Germline NLRP1 mutations cause skin inflammatory and cancer susceptibility syndromes via inflammasome activation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE85791 | GEO | 2016/09/15
SECONDARY ACCESSION(S): PRJNA339398
REPOSITORIES: GEO
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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 | GSE215035 | GEO
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
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
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.
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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
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
Project description:The innate immune system recognizes nucleic acids as a signature of microbial infection and initiates host-protective responses, including the production of type I IFN and proinflammatory cytokines. Z-DNA binding protein 1 (ZBP1, also known as DLM-1 or DAI) was previously identified as a dsDNA binding protein, triggering DNA-mediated activation of innate immune responses. However, mice or cells lacking ZBP1 produce normal levels of type I IFN in response to dsDNA. Therefore, the classification of ZBP1 as a true DNA sensor remains to be resolved. Here, we report that the single stranded RNA virus, influenza A virus (IAV) is a trigger of the cytosolic sensor ZBP1. Sensing of IAV infection by ZBP1 engages a novel NLRP3 inflammasome pathway that is not defined by the conventions of the canonical and non-canonical NLRP3 inflammasome pathways. Surprisingly, IAV-induced cell death was not prevented by the absence of the NLRP3 inflammasome. Instead, we identified parallel contributions from pyroptosis, necroptosis and apoptosis in the execution of ZBP1-dependent cell death, mediated by the kinase RIPK3. Overall, the ability of ZBP1 to sense IAV infection signifies a point of divergence for IAV-induced programmed cell death pathways and inflammasome activation. We used microarrays to explore the gene expression profiles differentially expressed in influenza-infected bone marrow derived macrophages (BMDM) isolated from Ifnar1-/- and wild-type mice.
2016-08-11 | E-GEOD-77611 | biostudies-arrayexpress
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| S-EPMC3953412 | biostudies-literature
Project description:Short interspersed element (SINE) RNAs are upregulated by cellular stresses1 (heat shock, DNA damage and viral infection) and accumulate in human diseases (macular degeneration2, lupus3, and Alzheimer’s disease4). These transcripts activate inflammasomes5, a family of cytoplasmic multiprotein complexes that sense danger molecules and initiate innate immune responses by activating caspase-1-dependent cytokine production and inflammatory death6, but the molecular sensor of SINE RNAs is unknown. Here, we identify DDX17, a member of the DEAD box family of RNA helicases7, as a sensor of SINE RNAs requisite for inflammasome activation. Induction of caspase-1 cleavage and release of IL-1 and IL-18 by SINE RNAs requires dual recruitment of NLRP3 and NLRC4 but proceeds independent of NAIPs, immune sensors required for canonical NLRC4 activation by bacterial proteins8,9. Instead, SINE RNAs trigger DDX17–NLRC4 interaction, which licenses inflammasome activation. We also report increased levels of DDX17 protein and association of DDX17 and NLRC4 in the retinal pigmented epithelium (RPE) of human eyes with an advanced, untreatable form of age-related macular degeneration (AMD). Disrupting DDX17–NLRC4 signalling blocks SINE RNA-induced inflammasome activation in human RPE cells and RPE degeneration in an animal model of AMD. Our findings uncover a non-canonical mode of inflammasome activation by endogenous retrotransposon transcripts, and provide new potential targets for macular degeneration and potentially other diseases.
2022-06-09 | PXD016019 | Pride
Project description:Inflammasomes are critical for mounting host defense against pathogens. The molecular mechanisms that control activation of the AIM2 inflammasome in response to different cytosolic pathogens remain unclear. Here we found that the transcription factor IRF1 was required for the activation of the AIM2 inflammasome during infection with the Francisella tularensis subspecies novicida (F. novicida), whereas engagement of the AIM2 inflammasome by mouse cytomegalovirus (MCMV) or transfected double-stranded DNA did not require IRF1. Infection of F. novicida detected by the DNA sensor cGAS and its adaptor STING induced type I interferon-dependent expression of IRF1, which drove the expression of guanylate-binding proteins (GBPs); this led to intracellular killing of bacteria and DNA release. Our results reveal a specific requirement for IRF1 and GBPs in the liberation of DNA for AIM2 sensing depending on the pathogen encountered by the cell. We used microarrays to explore the gene expression profiles differentially expressed in Francisella-infected bone marrow-derived macrophages (BMDMs) isolated from Irf1-/-, Ifnar1-/-, Aim2-/- and wild-type mice.
2015-03-04 | E-GEOD-66461 | biostudies-arrayexpress