Affinage

NLRP3

NACHT, LRR and PYD domains-containing protein 3 · UniProt Q96P20

Length
1036 aa
Mass
118.2 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NLRP3 is a cytosolic pattern-recognition receptor that nucleates an ASC- and caspase-1-containing inflammasome to drive maturation of IL-1β and IL-18 in response to diverse danger signals including monosodium urate and CPPD crystals, bacterial RNA, imidazoquinolines, and ATP (PMID:16407889, PMID:16407888, PMID:16546100). It senses these stimuli through convergent upstream events: phagocytosis-dependent lysosomal rupture and cathepsin B release from crystalline particulates (PMID:18604214), and accumulation of dysfunctional mitochondria with cytosolic mtDNA release driven by mitochondrial ROS (PMID:21151103), with NLRP3 directly binding mtDNA through its PYD domain (PMID:37253813). Activated NLRP3 assembles a 12–16-mer double-ring cage held by LRR-LRR contacts with shielded pyrin domains; cage formation drives dispersion from the trans-Golgi network and is required for inflammasome punctum formation, caspase-1 processing, and cell death (PMID:34861190), with downstream caspase-1 cleaving gasdermin D to execute pyroptosis (PMID:34321623). Inflammasome assembly proceeds via ASC nucleation and is supported by accessory partners including NEK7, RACK1, and β-catenin that promote the active conformation and ASC association (PMID:33207200, PMID:32244067), and NLRP3 can cooperate with the NLRC4 scaffold to drive caspase-1 activation during bacterial infection (PMID:27139490). NLRP3 activity is governed by an extensive post-translational code: activating S-palmitoylation by ZDHHC5 at the LRR and by ZDHHC7 at Cys126 that controls TGN localization (reversed by ABHD17A/ZDHHC12) (PMID:38092000, PMID:38583156), stabilizing SUMOylation at Lys204 by UBC9/SUMO1 and by TRIM28 (erased by SENP3) (PMID:31914638, PMID:34373456), activating K27-linked ubiquitination by MARCH5 at K324/K430 that enables NEK7 binding (PMID:37575012), and stabilizing K48-deubiquitination by UAF1/USP1 and BRCC3/BRISC (PMID:33931568, PMID:33247121), counterbalanced by inhibitory AKT phosphorylation at Ser5 and multiple inhibitory ubiquitin ligases (ARIH2, β-TrCP1 at K380 antagonized by YAP, gp78/Insig-1) (PMID:32929041, PMID:29021376, PMID:33976226, PMID:35110683). Transcriptionally, NLRP3 is directly repressed by AhR binding to a promoter XRE (PMID:25141024). Structural modeling places gain-of-function mutations causing cryopyrin-associated autoinflammatory disease at NBD oligomerization interfaces (PMID:14630794).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2006 High

    Established NLRP3 as the sensor component of a caspase-1-activating inflammasome, defining its core function as converting diverse danger signals into IL-1β/IL-18 maturation independently of TLR-driven NF-κB/MAPK signaling.

    Evidence Genetic knockouts (NALP3-/-, ASC-/-, caspase-1-/-) with crystal, bacterial RNA, imidazoquinoline, and ATP stimulation plus in vivo peritonitis and contact hypersensitivity models

    PMID:16407888 PMID:16407889 PMID:16546100

    Open questions at the time
    • Did not resolve how chemically distinct stimuli converge on a single sensor
    • Stimulus-specificity (e.g. Salmonella independence) left the upstream sensing mechanism undefined
  2. 2008 High

    Resolved how particulate stimuli are sensed, showing crystals act indirectly via phagocytosis-driven lysosomal rupture and cathepsin B release rather than direct receptor binding.

    Evidence Crystal phagocytosis assays, lysosomal disruption, cathepsin B and acidification inhibition in NALP3-deficient macrophages

    PMID:18604214

    Open questions at the time
    • The direct molecular link between cathepsin B and NLRP3 activation was not identified
    • Did not explain non-particulate (ATP/nigericin) activation
  3. 2010 High

    Identified mitochondrial damage and cytosolic mtDNA as an endogenous trigger linking autophagy quality control to inflammasome activation.

    Evidence LC3B/beclin-1 knockdown and LC3B-deficient macrophages, mtDNA cytosolic fractionation, ROS measurement, sepsis models

    PMID:21151103

    Open questions at the time
    • Did not establish whether mtDNA binds NLRP3 directly
    • Mechanism of mtDNA cytosolic translocation incompletely defined
  4. 2011 High

    Provided the first atomic-resolution view of the PYD interaction module, revealing a redox-sensitive disulfide that could couple NLRP3 activity to cellular redox state.

    Evidence X-ray crystallography of the NALP3 PYD at 1.7 Å with structural/sequence analysis

    PMID:21880711

    Open questions at the time
    • Functional role of the Cys8-Cys108 disulfide inferred but not tested
    • Full-length assembly context absent
  5. 2013 Medium

    Localized inflammasome assembly to the cytoplasm rather than a specific organelle, constraining models of where NLRP3/ASC/caspase-1 nucleation occurs.

    Evidence Confocal co-localization in primary macrophages against multiple organelle markers under ATP/nigericin/MSU

    PMID:23609011

    Open questions at the time
    • Single-lab imaging without biochemical fractionation
    • Apparent tension with later TGN-dispersion model unresolved
  6. 2014 High

    Defined transcriptional control of NLRP3 by showing AhR directly represses its promoter, and identified a metabolic priming partner (TXNIP).

    Evidence ChIP for AhR binding to the NLRP3 promoter XRE with siRNA/overexpression; TXNIP-NLRP3 Co-IP and knockdown in diabetic nephropathy model

    PMID:25017793 PMID:25141024

    Open questions at the time
    • TXNIP-NLRP3 interaction is single-lab and context-specific
    • How transcriptional repression integrates with post-translational control not addressed
  7. 2016 High

    Demonstrated cross-talk between inflammasome scaffolds, showing NLRP3 can be recruited to compensate for NLRC4 in caspase-1 activation during bacterial infection.

    Evidence Reciprocal Co-IP and genetic epistasis with Nlrc4(S533A) and Nlrp3-/- macrophages during Salmonella infection

    PMID:27139490

    Open questions at the time
    • Physical architecture of a joint NLRP3-NLRC4 complex not resolved
    • Physiological contexts requiring cooperation unclear
  8. 2021 High

    Defined the resting and active higher-order architecture of NLRP3, establishing the double-ring cage with shielded PYDs and linking cage formation to TGN dispersion as a prerequisite for activation.

    Evidence Cryo-EM of full-length mouse NLRP3 with structure-guided mutagenesis, membrane fractionation, and TGN dispersion/caspase-1 readouts

    PMID:34861190

    Open questions at the time
    • How specific stimuli release PYD shielding not mechanistically resolved
    • Conformational transition from cage to active inflammasome incompletely defined
  9. 2021 High

    Established ubiquitin removal as a licensing step for activation and SUMOylation as a competing stabilizing modification, building a PTM logic of NLRP3 control.

    Evidence BRISC/BRCC3 inhibition (thiolutin), UAF1/USP1 K48-deubiquitination, USP5 autophagic degradation, and TRIM28/SUMO1 plus YAP/β-TrCP1 K380 ubiquitination studies with KO and in vivo models

    PMID:33247121 PMID:33931568 PMID:33976226 PMID:34373456 PMID:34486483

    Open questions at the time
    • Temporal ordering and hierarchy among competing PTMs unresolved
    • Some erasers/ligases validated in single labs
  10. 2023 High

    Identified palmitoylation and K27-ubiquitination as positive controls that govern TGN localization and NEK7-dependent oligomerization, mechanistically connecting lipid/ubiquitin marks to assembly.

    Evidence Acyl-RAC, ZDHHC5/ZDHHC7 KO and site mutagenesis (C126/LRR), ABHD17A depalmitoylase assays, and MARCH5 K27-Ub mapping at K324/K430 with conditional KO mice

    PMID:37575012 PMID:38092000 PMID:38583156

    Open questions at the time
    • How palmitoylation, K27-Ub, and NEK7 recruitment are coordinated in time not resolved
    • Direct mtDNA-binding affinity model is computational (37253813)
  11. 2024 High

    Extended NLRP3 regulation into cell-type-specific and disease contexts, including Tau-mediated PYD acetylation in microglia and NLRP12 as a human-specific suppressor of NLRP3-driven ASC assembly.

    Evidence In vitro acetyltransferase assay with MS site mapping and AAV Tau model; ASC polymerization screen, Co-IP, and disease-mutant testing in patient PBMCs

    PMID:38261657 PMID:38488468

    Open questions at the time
    • Species differences (human vs murine NLRP3 regulation by NLRP12) limit generalization
    • Acetylation work is single-lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the dozens of identified PTMs, accessory partners, and localization cues are integrated into a single ordered activation pathway, and how individual stimuli select among them, remains unresolved.
  • No unified temporal model of competing/cooperating PTMs
  • Direct stimulus-to-conformational-change coupling undefined
  • Structural basis of the active inflammasome (vs resting cage) not fully resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 2 GO:0003677 DNA binding 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ASCMARCH5NEK7NLRC4NLRP12RACK1YAPZDHHC7
Complex memberships
NLRP3 inflammasome

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 NALP3 (NLRP3) forms a caspase-1-activating inflammasome complex with ASC that is required for monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystal-induced IL-1β and IL-18 maturation; macrophages deficient in NALP3, ASC, or caspase-1 are defective in crystal-induced IL-1β activation, and inflammasome-deficient mice show impaired neutrophil influx in crystal-induced peritonitis. Genetic knockout (NALP3-/-, ASC-/-, caspase-1-/- mice), in vivo peritonitis model, IL-1β/IL-18 secretion assays Nature High 16407889
2006 Cryopyrin (NLRP3/Nalp3) and ASC are essential components of the inflammasome required for caspase-1 activation and IL-1β/IL-18 production in response to bacterial RNA and imidazoquinoline compounds (R837, R848); NLRP3 deficiency did not affect TNF-α, IL-6, NF-κB, or MAPK activation, demonstrating a specific role in caspase-1 activation distinct from TLR signaling. Cryopyrin-deficient macrophages, cytokine secretion assays, NF-κB/MAPK activation assays Nature High 16407888
2006 NALP3 is essential for ATP-driven caspase-1 activation in LPS-stimulated macrophages and for secretion of IL-1α, IL-1β, and IL-18; NALP3 is not required for caspase-1 activation by Salmonella typhimurium, revealing stimulus-specific inflammasome assembly. NALP3-deficient and ASC-deficient mice, ATP stimulation of LPS-primed macrophages, contact hypersensitivity model in vivo Immunity High 16546100
2008 NALP3 inflammasome activation by silica crystals and aluminum salts requires phagocytosis of the crystals, followed by lysosomal damage/rupture; inhibition of phagosomal acidification or cathepsin B activity impaired NALP3 activation, identifying lysosomal damage as an endogenous danger signal sensed by NALP3. Crystal phagocytosis assays, lysosomal disruption experiments, cathepsin B inhibition, macrophage IL-1β secretion assays, NALP3-deficient cells Nature immunology High 18604214
2010 Depletion of autophagic proteins LC3B and beclin 1 enhances NLRP3 inflammasome activation (caspase-1 activation, IL-1β/IL-18 secretion) by promoting accumulation of dysfunctional mitochondria and cytosolic translocation of mitochondrial DNA (mtDNA); cytosolic mtDNA release depended on the NLRP3 inflammasome and mitochondrial ROS, and cytosolic mtDNA contributed to IL-1β/IL-18 secretion. LC3B/beclin-1 knockdown macrophages, LC3B-deficient mice, mtDNA cytosolic fractionation, ROS measurement, sepsis models Nature immunology High 21151103
2011 Crystal structure of the NALP3 pyrin domain (PYD) resolved at 1.7-Å resolution reveals a canonical six-helical bundle fold with a homodimeric interface, conserved surface residues implicated in ASC interaction, and an unexpected disulfide bond between Cys-8 and Cys-108 that may regulate NALP3 activity via redox potential. X-ray crystallography (1.7-Å resolution), structural and sequence analysis The Journal of biological chemistry High 21880711
2013 Activated ASC pyroptosome co-localizes with NLRP3 and caspase-1 in the cytoplasm but does not co-localize with mitochondria or seven other organelles tested in mouse peritoneal macrophages, establishing the cytoplasm (rather than specific organelles) as the site of NLRP3 inflammasome assembly under ATP, nigericin, or MSU stimulation. Confocal microscopy co-localization in primary macrophages, multiple organelle markers tested Protein & cell Medium 23609011
2014 Aryl hydrocarbon receptor (AhR) binds to the xenobiotic response element (XRE) in the NLRP3 promoter and directly inhibits NLRP3 transcription; AhR activation reduces NLRP3 protein level, caspase-1 activation, and IL-1β secretion, while AhR siRNA knockdown has opposite effects. ChIP assay (AhR binding to NLRP3 promoter XRE), siRNA knockdown, IL-1β/caspase-1 assays, in vivo alum peritonitis model Nature communications High 25141024
2015 NLRP3-activated caspase-1 cleaves the glucocorticoid receptor, diminishing glucocorticoid-induced transcriptional responses and increasing glucocorticoid resistance in acute lymphoblastic leukemia cells; knockdown or inhibition of CASP1 increased glucocorticoid receptor levels and mitigated resistance. CASP1 overexpression/knockdown, glucocorticoid receptor cleavage assays, transcriptional response assays, methylation analysis of CASP1/NLRP3 promoters in 444 patient samples Nature genetics Medium 25938942
2016 NLRP3 physically associates with NLRC4 via the NLRC4 NACHT domain in macrophages during Salmonella infection or flagellin transfection; when NLRC4 phosphorylation at S533 is ablated (S533A mutant), NLRP3 is recruited to compensate for caspase-1 activation, and the double KO (NLRC4 S533A/Nlrp3-/-) phenocopies NLRC4-/- cells, demonstrating functional overlap between the two inflammasome scaffolds. Co-immunoprecipitation, bone marrow-derived macrophages from Nlrc4(S533A/S533A) and Nlrp3-/- mice, Salmonella infection/flagellin transfection, caspase-1 activation assays The Journal of experimental medicine High 27139490
2017 E3 ubiquitin ligase ARIH2 interacts with NLRP3 via its NACHT domain (aa 220-575) and ubiquitinates NLRP3 via K48- and K63-linked chains using its RING2 domain; ARIH2 deletion by CRISPR/Cas9 inhibits NLRP3 ubiquitination and promotes inflammasome activation, while ARIH2 overexpression promotes ubiquitination and inhibits activation. Co-IP, CRISPR/Cas9 deletion, ubiquitin linkage mutants, IL-1β/ASC oligomerization assays Journal of immunology High 29021376
2019 Human NLRP3 is expressed as two major isoforms by alternative splicing: full-length and a variant lacking exon 5; the NLRP3 Δexon5 isoform lacks the interaction surface for NEK7 and is therefore inactive, establishing stochastic alternative splicing of LRR domain exons as a regulatory mechanism for NLRP3 activity. RT-PCR isoform identification, NEK7 interaction assays with Δexon5 mutant, functional activity assays Nature communications Medium 31324763
2019 SUMO1 SUMOylates NLRP3 at Lys204 via the SUMO-conjugating enzyme UBC9, facilitating ASC oligomerization and inflammasome activation; SENP3 deSUMOylates NLRP3 to attenuate ASC recruitment, speck formation, inflammasome activation, and IL-1β secretion. Co-IP, SUMOylation site mutagenesis (K204), SENP3 overexpression/knockdown, ASC speck formation assays, IL-1β cleavage assays FASEB journal High 31914638
2020 AKT kinase associates with NLRP3 and phosphorylates it at Ser5, limiting NLRP3 oligomerization; this S5 phosphorylation also stabilizes NLRP3 by reducing K496 ubiquitination and proteasome-mediated degradation by E3 ligase Trim31. Pharmacological AKT manipulation reciprocally modulates IL-1β production in vitro and in vivo. Co-IP (AKT-NLRP3), site-specific phosphorylation assays (S5 mutagenesis), ubiquitination assays (K496), Trim31 interaction, pharmacological AKT inhibition in vivo (LPS injection) Journal of immunology High 32929041
2020 RACK1 (receptor for activated protein C kinase 1) is a component of the NLRP3 complex in macrophages; RACK1 interacts with NLRP3 and NEK7 (but not ASC), promotes the active conformation of NLRP3 induced by activating stimuli, and is required for subsequent inflammasome assembly, caspase-1 activation, and IL-1β release specifically downstream of NLRP3 (not NLRC4 or AIM2). Co-IP, RACK1 siRNA knockdown, caspase-1 activation and IL-1β release assays, specificity testing across multiple inflammasomes Cell reports Medium 33207200
2020 β-catenin physically interacts with NLRP3 and promotes the association between NLRP3 and ASC; siRNA or pharmacological suppression of β-catenin impairs NLRP3 inflammasome activation, and β-catenin inhibitor attenuates LPS-induced systemic inflammation in vivo. Co-IP, siRNA knockdown, pharmacological inhibition, in vivo LPS model, IL-1β/caspase-1 assays Molecular immunology Medium 32244067
2021 Full-length mouse NLRP3 forms a 12- to 16-mer double-ring cage oligomer held together by LRR-LRR interactions, with pyrin domains shielded within the assembly to prevent premature activation; this NLRP3 cage is predominantly membrane-localized. Structure-guided mutagenesis shows that double-ring cage formation is required for trans-Golgi network (TGN) dispersion (an early event in NLRP3 activation by many stimuli) and for inflammasome punctum formation, caspase-1 processing, and cell death. Cryo-EM structure of full-length mouse NLRP3, structure-guided mutagenesis, membrane fractionation, TGN dispersion assays, caspase-1 processing and cell death assays Cell High 34861190
2021 TRIM28 (E3 SUMO ligase) binds NLRP3 and promotes its SUMOylation by SUMO1, SUMO2, and SUMO3; this SUMOylation inhibits NLRP3 ubiquitination and proteasomal degradation, thereby stabilizing NLRP3 and facilitating inflammasome activation. Trim28 deficiency attenuates NLRP3 inflammasome activation in vitro and in vivo. Co-IP, SUMO modification assays, ubiquitination assays, Trim28 KO (in vitro and in vivo), caspase-1/IL-1β assays Nature communications High 34373456
2021 YAP physically interacts with NLRP3 and maintains NLRP3 stability by blocking the association between NLRP3 and E3 ligase β-TrCP1; β-TrCP1 promotes NLRP3 proteasomal degradation via K27-linked ubiquitination at Lys380. YAP deficiency in myeloid cells attenuates LPS-induced systemic inflammation and MSU crystal-induced peritonitis. Co-IP (YAP-NLRP3, NLRP3-β-TrCP1), ubiquitination assays (K27, K380), myeloid-specific YAP KO mice, in vivo inflammation models Nature communications High 33976226
2021 BRISC complex (containing BRCC3 metalloprotease) mediates deubiquitination of NLRP3, which is required for efficient NLRP3 inflammasome activation; thiolutin (JAMM domain metalloprotease inhibitor) blocks BRISC-mediated NLRP3 deubiquitination and suppresses NLRP3 inflammasome activation across canonical, noncanonical, alternative, and transcription-independent pathways at nanomolar concentrations. BRISC/BRCC3 inhibition by thiolutin, NLRP3 ubiquitination assays, multiple NLRP3 activation pathway assays, in vivo models (sepsis, peritonitis, EAE, CAPS, NAFLD) Science immunology High 33931568
2021 UAF1/USP1 deubiquitinase complex selectively removes K48-linked polyubiquitination from NLRP3, suppressing its proteasomal degradation and enhancing cellular NLRP3 levels required for inflammasome assembly; UAF1/USP12 and UAF1/USP46 complexes additionally promote NF-κB activation to enhance NLRP3 transcription. Uaf1 deficiency attenuates NLRP3 inflammasome activation in vitro and in vivo. Co-IP, K48-linked ubiquitination assays, deubiquitinase activity assays, Uaf1 KD (in vitro and in vivo), IL-1β secretion assays Nature communications High 33247121
2021 USP5 deubiquitinase attenuates NLRP3 inflammasome activation by promoting autophagic degradation of NLRP3; USP5 deficiency or overexpression reciprocally modulates NLRP3 protein levels and inflammasome activation. USP5 KD/OE, co-IP, autophagy flux assays, NLRP3 degradation assays, IL-1β/caspase-1 assays Autophagy Medium 34486483
2022 E3 ubiquitin ligase gp78 mediates mixed ubiquitination of NLRP3, which inhibits NLRP3 inflammasome activation by suppressing NLRP3 oligomerization and subcellular translocation; Insig-1 (ER membrane protein) is required for the gp78-NLRP3 interaction and gp78-mediated NLRP3 ubiquitination. gp78 or Insig-1 deficiency in myeloid cells exacerbates NLRP3-dependent inflammation in vivo. Co-IP (gp78-NLRP3, gp78-Insig-1), ubiquitination assays, NLRP3 oligomerization assays, myeloid-specific KO mice, in vivo inflammation models Cell death and differentiation High 35110683
2022 USP22 deubiquitinase inhibits NLRP3 inflammasome activation by promoting ATG5-mediated macroautophagy/NLRP3 degradation; USP22 stabilizes ATG5 via decreasing K27- and K48-linked ubiquitination at Lys118. USP22 deficiency significantly increases alum-induced peritonitis and LPS-induced systemic inflammation in vivo. USP22 KD/KO, co-IP, ubiquitination assays (K27/K48-ATG5 K118), autophagy flux assays, in vivo models Autophagy Medium 35900990
2022 TRIM31 interacts with NLRP3 in retinal pigment epithelial cells and promotes NLRP3 ubiquitination, thereby inhibiting NLRP3 inflammasome activation and pyroptosis; TRIM31 knockdown phenocopies NLRP3 activation by ox-LDL. Co-IP, ubiquitination assays, TRIM31 KD/OE, NLRP3 inhibitor controls, IL-1β/caspase-1 assays Cell biology international Medium 32716108
2023 NLRP3 is S-palmitoylated at the LRR domain by ZDHHC5; this palmitoylation promotes NLRP3 oligomerization, NLRP3-NEK7 interaction, and ASC aggregate formation, leading to caspase-1 activation, IL-1β/IL-18 release, and GSDMD cleavage. ABHD17A acts as the depalmitoylase for NLRP3, and a disease-associated NLRP3 mutation shows defective ABHD17A binding and hyper-palmitoylation. Zdhhc5-/- mice exhibit defective NLRP3 inflammasome activation in vivo. Acyl-RAC palmitoylation assay, ZDHHC5 KO/siRNA, site-specific mutagenesis (LRR palmitoylation site), NLRP3 oligomerization assays, NEK7 interaction assays, ASC speck formation, Zdhhc5-/- mice, ABHD17A depalmitoylase assay Molecular cell High 38092000
2023 NLRP3 binds non-oxidized mtDNA with much higher affinity (IC50 ~4 nM) than Ox-mtDNA (IC50 ~247 nM); the NLRP3 PYD domain mediates DNA binding and preferentially binds Ox-mtDNA; a NOMID/FCAS gain-of-function mutant shows higher affinity for Ox-mtDNA (IC50 ~8.1 nM). A structural model based on alignment to DNA glycosylases suggests a DNA-binding mechanism involving the PYD domain fold. In vitro DNA-binding assays (IC50 determination), domain deletion/truncation constructs, monoclonal antibody blocking assays, structural homology modeling Communications biology Medium 37253813
2023 MARCH5 (mitochondria-associated E3 ubiquitin ligase) interacts with the NACHT domain of NLRP3 and promotes K27-linked polyubiquitination at K324 and K430 residues; this ubiquitination is required for NLRP3-NEK7 binding, NLRP3 oligomerization, and ASC speck formation. Myeloid-specific March5 cKO mice fail to secrete IL-1β/IL-18 and show attenuated LPS- or Pseudomonas-induced mortality. Co-IP (MARCH5-NLRP3 NACHT domain), K27-linked ubiquitination assays with K324A/K430A mutants, NEK7 binding assays, ASC speck assays, myeloid-specific March5 cKO mice, in vivo infection models The EMBO journal High 37575012
2024 ZDHHC7 palmitoylates NLRP3 at Cys126, which is critical for NLRP3 inflammasome activation; Cys126 palmitoylation by ZDHHC7 promotes resting NLRP3 localization on the trans-Golgi network (TGN) and activated NLRP3 on dispersed TGN, enabling ASC recruitment and oligomerization. ZDHHC7 KO, pharmacological inhibition, or C126 mutation diminishes NLRP3 activation in macrophages and in vivo. ZDHHC12 has a terminating/opposing palmitoylation effect on NLRP3. Acyl-RAC palmitoylation assay, ZDHHC7 KO, C126 site mutagenesis, TGN localization by live imaging/immunofluorescence, ASC oligomerization assays, in vivo inflammasome models Cell reports High 38583156
2024 Tau protein directly acetylates NLRP3 at K21, K22, and K24 within its PYD domain (via Tau's K18 domain acetyltransferase activity), inducing inflammasome activation in microglia; blocking the Tau-NLRP3 interaction with a designed peptide inhibits NLRP3 acetylation, inflammasome activation, microgliosis, and cognitive impairment in mice. In vitro acetylation assay (test-tube), co-IP, mass spectrometry (acetylation site identification), molecular docking, AAV-mediated Tau overexpression in mice, behavioral testing, PET/CT imaging, blocking peptide intervention Clinical and translational medicine High 38488468
2024 NLRP12 interacts with NLRP3 and inhibits human (but not murine) NLRP3-induced ASC inflammasome assembly; NLRP12 failed to nucleate ASC polymerization itself, and disease-associated NLRP12 mutants lost the ability to suppress NLRP3 inflammasome assembly. PBMCs from NLRP12-mutant patients showed increased IL-1β in response to NLRP3 stimulation. ASC polymerization/speck formation screen, Co-IP (NLRP12-NLRP3), NLRP12 disease mutant analysis, IL-1β assays in patient PBMCs, species specificity testing (human vs. murine NLRP3) Science signaling High 38261657
2014 TXNIP (thioredoxin-interacting protein) activates the NALP3 inflammasome by directly interacting with NLRP3 in high-glucose-exposed podocytes; TXNIP knockdown impedes NLRP3 inflammasome activation and attenuates podocyte injury. Blocking NLRP3 inflammasome activation by NLRP3/ASC shRNA or caspase-1 inhibition prevents IL-1β production and podocyte injury under diabetic conditions. Co-IP (TXNIP-NLRP3), TXNIP/NLRP3/ASC shRNA knockdown, caspase-1 inhibition, in vivo diabetic nephropathy model, IL-1β assays Biochimica et biophysica acta Medium 25017793
2022 CB1R (cannabinoid receptor 1) directly interacts with the NLRP3 inflammasome via amino acid residues 177-209; antipsychotics drive CB1R translocation to the cytoplasm where CB1R stabilizes the inflammasome. Cb1r KO significantly alleviates antipsychotic-induced cardiomyocyte pyroptosis and cardiotoxicity. Co-IP (CB1R-NLRP3, domain mapping 177-209), RNA sequencing, small-molecule screen, Cb1r KO mice, pyroptosis assays Signal transduction and targeted therapy Medium 35739093
2003 3D modeling of the NLRP3 NBD domain reveals structural similarity to AAA+ ATPases; most CAPS/MWS/FCU-associated mutations cluster on one side of the NBD in a region predicted to mediate intermolecular contacts, suggesting that defects in nucleotide binding, hydrolysis, or protein oligomerization underlie NLRP3 functional dysregulation in autoinflammatory diseases. 3D structural modeling of the NBD domain, mapping of known mutations onto the model, sequence/structural analysis Blood Low 14630794
2021 NLRP3 activated by diverse stimuli triggers gasdermin D cleavage by caspase-1, releasing the pore-forming N-terminal domain that drives pyroptosis; the assembled NLRP3 inflammasome contributes not only to pyroptosis but also to apoptosis, necroptosis, and ferroptosis. Review summarizing experimental findings from multiple studies including loss-of-function and caspase-1 activation assays Cellular & molecular immunology Low 34321623
2018 NLRP3 inflammasome activation requires intracellular copper; the copper chelator tetrathiomolybdate specifically inhibits canonical NLRP3 but not AIM2, NLRC4, or NLRP1 inflammasomes or NF-κB priming; the regulation involves copper at the active site of superoxide dismutase 1 (SOD1), and SOD1-deficient mice show impaired inflammasome function. In vivo copper depletion attenuated caspase-1-dependent inflammation. Copper chelation (tetrathiomolybdate), SOD1-deficient mice, multiple inflammasome specificity assays, in vivo endotoxic shock model Journal of immunology Medium 29358279
2024 FXR inhibits NLRP3 activity by restraining its Ser295 phosphorylation in hepatic stellate cells; knockdown or knockout of NLRP3 relieves GCDCA-induced hepatic fibrosis, placing NLRP3 downstream of bile acid signaling via FXR-mediated phosphorylation control. NLRP3 knockdown/knockout, FXR overexpression, Western blotting for Ser295 phosphorylation, in vivo mouse liver fibrosis model with GCDCA Hepatology international Low 38172440

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 4166 16407889
2010 Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nature immunology 2561 21151103
2008 Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature immunology 2428 18604214
2021 NLRP3 inflammasome activation and cell death. Cellular & molecular immunology 1237 34321623
2006 Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 931 16407888
2006 Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 808 16546100
2015 NLRP3 inflammasome and its inhibitors: a review. Frontiers in pharmacology 720 26594174
2014 Mechanism of NLRP3 inflammasome activation. Annals of the New York Academy of Sciences 604 24840700
2019 Pharmacological Inhibitors of the NLRP3 Inflammasome. Frontiers in immunology 564 31749805
2020 Interplay Between NLRP3 Inflammasome and Autophagy. Frontiers in immunology 516 33163006
2020 NLRP3 inflammasome in endothelial dysfunction. Cell death & disease 412 32948742
2017 NLRP3 inflammasome: Its regulation and involvement in atherosclerosis. Journal of cellular physiology 378 28345767
2020 NLRP3 Inflammasome and Inflammatory Diseases. Oxidative medicine and cellular longevity 294 32148650
2018 Metabolic regulation of NLRP3. Immunological reviews 250 29247992
2011 The Nlrp3 inflammasome: contributions to intestinal homeostasis. Trends in immunology 242 21388882
2003 Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU. Blood 228 14630794
2021 NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation. Cell 222 34861190
2018 Spotlight on the NLRP3 inflammasome pathway. Journal of inflammation research 219 30288079
2014 Aryl hydrocarbon receptor negatively regulates NLRP3 inflammasome activity by inhibiting NLRP3 transcription. Nature communications 191 25141024
2018 Regulation of NLRP3 Inflammasome by Phosphorylation. Frontiers in immunology 189 30349539
2023 Pharmacological Inhibition of the NLRP3 Inflammasome: Structure, Molecular Activation, and Inhibitor-NLRP3 Interaction. Pharmacological reviews 183 36669831
2011 Crystal structure of NALP3 protein pyrin domain (PYD) and its implications in inflammasome assembly. The Journal of biological chemistry 167 21880711
2012 Intrinsic properties and functional circuitry of the AII amacrine cell. Visual neuroscience 146 22310372
2018 NLRP3 inflammasome activation in inflammaging. Seminars in immunology 140 30268598
2015 NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells. Nature genetics 140 25938942
2009 Expression and regulation of the NALP3 inflammasome complex in periodontal diseases. Clinical and experimental immunology 136 19664151
2021 TRIM28 SUMOylates and stabilizes NLRP3 to facilitate inflammasome activation. Nature communications 135 34373456
2021 YAP promotes the activation of NLRP3 inflammasome via blocking K27-linked polyubiquitination of NLRP3. Nature communications 134 33976226
2016 NLRP3 recruitment by NLRC4 during Salmonella infection. The Journal of experimental medicine 124 27139490
2023 ZDHHC5-mediated NLRP3 palmitoylation promotes NLRP3-NEK7 interaction and inflammasome activation. Molecular cell 122 38092000
2014 Chrysophanol inhibits NALP3 inflammasome activation and ameliorates cerebral ischemia/reperfusion in mice. Mediators of inflammation 122 24876671
2017 ARIH2 Ubiquitinates NLRP3 and Negatively Regulates NLRP3 Inflammasome Activation in Macrophages. Journal of immunology (Baltimore, Md. : 1950) 118 29021376
2010 Nlrp3: an immune sensor of cellular stress and infection. The international journal of biochemistry & cell biology 115 20079456
2021 USP5 attenuates NLRP3 inflammasome activation by promoting autophagic degradation of NLRP3. Autophagy 113 34486483
2020 UAF1 deubiquitinase complexes facilitate NLRP3 inflammasome activation by promoting NLRP3 expression. Nature communications 112 33247121
2011 Lipopolysaccharide induces and activates the Nalp3 inflammasome in the liver. World journal of gastroenterology 109 22147977
2022 NLRP3 inflammasome in neurodegenerative disease. Translational research : the journal of laboratory and clinical medicine 105 35952982
2011 Gene silencing of NALP3 protects against liver ischemia-reperfusion injury in mice. Human gene therapy 105 21128730
2019 Interaction between autophagy and the NLRP3 inflammasome. Acta biochimica et biophysica Sinica 102 31609412
2013 Nalp3 inflammasome is activated and required for vascular smooth muscle cell calcification. International journal of cardiology 94 23453445
2020 Inhibiting the NLRP3 Inflammasome. Molecules (Basel, Switzerland) 92 33255820
2021 Licochalcone B specifically inhibits the NLRP3 inflammasome by disrupting NEK7-NLRP3 interaction. EMBO reports 91 34882936
2017 Rhein attenuates inflammation through inhibition of NF-κB and NALP3 inflammasome in vivo and in vitro. Drug design, development and therapy 91 28652704
2015 NLRP3 Inflammasome and Pathobiology in AMD. Journal of clinical medicine 91 26237026
2009 Expression and function of the NALP3 inflammasome in rheumatoid synovium. Immunology 86 19824913
2022 Salidroside Ameliorates Depression by Suppressing NLRP3-Mediated Pyroptosis via P2X7/NF-κB/NLRP3 Signaling Pathway. Frontiers in pharmacology 82 35496273
2022 Corilagin Restrains NLRP3 Inflammasome Activation and Pyroptosis through the ROS/TXNIP/NLRP3 Pathway to Prevent Inflammation. Oxidative medicine and cellular longevity 82 36299604
2021 NLRP3 Ubiquitination-A New Approach to Target NLRP3 Inflammasome Activation. International journal of molecular sciences 80 34445484
2020 Increasing complexity of NLRP3 inflammasome regulation. Journal of leukocyte biology 79 32531835
2024 NLRP3 Cys126 palmitoylation by ZDHHC7 promotes inflammasome activation. Cell reports 78 38583156
2018 Flavonoids interfere with NLRP3 inflammasome activation. Toxicology and applied pharmacology 78 29960001
2021 Pharmacological targeting of NLRP3 deubiquitination for treatment of NLRP3-associated inflammatory diseases. Science immunology 74 33931568
2014 Thioredoxin-interacting protein mediates NALP3 inflammasome activation in podocytes during diabetic nephropathy. Biochimica et biophysica acta 72 25017793
2022 USP22 suppresses the NLRP3 inflammasome by degrading NLRP3 via ATG5-dependent autophagy. Autophagy 69 35900990
2020 AKT Regulates NLRP3 Inflammasome Activation by Phosphorylating NLRP3 Serine 5. Journal of immunology (Baltimore, Md. : 1950) 68 32929041
2002 Fine structure mapping of CIAS1: identification of an ancestral haplotype and a common FCAS mutation, L353P. Human genetics 67 12522564
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2020 RACK1 Mediates NLRP3 Inflammasome Activation by Promoting NLRP3 Active Conformation and Inflammasome Assembly. Cell reports 64 33207200
2015 TLR4 and NALP3 inflammasome in the development of endothelial dysfunction in uraemia. European journal of clinical investigation 63 25496217
2023 Targeting NLRP3 inflammasome for neurodegenerative disorders. Molecular psychiatry 62 37670126
2019 SUMO1 SUMOylates and SENP3 deSUMOylates NLRP3 to orchestrate the inflammasome activation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 59 31914638
2022 Ubiquitination of NLRP3 by gp78/Insig-1 restrains NLRP3 inflammasome activation. Cell death and differentiation 57 35110683
2019 Alternative splicing regulates stochastic NLRP3 activity. Nature communications 57 31324763
2009 MEFV, TNF1rA, CARD15 and NLRP3 mutation analysis in PFAPA. Rheumatology international 56 19579027
2022 NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies. Frontiers in immunology 54 36275641
2014 Methylsulfonylmethane inhibits NLRP3 inflammasome activation. Cytokine 52 25461402
2018 Copper Regulates the Canonical NLRP3 Inflammasome. Journal of immunology (Baltimore, Md. : 1950) 51 29358279
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2021 NLRP3 inflammasomes that induce antitumor immunity. Trends in immunology 48 34034975
2021 NLRP3 inflammasome in sepsis (Review). Molecular medicine reports 47 33982766
2010 Nod1, Nod2 and Nalp3 receptors, new potential targets in treatment of allergic rhinitis? Allergy 45 20384614
2021 Reviewing the importance of TLR-NLRP3-pyroptosis pathway and mechanism of experimental NLRP3 inflammasome inhibitors. Scandinavian journal of immunology 44 34861056
2020 The NLRP3 Inflammasome and Its Role in T1DM. Frontiers in immunology 44 32973739
2023 Differential Binding of NLRP3 to non-oxidized and Ox-mtDNA mediates NLRP3 Inflammasome Activation. Communications biology 43 37253813
2017 Azithromycin decreases NALP3 mRNA stability in monocytes to limit inflammasome-dependent inflammation. Respiratory research 43 28659178
2020 Chronic cerebral hypoperfusion activates AIM2 and NLRP3 inflammasome. Brain research 42 32171704
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2023 MARCH5-dependent NLRP3 ubiquitination is required for mitochondrial NLRP3-NEK7 complex formation and NLRP3 inflammasome activation. The EMBO journal 40 37575012
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2015 Expression of dectin-1 and enhanced activation of NALP3 inflammasome are associated with resistance to paracoccidioidomycosis. Frontiers in microbiology 40 26388856
2024 Tau induces inflammasome activation and microgliosis through acetylating NLRP3. Clinical and translational medicine 39 38488468
2015 The NLRP3 inflammasome and stroke. International journal of clinical and experimental medicine 39 26131053
2020 Role of NLRP3 inflammasome in liver disease. Journal of digestive diseases 38 32585073
2021 Suppression of lncRNA NLRP3 inhibits NLRP3-triggered inflammatory responses in early acute lung injury. Cell death & disease 37 34599154
2016 Goldfish Leptin-AI and Leptin-AII: Function and Central Mechanism in Feeding Control. International journal of molecular sciences 37 27249000
2020 β-catenin promotes NLRP3 inflammasome activation via increasing the association between NLRP3 and ASC. Molecular immunology 36 32244067
2016 The Relationship between NALP3 and Autoinflammatory Syndromes. International journal of molecular sciences 36 27187378
2015 NALP3 inflammasome activation in protein misfolding diseases. Life sciences 36 26037399
2020 TRIM31 inhibits NLRP3 inflammasome and pyroptosis of retinal pigment epithelial cells through ubiquitination of NLRP3. Cell biology international 35 32716108
2019 Effects of phosphorylation on the NLRP3 inflammasome. Archives of biochemistry and biophysics 35 30844378
2022 NLRP3: Role in ischemia/reperfusion injuries. Frontiers in immunology 34 36238294
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2024 Bile acids induce liver fibrosis through the NLRP3 inflammasome pathway and the mechanism of FXR inhibition of NLRP3 activation. Hepatology international 33 38172440
2023 Natural products modulate NLRP3 in ulcerative colitis. Frontiers in pharmacology 33 37849728
2018 Assessing NLRP3 Inflammasome Activation by Nanoparticles. Methods in molecular biology (Clifton, N.J.) 33 29039099
2024 NLRP12 interacts with NLRP3 to block the activation of the human NLRP3 inflammasome. Science signaling 32 38261657
2022 CB1R-stabilized NLRP3 inflammasome drives antipsychotics cardiotoxicity. Signal transduction and targeted therapy 32 35739093
2022 Pyroptosis in NLRP3 inflammasome-related atherosclerosis. Cell stress 32 36304814
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