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Oxidized thioredoxin-1 restrains the NLRP1 inflammasome [mBMDM]

ABSTRACT: The danger signals that activate the NLRP1 inflammasome have yet to be firmly established. NLRP1 undergoes autoproteolysis to generate N-terminal (NT) and C-terminal (CT) fragment, which importantly, is a necessary step for its check-point regulation by the DPP9 ternary complex and the mechanistic activation of NLRP1 through functional degradation. Here, we report an added layer of regulatory complexity to NLRP1 activity, in the form of a repressive interaction that NLRP1 forms with the oxidized, but not reduced, form of thioredoxin-1 (TRX1). Loss of TRX1 destabilizes the NT fragment of NLRP1 and promotes enhanced inflammasome activation. The TRX1 interaction occurs through the NACHT-LRR of NLRP1 and requires nucleotide binding in its ATPase domain. In addition, we found that several patient-derived and ATPase-inactivating mutations in the NACHT-LRR region hyperactive the inflammasome by destabilize protein folding and are also shown to abrogate TRX1 binding. Thus, NLRP1 appears to detect intracellular reductive stress through a decrease in the fraction of intracellular oxidized TRX1, which enhances protein disorder, leading to inflammasome signaling. These findings link the cellular redox environment to NLRP1-mediated innate immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE215035 | GEO | 2022/11/04

REPOSITORIES: GEO

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Oxidized thioredoxin-1 restrains the NLRP1 inflammasome [NTERT-1]

Project description:The danger signals that activate the NLRP1 inflammasome have yet to be firmly established. NLRP1 undergoes autoproteolysis to generate N-terminal (NT) and C-terminal (CT) fragment, which importantly, is a necessary step for its check-point regulation by the DPP9 ternary complex and the mechanistic activation of NLRP1 through functional degradation. Here, we report an added layer of regulatory complexity to NLRP1 activity, in the form of a repressive interaction that NLRP1 forms with the oxidized, but not reduced, form of thioredoxin-1 (TRX1). Loss of TRX1 destabilizes the NT fragment of NLRP1 and promotes enhanced inflammasome activation. The TRX1 interaction occurs through the NACHT-LRR of NLRP1 and requires nucleotide binding in its ATPase domain. In addition, we found that several patient-derived and ATPase-inactivating mutations in the NACHT-LRR region hyperactive the inflammasome by destabilize protein folding and are also shown to abrogate TRX1 binding. Thus, NLRP1 appears to detect intracellular reductive stress through a decrease in the fraction of intracellular oxidized TRX1, which enhances protein disorder, leading to inflammasome signaling. These findings link the cellular redox environment to NLRP1-mediated innate immunity.

2022-11-04 | GSE215034 | GEO

Oxidized thioredoxin-1 restrains the NLRP1 inflammasome

Project description:To find cellular protein binding partners of the NLRP1 inflammasome, FLAG-tagged full length NLRP1 (or a GFP-FLAG protein control) was ectopically expressed in HEK 293T cells and affinity purified from cell lysates (Note: the NLRP1-FLAG-containing lysate samples were affinity purified in the presence or absence of excess proline) before proteins were reduced, alkylated, and trypsinized before TMT labelling and pooling of the differentially tested lysates to give three conditions (1. NLRP1-FLAG; 2. GFP-FLAG; 3. NLRP1-FLAG+proline) in duplicate. These data represent the results following sample and data processing.

2022-11-04 | PXD037391 | Pride

Germline NLRP1 mutations cause skin inflammatory and cancer susceptibility syndromes via inflammasome activation

Project description:We profiled the transcriptional changes in N/TERT-1 immortalized keratinocytes after doxycylin induction of gain-of-function mutants of the inflammasome sensor protein NLRP1.

2016-09-15 | GSE85791 | GEO

UVB-induced skin autoinflammation due to NLRP1 mutation and its inhibition by anti-IL-1b antibody

Project description:To analyze the pathogenic mechanism of the autoinflammatory skin syndromes caused by an NLRP1 mutation, we sought to generate Nlrp1b mutation knock-in mice mice as a mouse model of cutaneous autoinflammatory lesions due to NLRP1 mutants, and examine the expression of proteins, such as cytokines, and the mRNA expression profile, including inflammasome-related genes in the model lesions.

2022-06-14 | GSE172065 | GEO

Retention of ES cell-derived 129 genome drives NLRP1 hypersensitivity and gene expression changes in Nlrp3-/- mice

Project description:Immune response genes are disproportionately polymorphic in humans and mice, with heterogeneity amongst loci driving strain specific host defense responses. The inadvertent retention of polymorphic loci can confound results, lead to false conclusions, and delay scientific progress. By combining RNAseq and variant calling analyses, we identify a substantial region of 129S genome, including the highly polymorphic Nlrp1 locus proximal to Nlrp3, in one of the most commonly used mouse models of NLRP3 deficiency. We show that 129S NLRP1 can be tolerated at higher expression levels at steady-state, however this sensitizes Nlrp3-/- mice to NLRP1 inflammasome activation. Furthermore, the presence of 129S genome leads to altered gene and protein regulation across multiple cell-types, including of the key tissue-resident macrophage marker, TIM4. In order to resolve NLRP3 dependent phenotypes we validate a conditional Nlrp3 allele enabling temporal and cell-type specific control of NLRP3 deletion. Our study provides an accessible strategy to identify functionally relevant SNPs and assess genomic contamination in transgenic mice, to allow for unambiguous attribution of phenotypes to the target gene.

2024-01-23 | E-MTAB-13601 | biostudies-arrayexpress

Proximity proteomics reveals UCH-L1 as an essentialregulator of NLRP3-mediated IL-1β production in humanmacrophages and microglia

Project description:Activation of the NACHT, LRR family pyrin domain containing 3 (NLRP3) inflammasome complex is an essential innate immune signalling mechanism. To reveal how NLRP3 inflammasome assembly and activation are controlled, in particular by components of the ubiquitin system, proximity labelling, affinity purification and RNAi screening approaches were performed. Our study provides an intricate time-resolved molecular map of different phases of NLRP3 inflammasome activation. We discovered that ubiquitin C-terminal hydrolase 1 (UCH-L1) interacts with the NACHT domain of NLRP3, and downregulation of UCH-L1 decreases pro-IL-1β levels. UCH-L1 chemical inhibition with small molecules interfered with NLRP3 puncta formation and ASC oligomerisation, leading to altered IL-1β cleavage and secretion, particularly in microglia cells, which exhibited elevated UCH-L1 expression as compared to monocytes/macrophages. Altogether, we profiled NLRP3 inflammasome activation dynamics and highlight UCH-L1 as an important modulator of NLRP3-mediated IL-1β production, suggesting that a pharmacological inhibitor of UCH-L1 may decrease inflammation-associated pathologies.

2024-04-24 | PXD045862 | Pride

DPP9 activity and not protein binding inhibits the CARD8 inflammasome

Project description:Inflammasomes are multiprotein complexes formed in response to pathogens. NLRP1 and CARD8 are related proteins that form inflammasomes, but the pathogen-associated signal(s) and the molecular mechanisms controlling their activation have not been established. Inhibitors of the serine dipeptidyl peptidases DPP8 and DPP9 (DPP8/9) were recently discovered to activate both NLRP1 and CARD8. Interestingly, DPP9 binds directly to NLRP1 and CARD8, and this interaction, in addition to DPP9’s catalytic activity, may contribute to the inhibition of NLRP1. Here, we use activity-based probes, reconstituted inflammasome assays, and mass spectrometry-based proteomics to further investigate the DPP9-CARD8 interaction. We show that the DPP9-CARD8 interaction, unlike the DPP9-NLRP1 interaction, is not disrupted by DPP9 inhibitors or mutations that block autoproteolysis. Moreover, wild-type, but not catalytically-inactive mutant, DPP9 rescues CARD8-mediated cell death in DPP9 knockout cells. Together, this work reveals DPP9 activity and not direct protein binding restrains the CARD8 inflammasome, and suggests the binding interaction likely serves some other biological purpose.

2019-10-23 | PXD015047 | Pride

Influence of Interferon-beta on expression profile of memory T-cells

Project description:Inflammasomes are multi-protein complexes that control the production of pro-inflammatory cytokines such as IL-1beta. Inflammasomes play an important role in the control of immunity to tumors and infections, and also in autoimmune diseases, but the mechanisms controlling the activation of human inflammasomes are largely unknown. We found that human activated CD4+CD45RO+ memory T-cells specifically suppress P2X7R-mediated NLRP3 inflammasome activation, without affecting P2X7R-independent NLRP3 or NLRP1 inflammasome activation. The concomitant increase in pro-IL-1β production induced by activated memory T-cells concealed this effect. Priming with IFNβ decreased pro-IL-1β production in addition to NLRP3 inflammasome inhibition and thus unmasked the inhibitory effect on NLRP3 inflammasome activation. IFNβ did not suppress NLRP3 inflammasome activation by acting directly on monocytes. The inhibition of pro-IL-1β production and suppression of NLRP3 inflammasome activation by IFNβ-primed human CD4+CD45RO+ memory T-cells is partly mediated by soluble FasL and is associated with down-regulated P2X7R mRNA expression and reduced response to ATP in monocytes. CD4+CD45RO+ memory T-cells from multiple sclerosis (MS) patients showed a reduced ability to suppress NLRP3 inflammasome activation, however their suppressive ability was recovered following in vivo treatment with IFNβ. Thus, our data demonstrate that human P2X7R-mediated NLRP3 inflammasome activation is regulated by activated CD4+CD45RO+ memory T cells, and provide new information on the mechanisms mediating the therapeutic effects of IFNβ in MS. Memory T-cells were cultured in the presence of monocytes with and without Interferon-beta, resorted and expression profile was determined

2012-12-01 | E-GEOD-35601 | biostudies-arrayexpress

Effects of Diphtheria Toxin and Compound 6p on HPKs (human primary keratinocytes)

Project description:This study investigates the effect of diphtheria toxin (DT) as an activator of ZAKalpha-dependent ribotoxic stress response and the human NLRP1 inflammasome, specifically in primary human epithelial cells. This RNAseq experiments in particular seeks to identify the genes that are induced by DT in a manner that is dependent on the kinase activity of ZAKalpha.

2023-08-11 | GSE236652 | GEO

Influence of Interferon-beta on expression profile of memory T-cells

2012-12-01 | GSE35601 | GEO

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