. However, the precise molecular mechanisms by which A20 modulates the NLRP3 inflammasome remain poorly understood. Here our study revealed that macrophages deficient in A20 exhibit increased protein abundance and elevated mRNA level of NIMA-related kinase 7 (NEK7). Importantly, A20 directly binds with NEK7, mediating its K48-linked ubiquitination, thereby targeting NEK7 for proteasomal degradation. Our results demonstrate that A20 enhance the ubiquitination of NEK7 at K189 and K293 ubiquitinated sites, with K189 playing a crucial role in the binding of NEK7 to A20, albeit not significantly influencing the interaction between NEK7 and NLRP3. Furthermore, A20 disrupts the association of NEK7 with the NLRP3 complex, potentially through the OTU domain and/or synergistic effect of ZnF4 and ZnF7 motifs. Significantly, NEK7 deletion markedly attenuates the activation of the NLRP3 inflammasome in A20-deficient conditions, both in vitro and in vivo. This study uncovers a new mechanism by which A20 inhibits the NLRP3 inflammasome.

2024-07-03 | GSE253265 | GEO

Acetate attenuates inflammasome activation through GPR43-mediated Ca2+-dependent NLRP3 ubiquitination.

Project description:Acetate has been indicated to be elevated and to regulate inflammation in inflammatory and metabolic diseases. The inflammasome serves as a key component of immune homeostasis, and its dysregulation can lead to various inflammatory disorders. However, little is known about the effects of acetate on inflammasome activation and the underlying mechanism. Here, we demonstrate that acetate attenuates inflammasome activation via GPR43 in a Ca2+-dependent manner. Through binding to GPR43, acetate activates the Gq/11 subunit and subsequent phospholipase C-IP3 signaling to decrease Ca2+ mobilization. In addition, acetate activates soluble adenylyl cyclase (sAC), promotes NLRP3 inflammasome ubiquitination by PKA, and ultimately induces NLRP3 degradation through autophagy. In vivo, acetate protects mice from NLRP3 inflammasome-dependent peritonitis and LPS-induced endotoxemia. Collectively, our research demonstrates that acetate regulates the NLRP3 inflammasome via GPR43 and Ca2+-dependent mechanisms, which reveals the mechanism of metabolite-mediated NLRP3 inflammasome attenuation and highlights acetate as a possible therapeutic strategy for NLRP3 inflammasome-related diseases.

| S-EPMC6802670 | biostudies-literature

A20 restricts ubiquitination of pro-interleukin-1? protein complexes and suppresses NLRP3 inflammasome activity.

Project description:Inappropriate inflammasome activation contributes to multiple human diseases, but the mechanisms by which inflammasomes are suppressed are poorly understood. The NF-?B inhibitor A20 is a ubiquitin-modifying enzyme that might be critical in preventing human inflammatory diseases. Here, we report that A20-deficient macrophages, unlike normal cells, exhibit spontaneous NLRP3 inflammasome activity to LPS alone. The kinase RIPK3, but not the adaptor MyD88, is required for this response. In normal cells, A20 constitutively associates with caspase-1 and pro-IL-1?, and NLRP3 activation further promotes A20 recruitment to the inflammasome. Pro-IL-1? also co-immunoprecipitates with RIPK1, RIPK3, caspase-1, and caspase-8 in a complex that is modified with K63-linked and unanchored polyubiquitin. In A20-deficient macrophages, this pro-IL-1?-associated ubiquitination is markedly increased in a RIPK3-dependent manner. Mass spectrometric and mutational analyses reveal that K133 of pro-IL-1? is a physiological ubiquitination site that supports processing. Our study reveals a mechanism by which A20 prevents inflammatory diseases.

| S-EPMC4302274 | biostudies-literature

A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation.

Project description:Microglia, the mononuclear phagocytes of the central nervous system (CNS), are important for the maintenance of CNS homeostasis, but also critically contribute to CNS pathology. Here we demonstrate that the nuclear factor kappa B (NF-κB) regulatory protein A20 is crucial in regulating microglia activation during CNS homeostasis and pathology. In mice, deletion of A20 in microglia increases microglial cell number and affects microglial regulation of neuronal synaptic function. Administration of a sublethal dose of lipopolysaccharide induces massive microglia activation, neuroinflammation, and lethality in mice with microglia-confined A20 deficiency. Microglia A20 deficiency also exacerbates multiple sclerosis (MS)-like disease, due to hyperactivation of the Nlrp3 inflammasome leading to enhanced interleukin-1β secretion and CNS inflammation. Finally, we confirm a Nlrp3 inflammasome signature and IL-1β expression in brain and cerebrospinal fluid from MS patients. Collectively, these data reveal a critical role for A20 in the control of microglia activation and neuroinflammation.

| S-EPMC5964249 | biostudies-literature

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