NLRP3 (cryopyrin) is a cytosolic NLR-family protein of myeloid and other innate immune cells that nucleates the NLRP3 inflammasome, the platform that activates caspase-1 and so drives maturation of interleukin-1 beta and interleukin-18 and gasdermin-D-dependent pyroptosis. It is built from an N-terminal pyrin domain, a central nucleotide-binding NACHT domain and a C-terminal leucine-rich repeat. In the resting state it is held as an autoinhibited, ADP-bound, membrane-binding oligomeric cage - reported as a decamer and as a dodecamer by different groups - with the pyrin domains sequestered inside the leucine-rich-repeat shell. Activation converts the NACHT domain to an ATP-bound conformation and assembles an active disc in which the pyrin domains stack into a filament that nucleates unidirectional polymerisation of the adaptor ASC, which in turn recruits procaspase-1. NLRP3 has no established direct agonist ligand. It responds to an unusually wide range of stimuli - pore-forming toxins, extracellular ATP, crystals such as monosodium urate, silica and alum, cell swelling, and mitochondrial and lysosomal damage - and the prevailing view is that it detects a shared downstream cellular perturbation, with potassium efflux and disassembly of the trans-Golgi network as common intermediates, rather than binding each agonist. Recruitment to the dispersed trans-Golgi network occurs through ionic interaction between a conserved polybasic region and phosphatidylinositol-4-phosphate, after which microtubule-dependent transport concentrates NLRP3, together with the kinase NEK7, as condensates at the pericentriolar material of the microtubule organising centre. Whether this route is obligatory is disputed: low-molecular-weight, non-cage NLRP3 species can drive a slower, trans-Golgi- and MTOC-distal pathway that dominates in human neutrophils, and raising NLRP3 abundance can make potassium-efflux-driven activation independent of both NEK7 and priming. Gain-of-function mutations, mostly in the NACHT-encoding exon 3, cause the cryopyrin-associated periodic syndromes - familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease - which respond to interleukin-1 blockade, and NLRP3 activity contributes to gout, atherosclerosis, silicosis and neuroinflammation. A separate, inflammasome-independent role for NLRP3 as a nuclear transcriptional cofactor that binds the Il4 promoter with IRF4 in T helper 2 cells has been reported in mouse but is not independently corroborated.
Definition: The activity of a protein that detects a perturbation of cytoplasmic or organellar homeostasis - for example ion flux, membrane or organelle damage, or a change in a compartment's identity - and responds by changing conformation and nucleating assembly of an inflammasome. Unlike molecular sensor activity, this function does not require the protein to bind the agonist or the sensed species.
Justification: GO:0140299 molecular sensor activity is defined as binding a molecule and responding to its intracellular level, and is therefore inapplicable to NLRP3, which is activated by structurally unrelated agonists - crystals, pore-forming toxins, extracellular ATP, cell swelling - that it does not bind, via shared downstream perturbations such as potassium efflux and trans-Golgi disassembly. Curators are left choosing between a term that asserts a ligand that does not exist and no molecular-function term at all. The gap is general: NLRP1, NLRP6, NLRC4 and pyrin present the same problem.
Parent term: pattern recognition receptor activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: NLRP3 is a cytosolic protein; resting NLRP3 is soluble in the cytoplasm before stimulus-induced relocalisation. Reason: Correct and uncontroversial across six independent annotations, though the cytosol (GO:0005829) annotation this gene also carries is the more informative statement of the same fact. |
| GO:0050727 regulation of inflammatory response | IBA GO_REF:0000033 | ACCEPT | Summary: Regulation of inflammatory response, the direction-neutral parent, inferred phylogenetically across the NLRP family. Reason: Correct as a family-level statement: NLR-family members regulate inflammation in both directions, and the phylogenetic inference sensibly stops at the neutral parent. For NLRP3 specifically the positive child term is the informative one and is separately annotated. |
| GO:0043565 sequence-specific DNA binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Sequence-specific DNA binding, inferred phylogenetically and by orthology from mouse Nlrp3, which was reported to bind the Il4 promoter in T helper 2 cells. Reason: Surprising for an inflammasome sensor, and it deserves the scrutiny. Tracing it back: both the IBA (node PTN000648032, donor MGI:2653833) and the ISS (donor UniProtKB:Q8R4B8) rest on a single underlying result - Bruchard et al. 2015 reported that mouse Nlrp3 in CD4+ T cells binds the Il4 promoter and transactivates it with IRF4, independently of ASC and caspase-1. That is a real experimental claim, with a plausible molecular reading (the NACHT-LRR architecture is shared with the transcriptional activator CIITA), so it is not dismissed. But it is one laboratory, it carries a published corrigendum, no human experimental evidence exists, and no NLRP3 DNA-binding domain or NLRP3-DNA structure has been described in the decade since, despite intensive structural work on the protein. Kept as a non-core, cell-type-restricted, inflammasome-independent activity rather than accepted alongside the inflammasome functions or removed on grounds of surprise alone. The IBA is not challenged on propagation grounds: the node placement follows correctly from the mouse experimental annotation, so the question is the strength of that source, not the phylogeny. |
| GO:0072559 NLRP3 inflammasome complex | IBA GO_REF:0000033 | ACCEPT | Summary: NLRP3 is the defining sensor subunit of the NLRP3 inflammasome, together with ASC and caspase-1. Reason: Core, and about as securely established as any complex membership in GO: six annotations including the founding biochemical reconstitution, cryo-EM of the active disc and the phylogenetic inference. Supporting Evidence: PMID:15030775 Here, we report that NALP2 and NALP3 associate with ASC, the CARD-containing protein Cardinal, and caspase-1 (but not caspase-5), thereby forming an inflammasome with high proIL-1beta-processing activity. |
| GO:0140297 DNA-binding transcription factor binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Binding to the transcription factor IRF4, with which mouse Nlrp3 was reported to transactivate the Il4 promoter. Reason: The partner half of the same T helper 2 transcriptional claim as GO:0043565, from the same single source propagated by both IBA and ISS, and handled identically. |
| GO:1901223 negative regulation of non-canonical NF-kappaB signal transduction | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Suppression of NF-kappaB signalling by cryopyrin, reported in 2003: full-length CIAS1 and two natural short isoforms inhibited TNF-alpha-induced NF-kappaB reporter activity and p65 nuclear translocation. Reason: An early, inflammasome-independent activity that has not been integrated into the modern picture of NLRP3 and sits awkwardly beside the opposite-direction annotation this gene also carries (GO:1901224, positive regulation of the same pathway). GOA thus holds both signs simultaneously, on evidence from overexpression-based reporter assays in both cases. Retained on both sides rather than adjudicated, because neither has been tested at endogenous expression levels and the honest reading is that the NF-kappaB regulatory role of NLRP3 is unsettled. |
| GO:0000139 Golgi membrane | IEA GO_REF:0000120 | ACCEPT | Summary: On activation NLRP3 is recruited to Golgi membranes, specifically the dispersed trans-Golgi network. Reason: Correct, and mechanistically central rather than incidental: recruitment happens through ionic bonding between the NLRP3 polybasic region and PtdIns4P on the dispersed TGN. The trans-Golgi network membrane annotation (GO:0032588) that this gene also carries states the same localisation more precisely. Supporting Evidence: PMID:30487600 NLRP3 is recruited to the dispersed TGN (dTGN) through ionic bonding between its conserved polybasic region and negatively charged phosphatidylinositol-4-phosphate (PtdIns4P) on the dTGN. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Extracellular localisation of NLRP3, from the observation that oligomeric inflammasome particles are released by activated macrophages and act extracellularly. Reason: A genuine and well-controlled finding - released oligomeric NLRP3 particles stimulate caspase-1 activation in bystander cells and ASC particles are detectable in the serum of patients with active CAPS - but it describes the fate of the assembled complex after pyroptosis, not a compartment in which NLRP3 performs its function. Supporting Evidence: PMID:24952504 Here we found that upon activation of caspase-1, oligomeric NLRP3 inflammasome particles were released from macrophages. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nuclear localisation, from the UniProt mapping and transferred by similarity from mouse Nlrp3. Reason: Part of the inflammasome-independent transcriptional-cofactor claim: mouse Nlrp3 was reported to enter the nucleus of T helper 2 cells, bind the Il4 promoter and transactivate it with IRF4. That is a single-laboratory result, carries a published corrigendum, and has no independent human corroboration, so it is retained but kept well away from the core. Note the human annotation is orthology-based only. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Recruitment of NLRP3 to mitochondria, reported in two independent studies (mitochondrial ROS and damage; MAVS-dependent recruitment). Reason: Contested, and GOA carries the competing localisations side by side. Zhou et al. placed resting NLRP3 on ER structures and activated NLRP3 at perinuclear ER-mitochondria clusters, and Subramanian et al. showed MAVS-dependent recruitment to mitochondria; the later dispersed-TGN and MTOC work, which accounts for activation by structurally unrelated stimuli, has displaced the mitochondrion as the principal assembly site, and neither 2026 study invokes it. Retained rather than removed because these are experimental annotations and mitochondrial damage is a genuine upstream input to NLRP3; demoted because it is not where the inflammasome is now thought to assemble. Supporting Evidence: PMID:23582325 MAVS mediates recruitment of NLRP3 to mitochondria, promoting production of IL-1Ξ² and the pathophysiologic activity of the NLRP3 inflammasome in vivo. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Endoplasmic reticulum localisation, from the UniProt subcellular-location mapping and by similarity to mouse Nlrp3. Reason: Traceable to the report that resting NLRP3 associates with ER structures and redistributes to perinuclear ER-mitochondria clusters on activation. Same status as the mitochondrial annotation: a real observation from the pre-dispersed-TGN era that is not part of the current activation model. Supporting Evidence: PMID:21124315 Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. |
| GO:0005815 microtubule organizing center | IEA GO_REF:0000120 | ACCEPT | Summary: NLRP3 is transported along microtubules to the microtubule organising centre, where it forms condensates and assembles with NEK7 into the inflammasome. Reason: A well-supported and mechanistically important site, with two independent IDAs (MARK4-driven delivery; palmitoylation- and LATS1/2-dependent trafficking) and now a 2026 study placing microtubule transport, NEK7 localisation, priming and NLRP3 abundance together at the pericentriolar material. Recorded with the caveat that the MTOC route is not obligatory: a parallel MTOC-distal pathway exists and predominates in human neutrophils. Supporting Evidence: PMID:28656979 Here we show that microtubule-affinity regulating kinase 4 (MARK4) binds to NLRP3 and drives it to the microtubule-organizing centre, enabling the formation of one large inflammasome speck complex within a single cell. PMID:42378282 Microtubules, priming, and NEK7 synergistically converge on PCM abundance, thereby creating a permissive centrosomal environment for NLRP3 condensation and inflammasome assembly. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Resting NLRP3 is a soluble cytosolic protein, which is where it is held as an autoinhibited oligomer before activation. Reason: Core resting location. Supported by an IDA, the UniProt mapping and eleven Reactome pathway assertions covering NLRP3 oligomerisation, ASC recruitment and small-molecule activation. |
| GO:0009595 detection of biotic stimulus | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Detection of biotic stimulus, from the silica and aluminium salt study and from a review of NLR biology. Reason: Two problems, neither fatal. The agonists in the cited experimental study - silica crystals and aluminium salts - are abiotic, so they cannot support a biotic-stimulus term; and the paper's own conclusion is that what is sensed is lysosomal damage, an endogenous event downstream of the particle. NLRP3 genuinely does respond to biotic stimuli such as pore-forming toxins and viral proteins, which is why this is retained rather than removed, but as a downstream and indirect participation rather than as detection in the strict sense. Supporting Evidence: PMID:18604214 Our results indicate that the NALP3 inflammasome senses lysosomal damage as an endogenous 'danger' signal. |
| GO:0009615 response to virus | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Response to virus, assigned electronically. Reason: Consistent with the demonstrated activation of the NLRP3 inflammasome during SARS-CoV-2 and respiratory syncytial virus infection, but a context in which the core activity is deployed rather than a distinct function. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000117 | ACCEPT | Summary: The NACHT domain of NLRP3 hydrolyses ATP; MCC950 inhibits the inflammasome by targeting the ATP-hydrolysis motif. Reason: Core enzymatic property of the NACHT module, demonstrated with purified protein and independently corroborated by two structure-guided studies of the MCC950 mechanism. This is the switch that drives the conformational change between the ADP-bound cage and the ATP-bound active disc, not a catalytic output in its own right. Supporting Evidence: PMID:17483456 We demonstrate that purified cryopyrin binds ATP, dATP, and ATP-agarose, but not CTP, GTP, or UTP, and exhibits ATPase activity. |
| GO:0032731 positive regulation of interleukin-1 beta production | IEA GO_REF:0000117 | ACCEPT | Summary: The NLRP3 inflammasome drives caspase-1-dependent maturation and release of interleukin-1 beta. Reason: Core biological process and the principal physiological output of NLRP3, supported by thirteen annotations. The clinical corollary is that CAPS patients carrying gain-of-function NLRP3 mutations respond to interleukin-1 blockade. Supporting Evidence: PMID:15030775 Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. |
| GO:0035591 signaling adaptor activity | IEA GO_REF:0000117 | ACCEPT | Summary: NLRP3 acts as a signalling adaptor: its pyrin domain filament nucleates ASC polymerisation, which in turn recruits procaspase-1. Reason: Core molecular function and the mechanistic heart of inflammasome assembly. Supported by NMR and analytical ultracentrifugation of the NLRP3-ASC pyrin-domain interaction, by cryo-EM of the NLRP3 pyrin-domain filament showing directional ASC elongation, and by the active-disc structure. Supporting Evidence: PMID:35559676 Coupling a titration polymerization assay to cryo-EM, we demonstrate that ASC adaptor protein elongation on NLRP3PYD nucleation seeds is unidirectional, associating exclusively to the B-end of the filament. PMID:36442502 The N-terminal PYDs from all NLRP3 subunits combine to form a PYD filament that recruits ASC PYD to elicit downstream signalling. |
| GO:0044546 NLRP3 inflammasome complex assembly | IEA GO_REF:0000117 | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0050729 positive regulation of inflammatory response | IEA GO_REF:0000117 | ACCEPT | Summary: NLRP3 activation amplifies inflammation through caspase-1-dependent release of interleukin-1 beta and interleukin-18 and through pyroptosis. Reason: Core biological process, supported by nine annotations including the pharmacological demonstration that a selective NLRP3 inhibitor is anti-inflammatory in disease models. |
| GO:0051260 protein homooligomerization | IEA GO_REF:0000117 | ACCEPT | Summary: NLRP3 homo-oligomerises, both into the inactive cage and into the active disc and pyrin filament. Reason: Core, and the direct process counterpart of the self-association activity. Note for context, not as a reason to change the term: the oligomeric state of resting NLRP3 is itself contested - one cryo-EM study describes a decamer and another a dodecamer - and a 2026 study shows that low-molecular-weight, non-cage NLRP3 species can form functional inflammasomes through a trans-Golgi/MTOC-distal route that dominates in human neutrophils. |
| GO:0061702 canonical inflammasome complex | IEA GO_REF:0000044 | ACCEPT | Summary: The NLRP3 inflammasome is a canonical (caspase-1-activating) inflammasome. Reason: Correct parent of the NLRP3-specific complex term, supported by six experimental annotations. The child term GO:0072559 that this gene also carries is the more informative statement. |
| GO:0070273 phosphatidylinositol-4-phosphate binding | IEA GO_REF:0000117 | ACCEPT | Summary: The conserved polybasic region of NLRP3 binds phosphatidylinositol-4-phosphate on the dispersed trans-Golgi network, which is what recruits and concentrates it there. Reason: Core molecular function and the best-characterised genuine binding event in NLRP3 activation. Independently corroborated by the demonstration that BTK phosphorylation of the same polybasic linker modulates Golgi association and inflammasome nucleation by charge neutralisation. Supporting Evidence: PMID:30487600 NLRP3 is recruited to the dispersed TGN (dTGN) through ionic bonding between its conserved polybasic region and negatively charged phosphatidylinositol-4-phosphate (PtdIns4P) on the dTGN. PMID:30487600 Disruption of the interaction between NLRP3 and PtdIns4P on the dTGN blocked NLRP3 aggregation and downstream signalling. |
| GO:0071222 cellular response to lipopolysaccharide | IEA GO_REF:0000117 | ACCEPT | Summary: NLRP3 responds to lipopolysaccharide: LPS priming induces NLRP3 expression and licenses subsequent activation. Reason: Well supported and mechanistically real. Priming is now recognised as one of the four factors that converge on making the centrosome permissive for NLRP3 condensation, and raising NLRP3 abundance can substitute for it. Supporting Evidence: PMID:42378282 Elevated NLRP3 expression compensates for limited PCM abundance, rendering K+ efflux-induced activation independent of both NEK7 and priming in human and mouse macrophages. |
| GO:0072559 NLRP3 inflammasome complex | IEA GO_REF:0000117 | ACCEPT | Summary: NLRP3 is the defining sensor subunit of the NLRP3 inflammasome, together with ASC and caspase-1. Reason: Core, and about as securely established as any complex membership in GO: six annotations including the founding biochemical reconstitution, cryo-EM of the active disc and the phylogenetic inference. Supporting Evidence: PMID:15030775 Here, we report that NALP2 and NALP3 associate with ASC, the CARD-containing protein Cardinal, and caspase-1 (but not caspase-5), thereby forming an inflammasome with high proIL-1beta-processing activity. |
| GO:0140299 molecular sensor activity | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: NLRP3 assigned as a molecular sensor on the basis of inflammasome activation by uric acid and calcium pyrophosphate crystals, silica, asbestos and aluminium salts. Reason: The biology is right but the term is not. GO:0140299 is defined as 'Binding to a molecule and eliciting a change in the protein's activity in response to the intracellular level of that molecule' - it requires that the sensed species be bound. No direct NLRP3 agonist ligand has ever been identified, and the three papers cited here argue the opposite of direct binding: Hornung et al. state that activation required phagocytosis of crystals leading to lysosomal damage and rupture, and conclude that NLRP3 senses lysosomal damage as an endogenous danger signal. The field position is that NLRP3 reads a shared downstream cellular perturbation - potassium efflux, trans-Golgi disassembly, organelle damage - common to structurally unrelated agonists. Flagged as over-annotated rather than removed, because these are experimental annotations recording real activation events and because one NLRP3 binding event does fit the definition: PtdIns4P on the dispersed TGN, which is separately and correctly annotated as GO:0070273. Supporting Evidence: PMID:18604214 NALP3 activation required phagocytosis of crystals, and this uptake subsequently led to lysosomal damage and rupture. PMID:18604214 Our results indicate that the NALP3 inflammasome senses lysosomal damage as an endogenous 'danger' signal. |
| GO:0005515 protein binding | IPI PMID:11786556 PYPAF1, a PYRIN-containing Apaf1-like protein that assembles... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:15020601 Cryopyrin-induced interleukin 1beta secretion in monocytic c... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:19158675 AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activa... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:22801494 Novel role of PKR in inflammasome activation and HMGB1 relea... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:23582325 The adaptor MAVS promotes NLRP3 mitochondrial localization a... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:24630722 Unified polymerization mechanism for the assembly of ASC-dep... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:26814970 NEK7 is an essential mediator of NLRP3 activation downstream... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:28137891 Periodic Fever with Aphthous Stomatitis, Pharyngitis, and Ce... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:28229991 A Novel Mutation in the Pyrin Domain of the NOD-like Recepto... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:29408806 Loss-of-function CARD8 mutation causes NLRP3 inflammasome ac... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:31231549 SARS-Coronavirus Open Reading Frame-8b triggers intracellula... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:31421660 Expression of a PYCARD/ASC variant lacking exon 2 in Japanes... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:34341353 SARS-CoV-2 N protein promotes NLRP3 inflammasome activation ... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:34589402 Lonicerin targets EZH2 to alleviate ulcerative colitis by au... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:38593810 Truncating NFKB1 variants cause combined NLRP3 inflammasome ... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0042802 identical protein binding | IPI PMID:23582325 The adaptor MAVS promotes NLRP3 mitochondrial localization a... | ACCEPT | Summary: NLRP3 self-associates: into the autoinhibited resting cage and, on activation, into the NACHT-mediated disc and the pyrin-domain filament. Reason: Unlike bare protein binding, homotypic self-association is the mechanism here rather than an incidental interaction, and it is resolved at near-atomic detail in three cryo-EM structures. Note for context, not as a reason to change the term: the oligomeric state of resting NLRP3 is itself contested - one cryo-EM study describes a decamer and another a dodecamer - and a 2026 study shows that low-molecular-weight, non-cage NLRP3 species can form functional inflammasomes through a trans-Golgi/MTOC-distal route that dominates in human neutrophils. |
| GO:0042802 identical protein binding | IPI PMID:24630722 Unified polymerization mechanism for the assembly of ASC-dep... | ACCEPT | Summary: NLRP3 self-associates: into the autoinhibited resting cage and, on activation, into the NACHT-mediated disc and the pyrin-domain filament. Reason: Unlike bare protein binding, homotypic self-association is the mechanism here rather than an incidental interaction, and it is resolved at near-atomic detail in three cryo-EM structures. Note for context, not as a reason to change the term: the oligomeric state of resting NLRP3 is itself contested - one cryo-EM study describes a decamer and another a dodecamer - and a 2026 study shows that low-molecular-weight, non-cage NLRP3 species can form functional inflammasomes through a trans-Golgi/MTOC-distal route that dominates in human neutrophils. |
| GO:0042802 identical protein binding | IPI PMID:29408806 Loss-of-function CARD8 mutation causes NLRP3 inflammasome ac... | ACCEPT | Summary: NLRP3 self-associates: into the autoinhibited resting cage and, on activation, into the NACHT-mediated disc and the pyrin-domain filament. Reason: Unlike bare protein binding, homotypic self-association is the mechanism here rather than an incidental interaction, and it is resolved at near-atomic detail in three cryo-EM structures. Note for context, not as a reason to change the term: the oligomeric state of resting NLRP3 is itself contested - one cryo-EM study describes a decamer and another a dodecamer - and a 2026 study shows that low-molecular-weight, non-cage NLRP3 species can form functional inflammasomes through a trans-Golgi/MTOC-distal route that dominates in human neutrophils. |
| GO:0032588 trans-Golgi network membrane | IDA PMID:30487600 PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inf... | ACCEPT | Summary: NLRP3 is active at the membrane of the dispersed trans-Golgi network, where PtdIns4P binding concentrates it and the dTGN serves as the aggregation scaffold. Reason: The most informative localisation annotation NLRP3 carries, and the one that matches the current activation model. Qualified by the 2026 finding that a trans-Golgi-distal route also exists and dominates in human neutrophils, so this is a major site of activation rather than the only one. Supporting Evidence: PMID:30487600 These results indicate that recruitment of NLRP3 to dTGN is an early and common cellular event that leads to NLRP3 aggregation and activation in response to diverse stimuli. PMID:42215451 nigericin, a K+-dependent NLRP3 stimulus, can trigger two distinct activation pathways: (i) the rapidly engaged decameric cage-dependent pathway; and (ii) a decameric cage-independent, TGN/MTOC-distal, and slow-reacting pathway employed by low molecular weight NLRP3 species, that dominates in human neutrophils. |
| GO:0072559 NLRP3 inflammasome complex | IDA PMID:16407889 Gout-associated uric acid crystals activate the NALP3 inflam... | ACCEPT | Summary: NLRP3 is the defining sensor subunit of the NLRP3 inflammasome, together with ASC and caspase-1. Reason: Core, and about as securely established as any complex membership in GO: six annotations including the founding biochemical reconstitution, cryo-EM of the active disc and the phylogenetic inference. Supporting Evidence: PMID:15030775 Here, we report that NALP2 and NALP3 associate with ASC, the CARD-containing protein Cardinal, and caspase-1 (but not caspase-5), thereby forming an inflammasome with high proIL-1beta-processing activity. |
| GO:0140608 cysteine-type endopeptidase activator activity | IDA PMID:16407889 Gout-associated uric acid crystals activate the NALP3 inflam... | ACCEPT | Summary: The assembled NLRP3 inflammasome activates procaspase-1, the proximate output of NLRP3 function. Reason: Core. NLRP3 does not itself cleave caspase-1; it nucleates the platform on which proximity-induced caspase-1 autoprocessing occurs, which is exactly what an activator activity term asserts. Supported by the crystal-activation work and by the NEK7-licensed activation structure. Supporting Evidence: PMID:16407889 Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1beta and IL-18. |
| GO:0000139 Golgi membrane | EXP PMID:30487600 PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inf... | ACCEPT | Summary: On activation NLRP3 is recruited to Golgi membranes, specifically the dispersed trans-Golgi network. Reason: Correct, and mechanistically central rather than incidental: recruitment happens through ionic bonding between the NLRP3 polybasic region and PtdIns4P on the dispersed TGN. The trans-Golgi network membrane annotation (GO:0032588) that this gene also carries states the same localisation more precisely. Supporting Evidence: PMID:30487600 NLRP3 is recruited to the dispersed TGN (dTGN) through ionic bonding between its conserved polybasic region and negatively charged phosphatidylinositol-4-phosphate (PtdIns4P) on the dTGN. |
| GO:0005576 extracellular region | EXP PMID:24952504 The NLRP3 inflammasome is released as a particulate danger s... | KEEP AS NON CORE | Summary: Extracellular localisation of NLRP3, from the observation that oligomeric inflammasome particles are released by activated macrophages and act extracellularly. Reason: A genuine and well-controlled finding - released oligomeric NLRP3 particles stimulate caspase-1 activation in bystander cells and ASC particles are detectable in the serum of patients with active CAPS - but it describes the fate of the assembled complex after pyroptosis, not a compartment in which NLRP3 performs its function. Supporting Evidence: PMID:24952504 Here we found that upon activation of caspase-1, oligomeric NLRP3 inflammasome particles were released from macrophages. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Nuclear localisation, from the UniProt mapping and transferred by similarity from mouse Nlrp3. Reason: Part of the inflammasome-independent transcriptional-cofactor claim: mouse Nlrp3 was reported to enter the nucleus of T helper 2 cells, bind the Il4 promoter and transactivate it with IRF4. That is a single-laboratory result, carries a published corrigendum, and has no independent human corroboration, so it is retained but kept well away from the core. Note the human annotation is orthology-based only. |
| GO:0005739 mitochondrion | EXP PMID:21124315 A role for mitochondria in NLRP3 inflammasome activation. | KEEP AS NON CORE | Summary: Recruitment of NLRP3 to mitochondria, reported in two independent studies (mitochondrial ROS and damage; MAVS-dependent recruitment). Reason: Contested, and GOA carries the competing localisations side by side. Zhou et al. placed resting NLRP3 on ER structures and activated NLRP3 at perinuclear ER-mitochondria clusters, and Subramanian et al. showed MAVS-dependent recruitment to mitochondria; the later dispersed-TGN and MTOC work, which accounts for activation by structurally unrelated stimuli, has displaced the mitochondrion as the principal assembly site, and neither 2026 study invokes it. Retained rather than removed because these are experimental annotations and mitochondrial damage is a genuine upstream input to NLRP3; demoted because it is not where the inflammasome is now thought to assemble. Supporting Evidence: PMID:23582325 MAVS mediates recruitment of NLRP3 to mitochondria, promoting production of IL-1Ξ² and the pathophysiologic activity of the NLRP3 inflammasome in vivo. |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Endoplasmic reticulum localisation, from the UniProt subcellular-location mapping and by similarity to mouse Nlrp3. Reason: Traceable to the report that resting NLRP3 associates with ER structures and redistributes to perinuclear ER-mitochondria clusters on activation. Same status as the mitochondrial annotation: a real observation from the pre-dispersed-TGN era that is not part of the current activation model. Supporting Evidence: PMID:21124315 Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. |
| GO:0061702 canonical inflammasome complex | EXP PMID:11786556 PYPAF1, a PYRIN-containing Apaf1-like protein that assembles... | ACCEPT | Summary: The NLRP3 inflammasome is a canonical (caspase-1-activating) inflammasome. Reason: Correct parent of the NLRP3-specific complex term, supported by six experimental annotations. The child term GO:0072559 that this gene also carries is the more informative statement. |
| GO:0061702 canonical inflammasome complex | EXP PMID:14662828 Cutting edge: CIAS1/cryopyrin/PYPAF1/NALP3/CATERPILLER 1.1 i... | ACCEPT | Summary: The NLRP3 inflammasome is a canonical (caspase-1-activating) inflammasome. Reason: Correct parent of the NLRP3-specific complex term, supported by six experimental annotations. The child term GO:0072559 that this gene also carries is the more informative statement. |
| GO:0061702 canonical inflammasome complex | EXP PMID:17164409 Inflammasome components NALP 1 and 3 show distinct but separ... | ACCEPT | Summary: The NLRP3 inflammasome is a canonical (caspase-1-activating) inflammasome. Reason: Correct parent of the NLRP3-specific complex term, supported by six experimental annotations. The child term GO:0072559 that this gene also carries is the more informative statement. |
| GO:0061702 canonical inflammasome complex | EXP PMID:23871209 The DHX33 RNA helicase senses cytosolic RNA and activates th... | ACCEPT | Summary: The NLRP3 inflammasome is a canonical (caspase-1-activating) inflammasome. Reason: Correct parent of the NLRP3-specific complex term, supported by six experimental annotations. The child term GO:0072559 that this gene also carries is the more informative statement. |
| GO:0061702 canonical inflammasome complex | EXP PMID:25538194 ADP-ribosylation of NLRP3 by Mycoplasma pneumoniae CARDS tox... | ACCEPT | Summary: The NLRP3 inflammasome is a canonical (caspase-1-activating) inflammasome. Reason: Correct parent of the NLRP3-specific complex term, supported by six experimental annotations. The child term GO:0072559 that this gene also carries is the more informative statement. |
| GO:0061702 canonical inflammasome complex | EXP PMID:33231615 Inflammasomes are activated in response to SARS-CoV-2 infect... | ACCEPT | Summary: The NLRP3 inflammasome is a canonical (caspase-1-activating) inflammasome. Reason: Correct parent of the NLRP3-specific complex term, supported by six experimental annotations. The child term GO:0072559 that this gene also carries is the more informative statement. |
| GO:0002221 pattern recognition receptor signaling pathway | NAS PMID:22258606 Inflammasomes in health and disease. | ACCEPT | Summary: NLRP3 as a component of pattern recognition receptor signalling, from a review. Reason: NLRP3 is conventionally and reasonably classed as a cytosolic pattern-recognition receptor, and the process term makes a claim about the signalling pathway rather than about direct ligand binding, so it survives the objection that sinks the molecular sensor annotation. |
| GO:0005737 cytoplasm | NAS PMID:28263976 NLRP1 promotes tumor growth by enhancing inflammasome activa... | ACCEPT | Summary: NLRP3 is a cytosolic protein; resting NLRP3 is soluble in the cytoplasm before stimulus-induced relocalisation. Reason: Correct and uncontroversial across six independent annotations, though the cytosol (GO:0005829) annotation this gene also carries is the more informative statement of the same fact. |
| GO:0007231 osmosensory signaling pathway | NAS PMID:22981536 Cell volume regulation modulates NLRP3 inflammasome activati... | KEEP AS NON CORE | Summary: Osmosensory signalling, from the finding that a fall in extracellular osmolarity triggers a potassium-dependent conformational change in preassembled NLRP3 and activates caspase-1. Reason: A real and mechanistically interesting result that fits the modern picture - cell swelling is one more perturbation converging on potassium efflux - but it is a stimulus context, and 'osmosensory signaling pathway' overstates the specificity of a protein that responds to swelling only through the same common intermediate it uses for every other agonist. Supporting Evidence: PMID:22981536 We found that a decrease in extracellular osmolarity induced a K(+)-dependent conformational change of the preassembled NLRP3-inactive inflammasome during cell swelling, followed by activation of the NLRP3 inflammasome and caspase-1, which was controlled by transient receptor potential channels during RVD. |
| GO:0050729 positive regulation of inflammatory response | NAS PMID:29255148 Tyrosine phosphatase SHP2 negatively regulates NLRP3 inflamm... | ACCEPT | Summary: NLRP3 activation amplifies inflammation through caspase-1-dependent release of interleukin-1 beta and interleukin-18 and through pyroptosis. Reason: Core biological process, supported by nine annotations including the pharmacological demonstration that a selective NLRP3 inhibitor is anti-inflammatory in disease models. |
| GO:0070269 pyroptotic inflammatory response | NAS PMID:26611636 Gasdermin D is an executor of pyroptosis and required for in... | ACCEPT | Summary: NLRP3 inflammasome activation culminates in gasdermin-D-dependent pyroptosis. Reason: Core downstream process: caspase-1 activated on the NLRP3 platform cleaves gasdermin D, whose N-terminal fragment perforates the plasma membrane. The supporting reference establishes gasdermin D as the executor of pyroptosis and as required for interleukin-1 beta secretion, linking the two principal NLRP3 outputs. |
| GO:0072559 NLRP3 inflammasome complex | IPI PMID:29255148 Tyrosine phosphatase SHP2 negatively regulates NLRP3 inflamm... | ACCEPT | Summary: NLRP3 is the defining sensor subunit of the NLRP3 inflammasome, together with ASC and caspase-1. Reason: Core, and about as securely established as any complex membership in GO: six annotations including the founding biochemical reconstitution, cryo-EM of the active disc and the phylogenetic inference. Supporting Evidence: PMID:15030775 Here, we report that NALP2 and NALP3 associate with ASC, the CARD-containing protein Cardinal, and caspase-1 (but not caspase-5), thereby forming an inflammasome with high proIL-1beta-processing activity. |
| GO:0005515 protein binding | IPI PMID:39225180 ABHD8 antagonizes inflammation by facilitating chaperone-med... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005737 cytoplasm | IDA PMID:39225180 ABHD8 antagonizes inflammation by facilitating chaperone-med... | ACCEPT | Summary: NLRP3 is a cytosolic protein; resting NLRP3 is soluble in the cytoplasm before stimulus-induced relocalisation. Reason: Correct and uncontroversial across six independent annotations, though the cytosol (GO:0005829) annotation this gene also carries is the more informative statement of the same fact. |
| GO:0005737 cytoplasm | IDA PMID:34512673 The E3 Ubiquitin Ligase TRIM65 Negatively Regulates Inflamma... | ACCEPT | Summary: NLRP3 is a cytosolic protein; resting NLRP3 is soluble in the cytoplasm before stimulus-induced relocalisation. Reason: Correct and uncontroversial across six independent annotations, though the cytosol (GO:0005829) annotation this gene also carries is the more informative statement of the same fact. |
| GO:0060090 molecular adaptor activity | IDA PMID:1189953 [Profanities and the profane person]. | MODIFY | Summary: Generic molecular adaptor activity. Reason: Correct but two levels too general: what NLRP3 does is nucleate a signalling adaptor filament, which the specific term states. Separately, the supporting reference for this annotation in GOA is PMID:1189953, which resolves to a 1975 Spanish-language psychiatry abstract; it is almost certainly a digit-dropped PMID:31189953, the NEK7-licensed NLRP3 activation structure that supports the other annotations made on the same date. Proposed replacements: signaling adaptor activity |
| GO:0005815 microtubule organizing center | IDA PMID:39173637 Consecutive palmitoylation and phosphorylation orchestrates ... | ACCEPT | Summary: NLRP3 is transported along microtubules to the microtubule organising centre, where it forms condensates and assembles with NEK7 into the inflammasome. Reason: A well-supported and mechanistically important site, with two independent IDAs (MARK4-driven delivery; palmitoylation- and LATS1/2-dependent trafficking) and now a 2026 study placing microtubule transport, NEK7 localisation, priming and NLRP3 abundance together at the pericentriolar material. Recorded with the caveat that the MTOC route is not obligatory: a parallel MTOC-distal pathway exists and predominates in human neutrophils. Supporting Evidence: PMID:28656979 Here we show that microtubule-affinity regulating kinase 4 (MARK4) binds to NLRP3 and drives it to the microtubule-organizing centre, enabling the formation of one large inflammasome speck complex within a single cell. PMID:42378282 Microtubules, priming, and NEK7 synergistically converge on PCM abundance, thereby creating a permissive centrosomal environment for NLRP3 condensation and inflammasome assembly. |
| GO:0005829 cytosol | IDA PMID:11786556 PYPAF1, a PYRIN-containing Apaf1-like protein that assembles... | ACCEPT | Summary: Resting NLRP3 is a soluble cytosolic protein, which is where it is held as an autoinhibited oligomer before activation. Reason: Core resting location. Supported by an IDA, the UniProt mapping and eleven Reactome pathway assertions covering NLRP3 oligomerisation, ASC recruitment and small-molecule activation. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:39173637 Consecutive palmitoylation and phosphorylation orchestrates ... | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0030674 protein-macromolecule adaptor activity | IDA PMID:1189953 [Profanities and the profane person]. | MODIFY | Summary: Protein-macromolecule adaptor activity. Reason: Same case as GO:0060090: correct but under-specific, and carrying the same malformed reference PMID:1189953 (a 1975 psychiatry abstract, evidently a typographical error for PMID:31189953). The signalling adaptor term states what was actually shown. Proposed replacements: signaling adaptor activity |
| GO:0005524 ATP binding | IDA PMID:36442502 Cryo-EM structures of the active NLRP3 inflammasome disc. | ACCEPT | Summary: NLRP3 binds ATP and dATP through its NACHT nucleotide-binding domain. Reason: Direct and specific: purified cryopyrin binds ATP, dATP and ATP-agarose but not CTP, GTP or UTP, and cryo-EM of the active disc resolves the NACHT domain in an ATP-bound conformation. Nucleotide binding is required for caspase-1 activation and for the constitutive activity of disease mutants. Supporting Evidence: PMID:17483456 We demonstrate that purified cryopyrin binds ATP, dATP, and ATP-agarose, but not CTP, GTP, or UTP, and exhibits ATPase activity. PMID:17483456 Disruption of nucleotide binding abolishes the constitutive activation of disease-associated mutants, identifying nucleotide binding by cryopyrin as a potential target for antiinflammatory pharmacologic intervention. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:36442502 Cryo-EM structures of the active NLRP3 inflammasome disc. | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0051260 protein homooligomerization | IDA PMID:36442502 Cryo-EM structures of the active NLRP3 inflammasome disc. | ACCEPT | Summary: NLRP3 homo-oligomerises, both into the inactive cage and into the active disc and pyrin filament. Reason: Core, and the direct process counterpart of the self-association activity. Note for context, not as a reason to change the term: the oligomeric state of resting NLRP3 is itself contested - one cryo-EM study describes a decamer and another a dodecamer - and a 2026 study shows that low-molecular-weight, non-cage NLRP3 species can form functional inflammasomes through a trans-Golgi/MTOC-distal route that dominates in human neutrophils. |
| GO:0072559 NLRP3 inflammasome complex | IDA PMID:36442502 Cryo-EM structures of the active NLRP3 inflammasome disc. | ACCEPT | Summary: NLRP3 is the defining sensor subunit of the NLRP3 inflammasome, together with ASC and caspase-1. Reason: Core, and about as securely established as any complex membership in GO: six annotations including the founding biochemical reconstitution, cryo-EM of the active disc and the phylogenetic inference. Supporting Evidence: PMID:15030775 Here, we report that NALP2 and NALP3 associate with ASC, the CARD-containing protein Cardinal, and caspase-1 (but not caspase-5), thereby forming an inflammasome with high proIL-1beta-processing activity. |
| GO:1901224 positive regulation of non-canonical NF-kappaB signal transduction | IPI PMID:15817483 PYPAF3, a PYRIN-containing APAF-1-like protein, is a feedbac... | KEEP AS NON CORE | Summary: Positive regulation of non-canonical NF-kappaB signalling, from an interaction with ASC (UniProtKB:Q9ULZ3). Reason: The mirror image of GO:1901223, and the two are retained together so that the contradiction in GOA is visible rather than silently resolved. Consistent with the 2002 report that co-expression of PYPAF1 (NLRP3) with ASC synergistically activates NF-kappaB. Both directions rest on overexpression reporter assays and neither is core. Recorded separately: the cited reference is titled for the paralog PYPAF3, and the abstract does not mention NLRP3; the curator read the full text and the ASC interactor is recorded in the WITH/FROM field, so the annotation is not challenged, but the citation is flagged as unverified. |
| GO:0140693 molecular condensate scaffold activity | IDA PMID:35114687 Structure of the NLRP3 decamer bound to the cytokine release... | ACCEPT | Summary: NLRP3 scaffolds a biomolecular condensate at the microtubule organising centre within which the inflammasome assembles. Reason: Retained as a genuine molecular function, and strengthened rather than weakened by the 2026 literature, which treats centrosomal NLRP3 condensation as the organising principle of activation and shows that microtubule transport, priming, NEK7 and NLRP3 abundance all converge on making the pericentriolar material permissive for it. The qualification to record is that condensate formation is not the only route to an active inflammasome: low-molecular-weight NLRP3 species assemble by a trans-Golgi/MTOC-distal pathway. Supporting Evidence: PMID:42378282 The NLRP3 inflammasome is central to host defense and sterile inflammation and forms condensates at the microtubule-organizing center (also known as the centrosome), although the mechanisms regulating this process remain unclear. PMID:35114687 Here we report the cryo-electron microscopy structures of full-length human NLRP3 in its native form and complexed with the inhibitor CRID3 (also named MCC950)4. |
| GO:0051604 protein maturation | IDA PMID:31189953 Structural mechanism for NEK7-licensed activation of NLRP3 i... | KEEP AS NON CORE | Summary: Protein maturation, annotated from the NEK7-licensed NLRP3 activation structure, referring to caspase-1-mediated processing of pro-interleukin-1 beta. Reason: True but uninformatively general, and indirect - the maturation is performed by caspase-1, not by NLRP3. The informative statements, positive regulation of interleukin-1 beta production and cysteine-type endopeptidase activator activity, are already annotated for this gene. |
| GO:0140608 cysteine-type endopeptidase activator activity | IDA PMID:31189953 Structural mechanism for NEK7-licensed activation of NLRP3 i... | ACCEPT | Summary: The assembled NLRP3 inflammasome activates procaspase-1, the proximate output of NLRP3 function. Reason: Core. NLRP3 does not itself cleave caspase-1; it nucleates the platform on which proximity-induced caspase-1 autoprocessing occurs, which is exactly what an activator activity term asserts. Supported by the crystal-activation work and by the NEK7-licensed activation structure. Supporting Evidence: PMID:16407889 Here we show that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1beta and IL-18. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:27043286 NLRP3 tyrosine phosphorylation is controlled by protein tyro... | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:34554188 BTK operates a phospho-tyrosine switch to regulate NLRP3 inf... | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:1901981 phosphatidylinositol phosphate binding | IDA PMID:34554188 BTK operates a phospho-tyrosine switch to regulate NLRP3 inf... | MODIFY | Summary: Phosphoinositide binding by NLRP3, from the study of BTK phosphorylation of its polybasic linker. Reason: Correct but a generic parent. The lipid that NLRP3 actually binds has been identified as phosphatidylinositol-4-phosphate, and that specific term is already annotated for this gene, so the parent adds nothing. Proposed replacements: phosphatidylinositol-4-phosphate binding Supporting Evidence: PMID:34554188 Furthermore, BTK promotes NLRP3 relocalization, oligomerization, ASC polymerization, and full inflammasome assembly, probably by charge neutralization, upon modification of a polybasic linker known to direct NLRP3 Golgi association and inflammasome nucleation. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:28465465 NLRP3 inflammasome assembly is regulated by phosphorylation ... | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:28943315 NLRP3 Phosphorylation Is an Essential Priming Event for Infl... | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:34615873 NLRP3 phosphorylation in its LRR domain critically regulates... | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0005739 mitochondrion | IDA PMID:23582325 The adaptor MAVS promotes NLRP3 mitochondrial localization a... | KEEP AS NON CORE | Summary: Recruitment of NLRP3 to mitochondria, reported in two independent studies (mitochondrial ROS and damage; MAVS-dependent recruitment). Reason: Contested, and GOA carries the competing localisations side by side. Zhou et al. placed resting NLRP3 on ER structures and activated NLRP3 at perinuclear ER-mitochondria clusters, and Subramanian et al. showed MAVS-dependent recruitment to mitochondria; the later dispersed-TGN and MTOC work, which accounts for activation by structurally unrelated stimuli, has displaced the mitochondrion as the principal assembly site, and neither 2026 study invokes it. Retained rather than removed because these are experimental annotations and mitochondrial damage is a genuine upstream input to NLRP3; demoted because it is not where the inflammasome is now thought to assemble. Supporting Evidence: PMID:23582325 MAVS mediates recruitment of NLRP3 to mitochondria, promoting production of IL-1Ξ² and the pathophysiologic activity of the NLRP3 inflammasome in vivo. |
| GO:0005815 microtubule organizing center | IDA PMID:28656979 MARK4 regulates NLRP3 positioning and inflammasome activatio... | ACCEPT | Summary: NLRP3 is transported along microtubules to the microtubule organising centre, where it forms condensates and assembles with NEK7 into the inflammasome. Reason: A well-supported and mechanistically important site, with two independent IDAs (MARK4-driven delivery; palmitoylation- and LATS1/2-dependent trafficking) and now a 2026 study placing microtubule transport, NEK7 localisation, priming and NLRP3 abundance together at the pericentriolar material. Recorded with the caveat that the MTOC route is not obligatory: a parallel MTOC-distal pathway exists and predominates in human neutrophils. Supporting Evidence: PMID:28656979 Here we show that microtubule-affinity regulating kinase 4 (MARK4) binds to NLRP3 and drives it to the microtubule-organizing centre, enabling the formation of one large inflammasome speck complex within a single cell. PMID:42378282 Microtubules, priming, and NEK7 synergistically converge on PCM abundance, thereby creating a permissive centrosomal environment for NLRP3 condensation and inflammasome assembly. |
| GO:0016020 membrane | IDA PMID:30487600 PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inf... | MODIFY | Summary: Generic membrane localisation recorded as the site of NLRP3 activity. Reason: Correct in kind but uninformative. The same study that supports this annotation identifies the membrane in question as the dispersed trans-Golgi network, and NLRP3 is not an integral membrane protein but a peripherally recruited one. Proposed replacements: trans-Golgi network membrane |
| GO:0032731 positive regulation of interleukin-1 beta production | IDA PMID:23582325 The adaptor MAVS promotes NLRP3 mitochondrial localization a... | ACCEPT | Summary: The NLRP3 inflammasome drives caspase-1-dependent maturation and release of interleukin-1 beta. Reason: Core biological process and the principal physiological output of NLRP3, supported by thirteen annotations. The clinical corollary is that CAPS patients carrying gain-of-function NLRP3 mutations respond to interleukin-1 blockade. Supporting Evidence: PMID:15030775 Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. |
| GO:0032731 positive regulation of interleukin-1 beta production | IDA PMID:30487600 PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inf... | ACCEPT | Summary: The NLRP3 inflammasome drives caspase-1-dependent maturation and release of interleukin-1 beta. Reason: Core biological process and the principal physiological output of NLRP3, supported by thirteen annotations. The clinical corollary is that CAPS patients carrying gain-of-function NLRP3 mutations respond to interleukin-1 blockade. Supporting Evidence: PMID:15030775 Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:23582325 The adaptor MAVS promotes NLRP3 mitochondrial localization a... | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:28656979 MARK4 regulates NLRP3 positioning and inflammasome activatio... | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:30487600 PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inf... | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0070273 phosphatidylinositol-4-phosphate binding | IDA PMID:30487600 PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inf... | ACCEPT | Summary: The conserved polybasic region of NLRP3 binds phosphatidylinositol-4-phosphate on the dispersed trans-Golgi network, which is what recruits and concentrates it there. Reason: Core molecular function and the best-characterised genuine binding event in NLRP3 activation. Independently corroborated by the demonstration that BTK phosphorylation of the same polybasic linker modulates Golgi association and inflammasome nucleation by charge neutralisation. Supporting Evidence: PMID:30487600 NLRP3 is recruited to the dispersed TGN (dTGN) through ionic bonding between its conserved polybasic region and negatively charged phosphatidylinositol-4-phosphate (PtdIns4P) on the dTGN. PMID:30487600 Disruption of the interaction between NLRP3 and PtdIns4P on the dTGN blocked NLRP3 aggregation and downstream signalling. |
| GO:0032731 positive regulation of interleukin-1 beta production | IDA PMID:31189953 Structural mechanism for NEK7-licensed activation of NLRP3 i... | ACCEPT | Summary: The NLRP3 inflammasome drives caspase-1-dependent maturation and release of interleukin-1 beta. Reason: Core biological process and the principal physiological output of NLRP3, supported by thirteen annotations. The clinical corollary is that CAPS patients carrying gain-of-function NLRP3 mutations respond to interleukin-1 blockade. Supporting Evidence: PMID:15030775 Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. |
| GO:0035591 signaling adaptor activity | IDA PMID:27432880 ASC Pyrin Domain Self-associates and Binds NLRP3 Protein Usi... | ACCEPT | Summary: NLRP3 acts as a signalling adaptor: its pyrin domain filament nucleates ASC polymerisation, which in turn recruits procaspase-1. Reason: Core molecular function and the mechanistic heart of inflammasome assembly. Supported by NMR and analytical ultracentrifugation of the NLRP3-ASC pyrin-domain interaction, by cryo-EM of the NLRP3 pyrin-domain filament showing directional ASC elongation, and by the active-disc structure. Supporting Evidence: PMID:35559676 Coupling a titration polymerization assay to cryo-EM, we demonstrate that ASC adaptor protein elongation on NLRP3PYD nucleation seeds is unidirectional, associating exclusively to the B-end of the filament. PMID:36442502 The N-terminal PYDs from all NLRP3 subunits combine to form a PYD filament that recruits ASC PYD to elicit downstream signalling. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:27432880 ASC Pyrin Domain Self-associates and Binds NLRP3 Protein Usi... | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:31189953 Structural mechanism for NEK7-licensed activation of NLRP3 i... | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0050729 positive regulation of inflammatory response | IDA PMID:31189953 Structural mechanism for NEK7-licensed activation of NLRP3 i... | ACCEPT | Summary: NLRP3 activation amplifies inflammation through caspase-1-dependent release of interleukin-1 beta and interleukin-18 and through pyroptosis. Reason: Core biological process, supported by nine annotations including the pharmacological demonstration that a selective NLRP3 inhibitor is anti-inflammatory in disease models. |
| GO:0016887 ATP hydrolysis activity | IDA PMID:31086327 MCC950 directly targets the NLRP3 ATP-hydrolysis motif for i... | ACCEPT | Summary: The NACHT domain of NLRP3 hydrolyses ATP; MCC950 inhibits the inflammasome by targeting the ATP-hydrolysis motif. Reason: Core enzymatic property of the NACHT module, demonstrated with purified protein and independently corroborated by two structure-guided studies of the MCC950 mechanism. This is the switch that drives the conformational change between the ADP-bound cage and the ATP-bound active disc, not a catalytic output in its own right. Supporting Evidence: PMID:17483456 We demonstrate that purified cryopyrin binds ATP, dATP, and ATP-agarose, but not CTP, GTP, or UTP, and exhibits ATPase activity. |
| GO:0016887 ATP hydrolysis activity | IDA PMID:31086329 MCC950 closes the active conformation of NLRP3 to an inactiv... | ACCEPT | Summary: The NACHT domain of NLRP3 hydrolyses ATP; MCC950 inhibits the inflammasome by targeting the ATP-hydrolysis motif. Reason: Core enzymatic property of the NACHT module, demonstrated with purified protein and independently corroborated by two structure-guided studies of the MCC950 mechanism. This is the switch that drives the conformational change between the ADP-bound cage and the ATP-bound active disc, not a catalytic output in its own right. Supporting Evidence: PMID:17483456 We demonstrate that purified cryopyrin binds ATP, dATP, and ATP-agarose, but not CTP, GTP, or UTP, and exhibits ATPase activity. |
| GO:0031021 interphase microtubule organizing center | ISS GO_REF:0000024 | ACCEPT | Summary: Interphase microtubule organising centre, transferred by sequence similarity from mouse Nlrp3. Reason: A more precise statement of the MTOC localisation that human NLRP3 carries with direct experimental support, and appropriate for a protein whose assembly site is the interphase centrosome: NEK7 licenses NLRP3 in interphase specifically. |
| GO:0032731 positive regulation of interleukin-1 beta production | IDA PMID:25686105 A small-molecule inhibitor of the NLRP3 inflammasome for the... | ACCEPT | Summary: The NLRP3 inflammasome drives caspase-1-dependent maturation and release of interleukin-1 beta. Reason: Core biological process and the principal physiological output of NLRP3, supported by thirteen annotations. The clinical corollary is that CAPS patients carrying gain-of-function NLRP3 mutations respond to interleukin-1 blockade. Supporting Evidence: PMID:15030775 Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. |
| GO:0032731 positive regulation of interleukin-1 beta production | IDA PMID:31086327 MCC950 directly targets the NLRP3 ATP-hydrolysis motif for i... | ACCEPT | Summary: The NLRP3 inflammasome drives caspase-1-dependent maturation and release of interleukin-1 beta. Reason: Core biological process and the principal physiological output of NLRP3, supported by thirteen annotations. The clinical corollary is that CAPS patients carrying gain-of-function NLRP3 mutations respond to interleukin-1 blockade. Supporting Evidence: PMID:15030775 Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. |
| GO:0032731 positive regulation of interleukin-1 beta production | IDA PMID:31086329 MCC950 closes the active conformation of NLRP3 to an inactiv... | ACCEPT | Summary: The NLRP3 inflammasome drives caspase-1-dependent maturation and release of interleukin-1 beta. Reason: Core biological process and the principal physiological output of NLRP3, supported by thirteen annotations. The clinical corollary is that CAPS patients carrying gain-of-function NLRP3 mutations respond to interleukin-1 blockade. Supporting Evidence: PMID:15030775 Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. |
| GO:0035591 signaling adaptor activity | IDA PMID:35114687 Structure of the NLRP3 decamer bound to the cytokine release... | ACCEPT | Summary: NLRP3 acts as a signalling adaptor: its pyrin domain filament nucleates ASC polymerisation, which in turn recruits procaspase-1. Reason: Core molecular function and the mechanistic heart of inflammasome assembly. Supported by NMR and analytical ultracentrifugation of the NLRP3-ASC pyrin-domain interaction, by cryo-EM of the NLRP3 pyrin-domain filament showing directional ASC elongation, and by the active-disc structure. Supporting Evidence: PMID:35559676 Coupling a titration polymerization assay to cryo-EM, we demonstrate that ASC adaptor protein elongation on NLRP3PYD nucleation seeds is unidirectional, associating exclusively to the B-end of the filament. PMID:36442502 The N-terminal PYDs from all NLRP3 subunits combine to form a PYD filament that recruits ASC PYD to elicit downstream signalling. |
| GO:0035591 signaling adaptor activity | IDA PMID:35254907 Structural basis for the oligomerization-mediated regulation... | ACCEPT | Summary: NLRP3 acts as a signalling adaptor: its pyrin domain filament nucleates ASC polymerisation, which in turn recruits procaspase-1. Reason: Core molecular function and the mechanistic heart of inflammasome assembly. Supported by NMR and analytical ultracentrifugation of the NLRP3-ASC pyrin-domain interaction, by cryo-EM of the NLRP3 pyrin-domain filament showing directional ASC elongation, and by the active-disc structure. Supporting Evidence: PMID:35559676 Coupling a titration polymerization assay to cryo-EM, we demonstrate that ASC adaptor protein elongation on NLRP3PYD nucleation seeds is unidirectional, associating exclusively to the B-end of the filament. PMID:36442502 The N-terminal PYDs from all NLRP3 subunits combine to form a PYD filament that recruits ASC PYD to elicit downstream signalling. |
| GO:0035591 signaling adaptor activity | IDA PMID:35559676 Directionality of PYD filament growth determined by the tran... | ACCEPT | Summary: NLRP3 acts as a signalling adaptor: its pyrin domain filament nucleates ASC polymerisation, which in turn recruits procaspase-1. Reason: Core molecular function and the mechanistic heart of inflammasome assembly. Supported by NMR and analytical ultracentrifugation of the NLRP3-ASC pyrin-domain interaction, by cryo-EM of the NLRP3 pyrin-domain filament showing directional ASC elongation, and by the active-disc structure. Supporting Evidence: PMID:35559676 Coupling a titration polymerization assay to cryo-EM, we demonstrate that ASC adaptor protein elongation on NLRP3PYD nucleation seeds is unidirectional, associating exclusively to the B-end of the filament. PMID:36442502 The N-terminal PYDs from all NLRP3 subunits combine to form a PYD filament that recruits ASC PYD to elicit downstream signalling. |
| GO:0043531 ADP binding | IDA PMID:35114687 Structure of the NLRP3 decamer bound to the cytokine release... | ACCEPT | Summary: The inactive NLRP3 oligomer is ADP-bound; the ADP-to-ATP exchange at the NACHT domain is the conformational switch that licenses activation. Reason: Established by two independent cryo-EM structures of full-length inactive human NLRP3. Not a trivial nucleotide-binding annotation: which nucleotide is bound defines the resting versus active state, and it is the site where the clinical inhibitor MCC950 acts. Supporting Evidence: PMID:35114687 Inactive, ADP-bound NLRP3 is a decamer composed of homodimers of intertwined leucine-rich repeat (LRR) domains that assemble back-to-back as pentamers. PMID:35254907 The inactive NLRP3 oligomer represents the NLRP3 resting state, capable of binding to membranes and is likely disrupted for its activation. |
| GO:0043531 ADP binding | IDA PMID:35254907 Structural basis for the oligomerization-mediated regulation... | ACCEPT | Summary: The inactive NLRP3 oligomer is ADP-bound; the ADP-to-ATP exchange at the NACHT domain is the conformational switch that licenses activation. Reason: Established by two independent cryo-EM structures of full-length inactive human NLRP3. Not a trivial nucleotide-binding annotation: which nucleotide is bound defines the resting versus active state, and it is the site where the clinical inhibitor MCC950 acts. Supporting Evidence: PMID:35114687 Inactive, ADP-bound NLRP3 is a decamer composed of homodimers of intertwined leucine-rich repeat (LRR) domains that assemble back-to-back as pentamers. PMID:35254907 The inactive NLRP3 oligomer represents the NLRP3 resting state, capable of binding to membranes and is likely disrupted for its activation. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:25686105 A small-molecule inhibitor of the NLRP3 inflammasome for the... | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:35114687 Structure of the NLRP3 decamer bound to the cytokine release... | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:35254907 Structural basis for the oligomerization-mediated regulation... | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:35559676 Directionality of PYD filament growth determined by the tran... | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0050729 positive regulation of inflammatory response | IDA PMID:25686105 A small-molecule inhibitor of the NLRP3 inflammasome for the... | ACCEPT | Summary: NLRP3 activation amplifies inflammation through caspase-1-dependent release of interleukin-1 beta and interleukin-18 and through pyroptosis. Reason: Core biological process, supported by nine annotations including the pharmacological demonstration that a selective NLRP3 inhibitor is anti-inflammatory in disease models. |
| GO:0050729 positive regulation of inflammatory response | IDA PMID:31086327 MCC950 directly targets the NLRP3 ATP-hydrolysis motif for i... | ACCEPT | Summary: NLRP3 activation amplifies inflammation through caspase-1-dependent release of interleukin-1 beta and interleukin-18 and through pyroptosis. Reason: Core biological process, supported by nine annotations including the pharmacological demonstration that a selective NLRP3 inhibitor is anti-inflammatory in disease models. |
| GO:0050729 positive regulation of inflammatory response | IDA PMID:31086329 MCC950 closes the active conformation of NLRP3 to an inactiv... | ACCEPT | Summary: NLRP3 activation amplifies inflammation through caspase-1-dependent release of interleukin-1 beta and interleukin-18 and through pyroptosis. Reason: Core biological process, supported by nine annotations including the pharmacological demonstration that a selective NLRP3 inhibitor is anti-inflammatory in disease models. |
| GO:0050729 positive regulation of inflammatory response | IDA PMID:35114687 Structure of the NLRP3 decamer bound to the cytokine release... | ACCEPT | Summary: NLRP3 activation amplifies inflammation through caspase-1-dependent release of interleukin-1 beta and interleukin-18 and through pyroptosis. Reason: Core biological process, supported by nine annotations including the pharmacological demonstration that a selective NLRP3 inhibitor is anti-inflammatory in disease models. |
| GO:0050729 positive regulation of inflammatory response | IDA PMID:35254907 Structural basis for the oligomerization-mediated regulation... | ACCEPT | Summary: NLRP3 activation amplifies inflammation through caspase-1-dependent release of interleukin-1 beta and interleukin-18 and through pyroptosis. Reason: Core biological process, supported by nine annotations including the pharmacological demonstration that a selective NLRP3 inhibitor is anti-inflammatory in disease models. |
| GO:0050729 positive regulation of inflammatory response | IDA PMID:35559676 Directionality of PYD filament growth determined by the tran... | ACCEPT | Summary: NLRP3 activation amplifies inflammation through caspase-1-dependent release of interleukin-1 beta and interleukin-18 and through pyroptosis. Reason: Core biological process, supported by nine annotations including the pharmacological demonstration that a selective NLRP3 inhibitor is anti-inflammatory in disease models. |
| GO:0051260 protein homooligomerization | IDA PMID:35114687 Structure of the NLRP3 decamer bound to the cytokine release... | ACCEPT | Summary: NLRP3 homo-oligomerises, both into the inactive cage and into the active disc and pyrin filament. Reason: Core, and the direct process counterpart of the self-association activity. Note for context, not as a reason to change the term: the oligomeric state of resting NLRP3 is itself contested - one cryo-EM study describes a decamer and another a dodecamer - and a 2026 study shows that low-molecular-weight, non-cage NLRP3 species can form functional inflammasomes through a trans-Golgi/MTOC-distal route that dominates in human neutrophils. |
| GO:0051260 protein homooligomerization | IDA PMID:35254907 Structural basis for the oligomerization-mediated regulation... | ACCEPT | Summary: NLRP3 homo-oligomerises, both into the inactive cage and into the active disc and pyrin filament. Reason: Core, and the direct process counterpart of the self-association activity. Note for context, not as a reason to change the term: the oligomeric state of resting NLRP3 is itself contested - one cryo-EM study describes a decamer and another a dodecamer - and a 2026 study shows that low-molecular-weight, non-cage NLRP3 species can form functional inflammasomes through a trans-Golgi/MTOC-distal route that dominates in human neutrophils. |
| GO:0051260 protein homooligomerization | IDA PMID:35559676 Directionality of PYD filament growth determined by the tran... | ACCEPT | Summary: NLRP3 homo-oligomerises, both into the inactive cage and into the active disc and pyrin filament. Reason: Core, and the direct process counterpart of the self-association activity. Note for context, not as a reason to change the term: the oligomeric state of resting NLRP3 is itself contested - one cryo-EM study describes a decamer and another a dodecamer - and a 2026 study shows that low-molecular-weight, non-cage NLRP3 species can form functional inflammasomes through a trans-Golgi/MTOC-distal route that dominates in human neutrophils. |
| GO:0140299 molecular sensor activity | IDA PMID:16407889 Gout-associated uric acid crystals activate the NALP3 inflam... | MARK AS OVER ANNOTATED | Summary: NLRP3 assigned as a molecular sensor on the basis of inflammasome activation by uric acid and calcium pyrophosphate crystals, silica, asbestos and aluminium salts. Reason: The biology is right but the term is not. GO:0140299 is defined as 'Binding to a molecule and eliciting a change in the protein's activity in response to the intracellular level of that molecule' - it requires that the sensed species be bound. No direct NLRP3 agonist ligand has ever been identified, and the three papers cited here argue the opposite of direct binding: Hornung et al. state that activation required phagocytosis of crystals leading to lysosomal damage and rupture, and conclude that NLRP3 senses lysosomal damage as an endogenous danger signal. The field position is that NLRP3 reads a shared downstream cellular perturbation - potassium efflux, trans-Golgi disassembly, organelle damage - common to structurally unrelated agonists. Flagged as over-annotated rather than removed, because these are experimental annotations recording real activation events and because one NLRP3 binding event does fit the definition: PtdIns4P on the dispersed TGN, which is separately and correctly annotated as GO:0070273. Supporting Evidence: PMID:18604214 NALP3 activation required phagocytosis of crystals, and this uptake subsequently led to lysosomal damage and rupture. PMID:18604214 Our results indicate that the NALP3 inflammasome senses lysosomal damage as an endogenous 'danger' signal. |
| GO:0140299 molecular sensor activity | IDA PMID:18403674 Innate immune activation through Nalp3 inflammasome sensing ... | MARK AS OVER ANNOTATED | Summary: NLRP3 assigned as a molecular sensor on the basis of inflammasome activation by uric acid and calcium pyrophosphate crystals, silica, asbestos and aluminium salts. Reason: The biology is right but the term is not. GO:0140299 is defined as 'Binding to a molecule and eliciting a change in the protein's activity in response to the intracellular level of that molecule' - it requires that the sensed species be bound. No direct NLRP3 agonist ligand has ever been identified, and the three papers cited here argue the opposite of direct binding: Hornung et al. state that activation required phagocytosis of crystals leading to lysosomal damage and rupture, and conclude that NLRP3 senses lysosomal damage as an endogenous danger signal. The field position is that NLRP3 reads a shared downstream cellular perturbation - potassium efflux, trans-Golgi disassembly, organelle damage - common to structurally unrelated agonists. Flagged as over-annotated rather than removed, because these are experimental annotations recording real activation events and because one NLRP3 binding event does fit the definition: PtdIns4P on the dispersed TGN, which is separately and correctly annotated as GO:0070273. Supporting Evidence: PMID:18604214 NALP3 activation required phagocytosis of crystals, and this uptake subsequently led to lysosomal damage and rupture. PMID:18604214 Our results indicate that the NALP3 inflammasome senses lysosomal damage as an endogenous 'danger' signal. |
| GO:0140299 molecular sensor activity | IDA PMID:18604214 Silica crystals and aluminum salts activate the NALP3 inflam... | MARK AS OVER ANNOTATED | Summary: NLRP3 assigned as a molecular sensor on the basis of inflammasome activation by uric acid and calcium pyrophosphate crystals, silica, asbestos and aluminium salts. Reason: The biology is right but the term is not. GO:0140299 is defined as 'Binding to a molecule and eliciting a change in the protein's activity in response to the intracellular level of that molecule' - it requires that the sensed species be bound. No direct NLRP3 agonist ligand has ever been identified, and the three papers cited here argue the opposite of direct binding: Hornung et al. state that activation required phagocytosis of crystals leading to lysosomal damage and rupture, and conclude that NLRP3 senses lysosomal damage as an endogenous danger signal. The field position is that NLRP3 reads a shared downstream cellular perturbation - potassium efflux, trans-Golgi disassembly, organelle damage - common to structurally unrelated agonists. Flagged as over-annotated rather than removed, because these are experimental annotations recording real activation events and because one NLRP3 binding event does fit the definition: PtdIns4P on the dispersed TGN, which is separately and correctly annotated as GO:0070273. Supporting Evidence: PMID:18604214 NALP3 activation required phagocytosis of crystals, and this uptake subsequently led to lysosomal damage and rupture. PMID:18604214 Our results indicate that the NALP3 inflammasome senses lysosomal damage as an endogenous 'danger' signal. |
| GO:0005524 ATP binding | IDA PMID:17483456 Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires A... | ACCEPT | Summary: NLRP3 binds ATP and dATP through its NACHT nucleotide-binding domain. Reason: Direct and specific: purified cryopyrin binds ATP, dATP and ATP-agarose but not CTP, GTP or UTP, and cryo-EM of the active disc resolves the NACHT domain in an ATP-bound conformation. Nucleotide binding is required for caspase-1 activation and for the constitutive activity of disease mutants. Supporting Evidence: PMID:17483456 We demonstrate that purified cryopyrin binds ATP, dATP, and ATP-agarose, but not CTP, GTP, or UTP, and exhibits ATPase activity. PMID:17483456 Disruption of nucleotide binding abolishes the constitutive activation of disease-associated mutants, identifying nucleotide binding by cryopyrin as a potential target for antiinflammatory pharmacologic intervention. |
| GO:0006954 inflammatory response | IDA PMID:16407889 Gout-associated uric acid crystals activate the NALP3 inflam... | ACCEPT | Summary: NLRP3 participates in the inflammatory response. Reason: Correct general parent, supported by six annotations; the specific positive-regulation and interleukin-1 beta terms carried by this gene are the informative statements. |
| GO:0006954 inflammatory response | IDA PMID:17483456 Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires A... | ACCEPT | Summary: NLRP3 participates in the inflammatory response. Reason: Correct general parent, supported by six annotations; the specific positive-regulation and interleukin-1 beta terms carried by this gene are the informative statements. |
| GO:0006954 inflammatory response | IDA PMID:18403674 Innate immune activation through Nalp3 inflammasome sensing ... | ACCEPT | Summary: NLRP3 participates in the inflammatory response. Reason: Correct general parent, supported by six annotations; the specific positive-regulation and interleukin-1 beta terms carried by this gene are the informative statements. |
| GO:0006954 inflammatory response | IDA PMID:18604214 Silica crystals and aluminum salts activate the NALP3 inflam... | ACCEPT | Summary: NLRP3 participates in the inflammatory response. Reason: Correct general parent, supported by six annotations; the specific positive-regulation and interleukin-1 beta terms carried by this gene are the informative statements. |
| GO:0009595 detection of biotic stimulus | IDA PMID:18604214 Silica crystals and aluminum salts activate the NALP3 inflam... | KEEP AS NON CORE | Summary: Detection of biotic stimulus, from the silica and aluminium salt study and from a review of NLR biology. Reason: Two problems, neither fatal. The agonists in the cited experimental study - silica crystals and aluminium salts - are abiotic, so they cannot support a biotic-stimulus term; and the paper's own conclusion is that what is sensed is lysosomal damage, an endogenous event downstream of the particle. NLRP3 genuinely does respond to biotic stimuli such as pore-forming toxins and viral proteins, which is why this is retained rather than removed, but as a downstream and indirect participation rather than as detection in the strict sense. Supporting Evidence: PMID:18604214 Our results indicate that the NALP3 inflammasome senses lysosomal damage as an endogenous 'danger' signal. |
| GO:0016887 ATP hydrolysis activity | IDA PMID:17483456 Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires A... | ACCEPT | Summary: The NACHT domain of NLRP3 hydrolyses ATP; MCC950 inhibits the inflammasome by targeting the ATP-hydrolysis motif. Reason: Core enzymatic property of the NACHT module, demonstrated with purified protein and independently corroborated by two structure-guided studies of the MCC950 mechanism. This is the switch that drives the conformational change between the ADP-bound cage and the ATP-bound active disc, not a catalytic output in its own right. Supporting Evidence: PMID:17483456 We demonstrate that purified cryopyrin binds ATP, dATP, and ATP-agarose, but not CTP, GTP, or UTP, and exhibits ATPase activity. |
| GO:0032731 positive regulation of interleukin-1 beta production | IDA PMID:16407889 Gout-associated uric acid crystals activate the NALP3 inflam... | ACCEPT | Summary: The NLRP3 inflammasome drives caspase-1-dependent maturation and release of interleukin-1 beta. Reason: Core biological process and the principal physiological output of NLRP3, supported by thirteen annotations. The clinical corollary is that CAPS patients carrying gain-of-function NLRP3 mutations respond to interleukin-1 blockade. Supporting Evidence: PMID:15030775 Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. |
| GO:0032731 positive regulation of interleukin-1 beta production | IDA PMID:17483456 Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires A... | ACCEPT | Summary: The NLRP3 inflammasome drives caspase-1-dependent maturation and release of interleukin-1 beta. Reason: Core biological process and the principal physiological output of NLRP3, supported by thirteen annotations. The clinical corollary is that CAPS patients carrying gain-of-function NLRP3 mutations respond to interleukin-1 blockade. Supporting Evidence: PMID:15030775 Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. |
| GO:0032731 positive regulation of interleukin-1 beta production | IDA PMID:18403674 Innate immune activation through Nalp3 inflammasome sensing ... | ACCEPT | Summary: The NLRP3 inflammasome drives caspase-1-dependent maturation and release of interleukin-1 beta. Reason: Core biological process and the principal physiological output of NLRP3, supported by thirteen annotations. The clinical corollary is that CAPS patients carrying gain-of-function NLRP3 mutations respond to interleukin-1 blockade. Supporting Evidence: PMID:15030775 Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. |
| GO:0032731 positive regulation of interleukin-1 beta production | IDA PMID:18604214 Silica crystals and aluminum salts activate the NALP3 inflam... | ACCEPT | Summary: The NLRP3 inflammasome drives caspase-1-dependent maturation and release of interleukin-1 beta. Reason: Core biological process and the principal physiological output of NLRP3, supported by thirteen annotations. The clinical corollary is that CAPS patients carrying gain-of-function NLRP3 mutations respond to interleukin-1 blockade. Supporting Evidence: PMID:15030775 Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:17483456 Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires A... | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0044546 NLRP3 inflammasome complex assembly | IDA PMID:33231615 Inflammasomes are activated in response to SARS-CoV-2 infect... | ACCEPT | Summary: NLRP3 nucleates assembly of its own inflammasome, the process on which every other NLRP3 function depends. Reason: Core biological process, carried by nineteen annotations spanning structural biology, trafficking, phosphoregulation and pharmacology. The unresolved questions in the 2026 literature concern where and in what oligomeric state assembly happens, not whether NLRP3 drives it. Supporting Evidence: PMID:31189953 These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome. PMID:39173637 This dynamic trafficking culminates in the localization of NLRP3 to the MTOC, where LATS1/2, pre-recruited to MTOC during priming, phosphorylates NLRP3 to further facilitate its interaction with NIMA-related kinase 7 (NEK7), ultimately leading to full NLRP3 activation. |
| GO:0098586 cellular response to virus | IDA PMID:33231615 Inflammasomes are activated in response to SARS-CoV-2 infect... | KEEP AS NON CORE | Summary: Cellular response to virus, from the demonstration that the NLRP3 inflammasome is active in cells and tissues of COVID-19 patients. Reason: A genuine experimental result and clinically important, but one of many stimulus contexts for the same core inflammasome activity. Kept consistent with the parent response-to-virus term. Supporting Evidence: PMID:33231615 Here we demonstrate that the NLRP3 inflammasome is activated in response to SARS-CoV-2 infection and is active in COVID-19 patients. |
| GO:0140297 DNA-binding transcription factor binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Binding to the transcription factor IRF4, with which mouse Nlrp3 was reported to transactivate the Il4 promoter. Reason: The partner half of the same T helper 2 transcriptional claim as GO:0043565, from the same single source propagated by both IBA and ISS, and handled identically. |
| GO:0005515 protein binding | IPI PMID:23809162 Omega-3 fatty acids prevent inflammation and metabolic disor... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0000139 Golgi membrane | IDA PMID:23229815 Human respiratory syncytial virus viroporin SH: a viral reco... | ACCEPT | Summary: On activation NLRP3 is recruited to Golgi membranes, specifically the dispersed trans-Golgi network. Reason: Correct, and mechanistically central rather than incidental: recruitment happens through ionic bonding between the NLRP3 polybasic region and PtdIns4P on the dispersed TGN. The trans-Golgi network membrane annotation (GO:0032588) that this gene also carries states the same localisation more precisely. Supporting Evidence: PMID:30487600 NLRP3 is recruited to the dispersed TGN (dTGN) through ionic bonding between its conserved polybasic region and negatively charged phosphatidylinositol-4-phosphate (PtdIns4P) on the dTGN. |
| GO:0071222 cellular response to lipopolysaccharide | IDA PMID:28847925 NLRP3 mutation and cochlear autoinflammation cause syndromic... | ACCEPT | Summary: NLRP3 responds to lipopolysaccharide: LPS priming induces NLRP3 expression and licenses subsequent activation. Reason: Well supported and mechanistically real. Priming is now recognised as one of the four factors that converge on making the centrosome permissive for NLRP3 condensation, and raising NLRP3 abundance can substitute for it. Supporting Evidence: PMID:42378282 Elevated NLRP3 expression compensates for limited PCM abundance, rendering K+ efflux-induced activation independent of both NEK7 and priming in human and mouse macrophages. |
| GO:0006954 inflammatory response | IMP PMID:28847925 NLRP3 mutation and cochlear autoinflammation cause syndromic... | ACCEPT | Summary: NLRP3 participates in the inflammatory response. Reason: Correct general parent, supported by six annotations; the specific positive-regulation and interleukin-1 beta terms carried by this gene are the informative statements. |
| GO:0032731 positive regulation of interleukin-1 beta production | IMP PMID:28847925 NLRP3 mutation and cochlear autoinflammation cause syndromic... | ACCEPT | Summary: The NLRP3 inflammasome drives caspase-1-dependent maturation and release of interleukin-1 beta. Reason: Core biological process and the principal physiological output of NLRP3, supported by thirteen annotations. The clinical corollary is that CAPS patients carrying gain-of-function NLRP3 mutations respond to interleukin-1 blockade. Supporting Evidence: PMID:15030775 Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. |
| GO:0005515 protein binding | IPI PMID:24531343 The PYRIN domain-only protein POP3 inhibits ALR inflammasome... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:23871209 The DHX33 RNA helicase senses cytosolic RNA and activates th... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5691439 | ACCEPT | Summary: Resting NLRP3 is a soluble cytosolic protein, which is where it is held as an autoinhibited oligomer before activation. Reason: Core resting location. Supported by an IDA, the UniProt mapping and eleven Reactome pathway assertions covering NLRP3 oligomerisation, ASC recruitment and small-molecule activation. |
| GO:0005515 protein binding | IPI PMID:26347139 TRIM-mediated precision autophagy targets cytoplasmic regula... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0002830 positive regulation of type 2 immune response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of type 2 immune response, transferred by similarity from mouse Nlrp3. Reason: Part of the T helper 2 transcriptional-cofactor cluster propagated from mouse Nlrp3, all tracing to one 2015 report that carries a published corrigendum and lacks independent or human corroboration. Retained as a plausible cell-type-restricted, inflammasome-independent role and kept consistent with the sibling terms. |
| GO:0032753 positive regulation of interleukin-4 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of interleukin-4 production, transferred by similarity from mouse Nlrp3, which was reported to transactivate the Il4 promoter. Reason: Same single mouse source as the rest of the T helper 2 cluster; handled consistently with it. |
| GO:0043565 sequence-specific DNA binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-specific DNA binding, inferred phylogenetically and by orthology from mouse Nlrp3, which was reported to bind the Il4 promoter in T helper 2 cells. Reason: Surprising for an inflammasome sensor, and it deserves the scrutiny. Tracing it back: both the IBA (node PTN000648032, donor MGI:2653833) and the ISS (donor UniProtKB:Q8R4B8) rest on a single underlying result - Bruchard et al. 2015 reported that mouse Nlrp3 in CD4+ T cells binds the Il4 promoter and transactivates it with IRF4, independently of ASC and caspase-1. That is a real experimental claim, with a plausible molecular reading (the NACHT-LRR architecture is shared with the transcriptional activator CIITA), so it is not dismissed. But it is one laboratory, it carries a published corrigendum, no human experimental evidence exists, and no NLRP3 DNA-binding domain or NLRP3-DNA structure has been described in the decade since, despite intensive structural work on the protein. Kept as a non-core, cell-type-restricted, inflammasome-independent activity rather than accepted alongside the inflammasome functions or removed on grounds of surprise alone. The IBA is not challenged on propagation grounds: the node placement follows correctly from the mouse experimental annotation, so the question is the strength of that source, not the phylogeny. |
| GO:0045630 positive regulation of T-helper 2 cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of T helper 2 cell differentiation, transferred by similarity from mouse Nlrp3. Reason: Same single mouse source as the rest of the T helper 2 cluster; handled consistently with it. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of transcription by RNA polymerase II, transferred by similarity from mouse Nlrp3 acting at the Il4 promoter with IRF4. Reason: The transcriptional-output term of the same T helper 2 claim as GO:0043565 and GO:0140297, from the same single mouse source, and given the same treatment: retained, restricted, and explicitly not part of the core inflammasome function. |
| GO:2000553 positive regulation of T-helper 2 cell cytokine production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of T helper 2 cell cytokine production, transferred by similarity from mouse Nlrp3. Reason: Same single mouse source as the rest of the T helper 2 cluster; handled consistently with it. |
| GO:0005515 protein binding | IPI PMID:22461501 GBP5 promotes NLRP3 inflammasome assembly and immunity in ma... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0002674 negative regulation of acute inflammatory response | IMP PMID:11687797 Mutation of a new gene encoding a putative pyrin-like protei... | MODIFY | Summary: Negative regulation of acute inflammatory response, annotated from the founding paper identifying CIAS1 mutations in familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Reason: Same inverted direction. The mutations described are dominant gain-of-function alleles producing recurrent fever and urticaria; the process NLRP3 drives is positive regulation of inflammation. Proposed replacements: positive regulation of inflammatory response |
| GO:0032691 negative regulation of interleukin-1 beta production | IMP PMID:12483741 De novo CIAS1 mutations, cytokine activation, and evidence f... | MODIFY | Summary: Negative regulation of interleukin-1 beta production, annotated from patients with neonatal-onset multisystem inflammatory disease carrying de novo CIAS1 mutations. Reason: The direction is inverted relative to the biology of the mutations described. CAPS-associated NLRP3 mutations, including the NOMID mutations in this study, are gain-of-function: they cause constitutive inflammasome activity and excess interleukin-1 beta, which is why interleukin-1 blockade is effective. GOA already carries the positive term with thirteen independent annotations including an IMP. Proposed as a correction of sign rather than a removal, since the underlying patient data are sound and it is only the direction of the inference that is at issue. Proposed replacements: positive regulation of interleukin-1 beta production |
| GO:0050728 negative regulation of inflammatory response | IMP PMID:12483741 De novo CIAS1 mutations, cytokine activation, and evidence f... | MODIFY | Summary: Negative regulation of inflammatory response, annotated from three cryopyrin-associated periodic syndrome cohorts. Reason: Same directional problem as GO:0032691, and from the same class of evidence: patients carrying NLRP3 mutations have excessive, not deficient, inflammation, and two of the three cited studies are reports of clinical improvement on interleukin-1 receptor antagonism. GOA carries the positive term for this gene with nine annotations. One alternative reading is recorded for completeness: early work did report that wild-type cryopyrin suppresses NF-kappaB signalling, which could motivate a negative regulatory annotation - but that is captured separately by GO:1901223, and these three references are CAPS genotype-phenotype studies rather than NF-kappaB assays. Proposed replacements: positive regulation of inflammatory response |
| GO:0071222 cellular response to lipopolysaccharide | IMP PMID:12483741 De novo CIAS1 mutations, cytokine activation, and evidence f... | ACCEPT | Summary: NLRP3 responds to lipopolysaccharide: LPS priming induces NLRP3 expression and licenses subsequent activation. Reason: Well supported and mechanistically real. Priming is now recognised as one of the four factors that converge on making the centrosome permissive for NLRP3 condensation, and raising NLRP3 abundance can substitute for it. Supporting Evidence: PMID:42378282 Elevated NLRP3 expression compensates for limited PCM abundance, rendering K+ efflux-induced activation independent of both NEK7 and priming in human and mouse macrophages. |
| GO:0072559 NLRP3 inflammasome complex | IDA PMID:15030775 NALP3 forms an IL-1beta-processing inflammasome with increas... | ACCEPT | Summary: NLRP3 is the defining sensor subunit of the NLRP3 inflammasome, together with ASC and caspase-1. Reason: Core, and about as securely established as any complex membership in GO: six annotations including the founding biochemical reconstitution, cryo-EM of the active disc and the phylogenetic inference. Supporting Evidence: PMID:15030775 Here, we report that NALP2 and NALP3 associate with ASC, the CARD-containing protein Cardinal, and caspase-1 (but not caspase-5), thereby forming an inflammasome with high proIL-1beta-processing activity. |
| GO:0050728 negative regulation of inflammatory response | IMP PMID:16531551 Hearing improvement in a patient with variant Muckle-Wells s... | MODIFY | Summary: Negative regulation of inflammatory response, annotated from three cryopyrin-associated periodic syndrome cohorts. Reason: Same directional problem as GO:0032691, and from the same class of evidence: patients carrying NLRP3 mutations have excessive, not deficient, inflammation, and two of the three cited studies are reports of clinical improvement on interleukin-1 receptor antagonism. GOA carries the positive term for this gene with nine annotations. One alternative reading is recorded for completeness: early work did report that wild-type cryopyrin suppresses NF-kappaB signalling, which could motivate a negative regulatory annotation - but that is captured separately by GO:1901223, and these three references are CAPS genotype-phenotype studies rather than NF-kappaB assays. Proposed replacements: positive regulation of inflammatory response |
| GO:0050728 negative regulation of inflammatory response | IMP PMID:17178985 Phenotype, genotype, and sustained response to anakinra in 2... | MODIFY | Summary: Negative regulation of inflammatory response, annotated from three cryopyrin-associated periodic syndrome cohorts. Reason: Same directional problem as GO:0032691, and from the same class of evidence: patients carrying NLRP3 mutations have excessive, not deficient, inflammation, and two of the three cited studies are reports of clinical improvement on interleukin-1 receptor antagonism. GOA carries the positive term for this gene with nine annotations. One alternative reading is recorded for completeness: early work did report that wild-type cryopyrin suppresses NF-kappaB signalling, which could motivate a negative regulatory annotation - but that is captured separately by GO:1901223, and these three references are CAPS genotype-phenotype studies rather than NF-kappaB assays. Proposed replacements: positive regulation of inflammatory response |
| GO:0005515 protein binding | IPI PMID:19337385 Evaluation of Nod-like receptor (NLR) effector domain intera... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005737 cytoplasm | IDA PMID:17164409 Inflammasome components NALP 1 and 3 show distinct but separ... | ACCEPT | Summary: NLRP3 is a cytosolic protein; resting NLRP3 is soluble in the cytoplasm before stimulus-induced relocalisation. Reason: Correct and uncontroversial across six independent annotations, though the cytosol (GO:0005829) annotation this gene also carries is the more informative statement of the same fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1296421 | ACCEPT | Summary: Resting NLRP3 is a soluble cytosolic protein, which is where it is held as an autoinhibited oligomer before activation. Reason: Core resting location. Supported by an IDA, the UniProt mapping and eleven Reactome pathway assertions covering NLRP3 oligomerisation, ASC recruitment and small-molecule activation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1306876 | ACCEPT | Summary: Resting NLRP3 is a soluble cytosolic protein, which is where it is held as an autoinhibited oligomer before activation. Reason: Core resting location. Supported by an IDA, the UniProt mapping and eleven Reactome pathway assertions covering NLRP3 oligomerisation, ASC recruitment and small-molecule activation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-844440 | ACCEPT | Summary: Resting NLRP3 is a soluble cytosolic protein, which is where it is held as an autoinhibited oligomer before activation. Reason: Core resting location. Supported by an IDA, the UniProt mapping and eleven Reactome pathway assertions covering NLRP3 oligomerisation, ASC recruitment and small-molecule activation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-844610 | ACCEPT | Summary: Resting NLRP3 is a soluble cytosolic protein, which is where it is held as an autoinhibited oligomer before activation. Reason: Core resting location. Supported by an IDA, the UniProt mapping and eleven Reactome pathway assertions covering NLRP3 oligomerisation, ASC recruitment and small-molecule activation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-844612 | ACCEPT | Summary: Resting NLRP3 is a soluble cytosolic protein, which is where it is held as an autoinhibited oligomer before activation. Reason: Core resting location. Supported by an IDA, the UniProt mapping and eleven Reactome pathway assertions covering NLRP3 oligomerisation, ASC recruitment and small-molecule activation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-873951 | ACCEPT | Summary: Resting NLRP3 is a soluble cytosolic protein, which is where it is held as an autoinhibited oligomer before activation. Reason: Core resting location. Supported by an IDA, the UniProt mapping and eleven Reactome pathway assertions covering NLRP3 oligomerisation, ASC recruitment and small-molecule activation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9603905 | ACCEPT | Summary: Resting NLRP3 is a soluble cytosolic protein, which is where it is held as an autoinhibited oligomer before activation. Reason: Core resting location. Supported by an IDA, the UniProt mapping and eleven Reactome pathway assertions covering NLRP3 oligomerisation, ASC recruitment and small-molecule activation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9685268 | ACCEPT | Summary: Resting NLRP3 is a soluble cytosolic protein, which is where it is held as an autoinhibited oligomer before activation. Reason: Core resting location. Supported by an IDA, the UniProt mapping and eleven Reactome pathway assertions covering NLRP3 oligomerisation, ASC recruitment and small-molecule activation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9685281 | ACCEPT | Summary: Resting NLRP3 is a soluble cytosolic protein, which is where it is held as an autoinhibited oligomer before activation. Reason: Core resting location. Supported by an IDA, the UniProt mapping and eleven Reactome pathway assertions covering NLRP3 oligomerisation, ASC recruitment and small-molecule activation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9757097 | ACCEPT | Summary: Resting NLRP3 is a soluble cytosolic protein, which is where it is held as an autoinhibited oligomer before activation. Reason: Core resting location. Supported by an IDA, the UniProt mapping and eleven Reactome pathway assertions covering NLRP3 oligomerisation, ASC recruitment and small-molecule activation. |
| GO:1901223 negative regulation of non-canonical NF-kappaB signal transduction | IDA PMID:14662828 Cutting edge: CIAS1/cryopyrin/PYPAF1/NALP3/CATERPILLER 1.1 i... | KEEP AS NON CORE | Summary: Suppression of NF-kappaB signalling by cryopyrin, reported in 2003: full-length CIAS1 and two natural short isoforms inhibited TNF-alpha-induced NF-kappaB reporter activity and p65 nuclear translocation. Reason: An early, inflammasome-independent activity that has not been integrated into the modern picture of NLRP3 and sits awkwardly beside the opposite-direction annotation this gene also carries (GO:1901224, positive regulation of the same pathway). GOA thus holds both signs simultaneously, on evidence from overexpression-based reporter assays in both cases. Retained on both sides rather than adjudicated, because neither has been tested at endogenous expression levels and the honest reading is that the NF-kappaB regulatory role of NLRP3 is unsettled. |
| GO:0005515 protein binding | IPI PMID:15030775 NALP3 forms an IL-1beta-processing inflammasome with increas... | REMOVE | Summary: Bare protein binding from twenty-four separate interaction studies. Reason: Uninformative as a molecular function. Several of the underlying interactions are biologically important - NEK7, ASC, MAVS, MARK4, BTK, SHP2, TRIM65 - but each is captured by a specific process or complex annotation elsewhere in this set; the bare term adds nothing. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0032731 positive regulation of interleukin-1 beta production | IDA PMID:15030775 NALP3 forms an IL-1beta-processing inflammasome with increas... | ACCEPT | Summary: The NLRP3 inflammasome drives caspase-1-dependent maturation and release of interleukin-1 beta. Reason: Core biological process and the principal physiological output of NLRP3, supported by thirteen annotations. The clinical corollary is that CAPS patients carrying gain-of-function NLRP3 mutations respond to interleukin-1 blockade. Supporting Evidence: PMID:15030775 Macrophages from Muckle-Wells patients spontaneously secrete active IL-1beta. |
| GO:0005737 cytoplasm | TAS PMID:15967716 NLRs join TLRs as innate sensors of pathogens. | ACCEPT | Summary: NLRP3 is a cytosolic protein; resting NLRP3 is soluble in the cytoplasm before stimulus-induced relocalisation. Reason: Correct and uncontroversial across six independent annotations, though the cytosol (GO:0005829) annotation this gene also carries is the more informative statement of the same fact. |
| GO:0006952 defense response | TAS PMID:15967716 NLRs join TLRs as innate sensors of pathogens. | ACCEPT | Summary: Defense response, from a review of NLR biology. Reason: Correct but very general; retained as a true high-level statement, with the informative detail supplied by the inflammasome-assembly and interleukin-1 beta terms. |
| GO:0009595 detection of biotic stimulus | TAS PMID:15967716 NLRs join TLRs as innate sensors of pathogens. | KEEP AS NON CORE | Summary: Detection of biotic stimulus, from the silica and aluminium salt study and from a review of NLR biology. Reason: Two problems, neither fatal. The agonists in the cited experimental study - silica crystals and aluminium salts - are abiotic, so they cannot support a biotic-stimulus term; and the paper's own conclusion is that what is sensed is lysosomal damage, an endogenous event downstream of the particle. NLRP3 genuinely does respond to biotic stimuli such as pore-forming toxins and viral proteins, which is why this is retained rather than removed, but as a downstream and indirect participation rather than as detection in the strict sense. Supporting Evidence: PMID:18604214 Our results indicate that the NALP3 inflammasome senses lysosomal damage as an endogenous 'danger' signal. |
| GO:0042834 peptidoglycan binding | TAS PMID:15967716 NLRs join TLRs as innate sensors of pathogens. | REMOVE | Summary: Peptidoglycan binding, asserted by a curator from a 2005 review of NLR biology. Reason: No experimental support exists for this, in this reference or elsewhere. The annotation is TAS from a review, not an experimental call, so no curator's reading of a primary dataset is being second-guessed. It descends from the mid-2000s proposal that NALP3 senses bacterial peptidoglycan and muramyl dipeptide; direct binding of peptidoglycan to NLRP3 was never demonstrated, the dedicated peptidoglycan sensors were subsequently established to be NOD1 and NOD2, and the modern model has NLRP3 responding to a common downstream perturbation rather than to any specific microbial polymer. Leaving a ligand-binding molecular function asserted for a protein with no known direct ligand is actively misleading, and it is the kind of claim that downstream tooling will believe. |
| GO:0006915 apoptotic process | NAS PMID:12032915 Chronic infantile neurological cutaneous and articular syndr... | MARK AS OVER ANNOTATED | Summary: Apoptotic process, asserted by a curator from the 2002 CINCA syndrome gene-identification paper. Reason: A non-traceable author statement from the era when NACHT-domain proteins were assumed to be APAF1-like apoptosis regulators - the protein family names of the period, PYPAF and Apaf1-like, record that assumption. The death modality NLRP3 actually drives is gasdermin-D-dependent pyroptosis, which is separately and correctly annotated; no evidence that NLRP3 promotes apoptosis has accumulated since. |
| GO:0006954 inflammatory response | IMP PMID:12093792 A novel PAAD-containing protein that modulates NF-kappa B in... | ACCEPT | Summary: NLRP3 participates in the inflammatory response. Reason: Correct general parent, supported by six annotations; the specific positive-regulation and interleukin-1 beta terms carried by this gene are the informative statements. |
| GO:0007165 signal transduction | NAS PMID:11786556 PYPAF1, a PYRIN-containing Apaf1-like protein that assembles... | KEEP AS NON CORE | Summary: Signal transduction, from the original PYPAF1 characterisation. Reason: A root-level term that conveys nothing NLRP3-specific. Retained because it is not wrong, but it is superseded entirely by the inflammasome assembly, adaptor and caspase-activator annotations this gene carries. |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: Is NEK7 required for NLRP3 activation, and under what conditions? The 2026 PNAS study reports that elevated NLRP3 expression renders K+-efflux-driven activation independent of both NEK7 and priming, while only partially bypassing NEK7 for imiquimod; the 2026 Nature Communications study describes a cage-independent, MTOC-distal pathway in which the structural basis of NEK7 engagement is unclear because NEK7 cannot bind the inactive oligomer. Are these two descriptions of one abundance-threshold phenomenon, or genuinely different pathways?
Q: What is the resting oligomeric state of NLRP3 in cells? Cryo-EM has yielded a decamer and a dodecamer for the same inactive species, and a 2026 study shows that low-molecular-weight non-cage species are competent to form inflammasomes and predominate in human neutrophils. Is the cage a storage form whose disassembly is required, an obligate intermediate, or one of several interchangeable resting states?
Q: Should NLRP3 carry any ligand-binding molecular function at all? No direct agonist has been identified, PtdIns4P is the only well-established direct binding partner, and GO:0140299 molecular sensor activity presupposes a bound ligand. Would the field support a molecular function for inflammasome sensors that is explicitly not ligand-based?
Q: Does human NLRP3 have a nuclear, transcriptional role? The claim that NLRP3 binds the Il4 promoter and transactivates it with IRF4 in T helper 2 cells rests on a single mouse study from 2015, carries a corrigendum, and has never been reproduced in human cells or given a structural basis - yet it is the sole source of six current human annotations propagated by IBA and ISS. Is there unpublished replication, or should these be retired?
Q: Why do the cryopyrin-associated periodic syndrome cohort papers support negative-regulation annotations for interleukin-1 beta production and inflammatory response, when the mutations concerned are gain-of-function and the patients respond to interleukin-1 blockade? Is this a systematic sign error in the annotations, or does it record an intended reading that is not recoverable from the text?
Q: Does NLRP3 regulate NF-kappaB, and in which direction? GOA carries both positive and negative regulation of non-canonical NF-kappaB signalling, each from overexpression-based reporter assays of the early 2000s. Has either been tested at endogenous expression levels?
Experiment: Place NLRP3 under a titratable degron-plus-inducible-promoter system in NEK7-null and NEK7-competent human macrophages and neutrophil-like cells, and scan expression across two orders of magnitude. At each level, measure the decamer-to-low-molecular-weight ratio by native gradient fractionation and mass photometry, score speck position relative to the pericentriolar material by live imaging, and read out caspase-1 activation for nigericin (K+-dependent) and imiquimod (K+-independent) in parallel. If abundance alone moves cells between the two routes, the two 2026 papers are describing one threshold phenomenon.
Hypothesis: The cage-dependent and MTOC-distal activation routes are distinguished by NLRP3 concentration rather than by cell type, and NEK7 dependence tracks with the route rather than with the stimulus.
Experiment: In cells expressing a NLRP3 conformational FRET reporter, impose candidate common intermediates one at a time in the absence of any agonist - controlled K+ efflux via a selective ionophore at defined concentration, acute PtdIns4P depletion or forced dTGN dispersal by rapamycin-inducible phosphatase recruitment, and selective lysosomal permeabilisation - and ask which are individually sufficient. Combine with photo-crosslinking mass spectrometry from NLRP3 under each condition to look, without prior hypothesis, for any small molecule or lipid that becomes bound.
Hypothesis: NLRP3 requires no agonist-specific binding event; a single common membrane or ionic perturbation is sufficient for activation.
Experiment: In primary human CD4+ T cells differentiated to a T helper 2 phenotype, perform CUT&RUN and ChIP-seq for endogenous, epitope-tagged NLRP3 alongside IRF4, with NLRP3-knockout cells as the specificity control, and test IL4 locus output after acute NLRP3 degradation. Complement with in vitro binding of purified full-length NLRP3 to the IL4 promoter by EMSA and fluorescence anisotropy. A clean negative in human cells would justify retiring six propagated annotations; a positive would supply the human evidence the claim has lacked for a decade.
Hypothesis: Human NLRP3 does not act as a sequence-specific DNA-binding transcriptional cofactor.
Experiment: Use optogenetic clustering to nucleate NLRP3 condensates at defined subcellular positions - centrosome, dispersed TGN, or a neutral cytosolic anchor - in the absence of any inflammasome stimulus, and measure ASC speck formation, caspase-1 activity and interleukin-1 beta release from each position. Pair with in vitro reconstitution of NLRP3 condensates from purified components to establish which partners are needed for the material properties, and test whether pericentriolar-material scaffolding proteins alter the threshold.
Hypothesis: Condensate formation at the pericentriolar material is required for a distinct, high-magnitude mode of NLRP3 signalling and not merely a consequence of local concentration.
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)