{"gene":"NLRP6","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2002,"finding":"NLRP6 (PYPAF5) co-expressed with the adaptor ASC synergistically activates NF-κB and recruits NLRP6 to punctate cytoplasmic structures; it also synergistically activates caspase-1-dependent cytokine processing when co-expressed with ASC, placing NLRP6 upstream of both NF-κB and caspase-1 in inflammatory signaling.","method":"Co-expression/overexpression assays in cells; NF-κB reporter assay; caspase-1 activity assay; subcellular colocalization imaging","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts (NF-κB, caspase-1, localization) in a single study; single lab, no in vitro reconstitution","pmids":["12387869"],"is_preprint":false},{"year":2011,"finding":"NLRP6 inflammasome deficiency in colonic epithelial cells reduces IL-18 levels and alters fecal microbiota composition, establishing that NLRP6—acting together with ASC and caspase-1—controls IL-18 maturation and microbial ecology in the colon.","method":"Nlrp6-/- mouse model; IL-18 ELISA; 16S microbiome sequencing; cohousing/cross-fostering experiments; DSS colitis model","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods in vivo (KO, microbiome, cytokine measurement, cohousing transfer), replicated across genetic contexts","pmids":["21565393"],"is_preprint":false},{"year":2011,"finding":"NLRP6 activity in hematopoietic cells is critical for protection against DSS-induced colitis and colitis-associated tumorigenesis, demonstrated by bone marrow chimera experiments.","method":"Nlrp6-/- mouse model; bone marrow chimera experiments; DSS colitis and azoxymethane/DSS tumorigenesis models","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chimera experiments define cellular compartment; single lab","pmids":["21543645"],"is_preprint":false},{"year":2012,"finding":"NLRP6 negatively regulates TLR-triggered MAPK and canonical NF-κB signaling in macrophages and other cells; Nlrp6-deficient cells produce increased NF-κB- and MAPK-dependent cytokines/chemokines after TLR ligation but not after NOD1/2 ligation, placing NLRP6 specifically as an inhibitor of TLR-driven inflammatory signaling.","method":"Nlrp6-/- mouse model; in vitro TLR/NOD ligand stimulation assays; cytokine/chemokine measurement; phospho-MAPK/NF-κB western blot","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo and in vitro experiments; pathway specificity established by NOD1/2 negative control; published in Nature","pmids":["22763455"],"is_preprint":false},{"year":2014,"finding":"The NLRP6 inflammasome controls goblet cell mucin granule exocytosis (Muc2 secretion) into the large intestinal lumen; NLRP6 deficiency leads to defective autophagy in goblet cells and abrogated mucus secretion, rendering mice unable to clear enteric pathogens from the mucosal surface.","method":"Nlrp6-/- mouse model; electron microscopy; goblet cell exocytosis assays; autophagy markers; enteric pathogen clearance assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct cellular phenotype (exocytosis, autophagy) linked to NLRP6 with multiple methods; replicated across infection models","pmids":["24581500"],"is_preprint":false},{"year":2015,"finding":"NLRP6 binds viral RNA via the RNA helicase DHX15 and interacts with mitochondrial antiviral signaling protein (MAVS) to induce type I/III interferons and interferon-stimulated genes in intestinal cells, functioning as a viral RNA sensor independently of inflammasome activation.","method":"Nlrp6-/- mouse model; co-immunoprecipitation (NLRP6-DHX15-MAVS interaction); viral load measurement (EMCV, MNV); interferon/ISG measurement","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying binding partners, in vivo KO with defined phenotype, multiple virus models","pmids":["26494172"],"is_preprint":false},{"year":2016,"finding":"A 'sentinel' goblet cell at the colonic crypt entrance activates the Nlrp6 inflammasome downstream of TLR- and MyD88-dependent Nox/Duox reactive oxygen species synthesis in response to TLR2/1, TLR4, and TLR5 ligands; this triggers calcium ion-dependent compound exocytosis of Muc2 mucin and propagates an intercellular gap junction signal to adjacent goblet cells.","method":"Live imaging of colonic tissue; TLR ligand stimulation; MyD88/Nox/Duox pathway inhibition; calcium signaling assays; Nlrp6-/- mice","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (imaging, genetic KO, pharmacological inhibition, pathway epistasis) in a rigorous single study","pmids":["27339979"],"is_preprint":false},{"year":2017,"finding":"NLRP6 facilitates the interaction between TAB2/3 and the E3 ligase TRIM38 in rheumatoid arthritis fibroblast-like synoviocytes, promoting lysosome-dependent degradation of TAB2/3 and thereby suppressing NF-κB activation.","method":"Co-immunoprecipitation; NLRP6 overexpression in RA-FLS; NF-κB reporter assay; cytokine measurement; TAB2/3 degradation assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional overexpression with defined molecular mechanism; single lab","pmids":["28295271"],"is_preprint":false},{"year":2018,"finding":"Lipoteichoic acid (LTA) from Gram-positive bacteria directly binds and activates NLRP6; cytosolic LTA triggers NLRP6 to recruit caspase-11 and caspase-1 via the adaptor ASC, leading to caspase-11 processing, caspase-1 activation, and IL-1β/IL-18 maturation in macrophages.","method":"LTA binding assay; Nlrp6-/- and Casp11-/- mouse infection models; caspase-1/11 processing assays; IL-18 reconstitution experiment (IL-18 administration rescuing susceptibility phenotype)","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct ligand binding established, caspase recruitment complex defined biochemically, in vivo rescue with IL-18 confirms pathway; published in Cell","pmids":["30392956"],"is_preprint":false},{"year":2019,"finding":"NLRP6 PYD alone self-assembles into filamentous structures with large conformational changes and recruits ASC via PYD-PYD interactions; full-length NLRP6 assembles into wider filaments with a PYD core surrounded by NBD and LRR domains; MD simulations identified the surface used by NLRP6 PYD filaments to recruit ASC PYD.","method":"Cryo-EM; X-ray crystallography of NLRP6 PYD; molecular dynamics simulations; in vitro filament assembly assays","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure + cryo-EM + in vitro reconstitution of filament assembly, multiple complementary structural methods in one study","pmids":["30674671"],"is_preprint":false},{"year":2019,"finding":"NLRP6 deficiency in kidney tubular epithelial cells results in upregulation of ERK1/2 and p38 MAPK phosphorylation and increased chemokine expression; MAPK inhibition prevented the inflammatory response in Nlrp6-deficient cells, establishing NLRP6 as a suppressor of MAP kinase signaling in sterile renal inflammation.","method":"Nlrp6-/- mice; cisplatin/folic acid AKI models; siRNA knockdown in cultured tubular cells; phospho-MAPK western blot; MAPK inhibitor experiments","journal":"Nephrology, dialysis, transplantation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO and in vitro siRNA with pharmacological rescue; single lab, two model systems","pmids":["31504777"],"is_preprint":false},{"year":2020,"finding":"The deubiquitinase CYLD deubiquitinates NLRP6, and this deubiquitination inhibits the NLRP6-ASC inflammasome complex, reducing IL-18 maturation; CYLD deficiency leads to elevated active IL-18 and severe colonic inflammation.","method":"Co-immunoprecipitation of CYLD-NLRP6; ubiquitination assays; Cyld-/- mouse colitis model; IL-18 ELISA; patient samples (CYLD/IL-18 inverse correlation)","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, in vivo KO with defined phenotype, and human correlative validation; multiple orthogonal approaches","pmids":["32424362"],"is_preprint":false},{"year":2020,"finding":"NLRP6 deficiency in CD4+ T cells increases caspase-1 activation and cell death following adoptive transfer, indicating that NLRP6 promotes T cell survival in an inflammasome-dependent manner.","method":"Nlrp6-/- CD4+ T cell adoptive transfer into Rag2-/- mice; caspase-1 activation assay; cell death measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — adoptive transfer with defined cellular phenotype; single lab, single method for mechanism","pmids":["31152078"],"is_preprint":false},{"year":2021,"finding":"NLRP6 undergoes liquid-liquid phase separation (LLPS) upon interaction with double-stranded RNA (dsRNA) in vitro and in cells; an intrinsically disordered poly-lysine sequence (K350-354) is required for multivalent interactions, phase separation, and inflammasome activation. Recruitment of ASC via helical assembly solidifies NLRP6 condensates, and ASC further recruits and activates caspase-1. LTA also promotes NLRP6 LLPS, and DHX15 co-forms condensates with NLRP6 and dsRNA.","method":"In vitro LLPS assay with purified NLRP6 and dsRNA; live-cell imaging of condensate formation; Nlrp6K350-354A knock-in mice; mouse hepatitis virus and rotavirus infection models; cryo-EM/structural analysis of ASC helical assembly","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of LLPS, mutagenesis (K350-354A knock-in), multiple ligands tested, in vivo validation; published in Cell","pmids":["34678144"],"is_preprint":false},{"year":2021,"finding":"NLRP6 is the only NLR required for inflammasome-dependent innate control of Cryptosporidium infection in enterocytes; enterocyte-specific caspase-1 deletion phenocopies whole-body KO, and the response is sufficient in germ-free mice, establishing an enterocyte-intrinsic NLRP6-caspase-1-IL-18 axis for anti-parasite defense.","method":"Nlrp6-/- mouse infection model with C. tyzzeri; conditional caspase-1 KO in enterocytes; germ-free mouse experiments; IL-18 KO and recombinant IL-18 rescue","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO, germ-free control, cytokine rescue experiment; multiple orthogonal genetic approaches","pmids":["33372132"],"is_preprint":false},{"year":2015,"finding":"Loss of Nlrp6 leads to strongly impaired nerve function upon sciatic nerve crush, but loss of the inflammasome adaptor ASC and caspase-1/11 did not affect nerve function, establishing that Nlrp6 promotes recovery after peripheral nerve injury independently of inflammasomes; Nlrp6 deficiency was associated with increased pro-inflammatory ERK signaling.","method":"Nlrp6-/-, ASC-/-, Casp1/11-/- mouse sciatic nerve crush models; functional nerve assessment; ERK phosphorylation western blot; IL-1β measurement","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple KO lines establishes inflammasome independence; single lab","pmids":["26253422"],"is_preprint":false},{"year":2016,"finding":"NLRP6 is upregulated in Ly6C-hi inflammatory monocytes infiltrating the colon during DSS-induced inflammation; adoptive transfer of WT Ly6C-hi monocytes into Nlrp6-/- mice protects from mortality and reduces intestinal permeability; NLRP6-deficient monocytes are defective in TNFα production, which depends on autocrine IL-18 signaling.","method":"Flow cytometry; adoptive transfer of Ly6C-hi monocytes; Nlrp6-/- mice; IL-18 and TNFα measurement; intestinal permeability assay","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — adoptive transfer rescue, autocrine signaling mechanism defined; single lab","pmids":["27353251"],"is_preprint":false},{"year":2017,"finding":"NLRP6 overexpression in rheumatoid arthritis fibroblast-like synoviocytes inhibits NF-κB and ERK signaling, reducing IL-6 and TNF-α production; NLRP6 knockdown enhances NF-κB and ERK activation and upregulates NLRP3 and Pro-IL-1β while downregulating ASC.","method":"NLRP6 overexpression and siRNA knockdown in HPDLCs; NF-κB and ERK western blot; cytokine ELISA; qRT-PCR","journal":"International endodontic journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method set (overexpression/knockdown with reporter assays), no in vitro reconstitution","pmids":["30712265"],"is_preprint":false},{"year":2018,"finding":"NLRP6 overexpression in gingival fibroblasts activates caspase-1 and gasdermin-D and induces pyroptosis with release of IL-1β and IL-18; Porphyromonas gingivalis triggers NLRP6-dependent pyroptosis.","method":"NLRP6 overexpression in human gingival fibroblasts; caspase-1 and GSDMD activation assays; IL-1β/IL-18 ELISA; P. gingivalis infection","journal":"Journal of dental research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression without loss-of-function confirmation or in vitro reconstitution","pmids":["29791256"],"is_preprint":false},{"year":2020,"finding":"NLRP6 suppresses gastric cancer cell growth by binding GRP78 through its Pyrin domain (while the SBD domain of GRP78 mediates binding to NLRP6) and promoting polyubiquitination and degradation of GRP78; GRP78 overexpression abolishes NLRP6-mediated growth suppression.","method":"Flag-tagged immunoprecipitation + LC-MS proteomics to identify GRP78 as NLRP6 interactor; domain mapping by co-IP; ubiquitination assay; GRP78 overexpression/knockdown rescue experiments; xenograft tumor model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interactome + Co-IP domain mapping + functional rescue; single lab","pmids":["32682010"],"is_preprint":false},{"year":2020,"finding":"Alternative promoter utilization determines NLRP6 expression in a tissue-selective manner: human NLRP6 contains an internal alternative promoter within exon 2 of the PYD resulting in a truncated, translationally silenced mRNA in non-intestinal tissue; in mice, a proximal promoter expands the 5' leader sequence restricting nuclear export and abolishing translational efficiency.","method":"Promoter reporter assays; 5' RACE; polysome profiling; nuclear/cytoplasmic fractionation; Nlrp6-/- mice in kidney disease models (negative functional result outside intestine)","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple molecular biology methods defining promoter usage and translational control; single lab","pmids":["33376129"],"is_preprint":false},{"year":2021,"finding":"In inflamed dental pulp cells, cytosolic Streptococcus mutans LTA activates an NLRP6-caspase-4 inflammasome complex (distinct from NLRP3); knockdown of NLRP6 or CASP4, or the caspase-4 inhibitor Ac-FLTD-CMK (but not the NLRP3 inhibitor MCC950), suppresses this LTA-triggered inflammasome activation.","method":"siRNA knockdown of NLRP6 and CASP4; pharmacological inhibitors (Ac-FLTD-CMK, MCC950); western blot and ELISA for inflammasome activation; LTA cytosolic delivery assay","journal":"International endodontic journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA + pharmacological inhibitor epistasis identifying NLRP6-caspase-4 as the relevant complex; single lab","pmids":["33377178"],"is_preprint":false},{"year":2021,"finding":"The E3 ligase TRIM29 promotes K48-linked ubiquitination of NLRP6 (and NLRP9b), leading to their proteasomal degradation and decreased IFN-λ and IL-18 production by intestinal epithelial cells; TRIM29-deficient mice show increased NLRP6 and NLRP9b protein levels and restricted intestinal inflammation upon enteric RNA virus challenge.","method":"TRIM29-/- mice; rotavirus and EMCV intestinal infection models; K48-ubiquitination assay; Co-IP of TRIM29-NLRP6; IFN-λ and IL-18 measurement","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + ubiquitination assay + in vivo KO with defined phenotype; single lab","pmids":["39396665"],"is_preprint":false},{"year":2022,"finding":"Estrogen receptor β (ERβ) directly activates NLRP6 gene expression by binding to estrogen responsive elements in the Nlrp6 promoter and also physically interacts with the NLRP6 nucleotide-binding domain to promote inflammasome assembly; the ERβ-NLRP6 axis then interacts with autophagy-related proteins (ULK1, BECN1, ATG16L1, LC3B, p62) and promotes K48-linked polyubiquitination and degradation of ASC, Casp-1 p20, IL-1β, TNF-α, and prohibitin-2 to suppress inflammation.","method":"ChIP assay (ERβ binding to Nlrp6 promoter); Co-IP (ERβ-NLRP6 NDB interaction); autophagy flux assays; ubiquitination assays; ERβ/NLRP6 KO mouse colitis models","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + Co-IP + ubiquitination assay + in vivo KO; single lab, multiple methods","pmids":["36223738"],"is_preprint":false},{"year":2021,"finding":"NLRP6 inflammasome activation leads to caspase-1 activation, GSDMD cleavage, ASC oligomerization, and IL-1β/IL-18 maturation in macrophages infected with Streptococcus pneumoniae; NLRP6 activation simultaneously reduces NF-κB and ERK signaling in S. pneumoniae-infected macrophages.","method":"Nlrp6-/- macrophages; caspase-1/11 and GSDMD western blot; ASC oligomerization assay; NF-κB/ERK western blot; IL-1β maturation assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical readouts in KO macrophages; single lab","pmids":["33918100"],"is_preprint":false},{"year":2023,"finding":"NLRP6 potentiates PI3K/AKT signaling by binding p85α (the regulatory subunit of PI3K) and recruiting the E3 ligase RBX1 to ubiquitinate p85α at lysine 256; ubiquitinated p85α is recognized by the autophagy cargo receptor OPTN, causing selective autophagic degradation of p85α and subsequent AKT activation with reduced PTEN stability.","method":"Co-IP of NLRP6-p85α-RBX1; K256 ubiquitination site mutagenesis; OPTN pulldown; autophagic flux assays; NLRP6 KO in glioblastoma cells; in vivo tumor growth; Pep9 peptide disruption of NLRP6/p85α interaction","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-specific mutagenesis, Co-IP, cargo receptor identification, in vivo tumor model, peptide inhibitor; multiple orthogonal methods in one study","pmids":["37770465"],"is_preprint":false},{"year":2021,"finding":"NLRP6 deficiency in hippocampal neural stem cells (NSCs) causes increased expression of ECRG4 and mitochondrial dysfunction; corticosterone downregulates NLRP6 and promotes ECRG4-mediated mitochondrial dysfunction and NSC proliferation suppression; NLRP6 is required for NSC proliferation and hippocampal neurogenesis to sustain stress resilience.","method":"Nlrp6-/- and NSC-conditional Nlrp6CKO mice; ECRG4 knockdown rescue; mitochondrial function assays; NSC proliferation assays; corticosterone treatment; NLRP6 overexpression rescue","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO + genetic rescue + mechanistic pathway delineation; single lab","pmids":["37250149"],"is_preprint":false},{"year":2024,"finding":"Nlrp6 acts as a sensor for RIG-1/MAVS-mediated mitophagy in hippocampal NSCs; Nlrp6 deficiency suppresses RIG-1/MAVS-mediated autophagy and drives ferroptotic cell death; short-chain fatty acids (SCFAs) upregulate Nlrp6 and promote RIG-1/MAVS-mediated mitophagy, preventing corticosterone-induced NSPC ferroptosis.","method":"siNlrp6 transfection; RIG-1/MAVS pathway assays; mitophagy/autophagy flux assays; ferroptosis markers; SCFA treatment","journal":"Redox biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — siRNA knockdown with pathway assays; single lab, limited mechanistic validation of direct NLRP6-RIG-1/MAVS interaction","pmids":["38772149"],"is_preprint":false},{"year":2021,"finding":"NLRP6 in hepatic stellate cells (LX-2) suppresses TGF-β1/Smad2/3 signaling by forming a complex with the Smad2/3 phosphatase PPM1A; NLRP6 overexpression enhances PPM1A expression and reduces p-Smad2/3; PPM1A knockdown abolishes the anti-fibrotic effects of NLRP6 overexpression.","method":"Co-immunoprecipitation (NLRP6-PPM1A complex); NLRP6 overexpression/knockdown in LX-2 cells; p-Smad2/3 western blot; PPM1A siRNA rescue experiment","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + genetic epistasis (siRNA rescue) defines PPM1A-dependent mechanism; single lab","pmids":["29966662"],"is_preprint":false},{"year":2021,"finding":"Nlrp6 deficiency in hepatocytes promotes CD36-mediated lipid uptake and increases NF-κB phosphorylation; Nlrp6 promotes lysosomal-dependent degradation of TAB2/3 to suppress NF-κB activation; CD36 inhibition blocks the enhanced fatty acid uptake caused by Nlrp6 deficiency.","method":"Hepatocyte-specific Nlrp6-/- mice; HFD/MCD diet models; CD36 inhibitor experiment; TAB2/3 lysosomal degradation assay; NF-κB phosphorylation western blot","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO + pharmacological rescue + lysosomal degradation mechanism; single lab","pmids":["33857628"],"is_preprint":false},{"year":2025,"finding":"In platelets, NLRP6 facilitates the interaction between TRIM21 and TAB1, resulting in K48-linked polyubiquitination and degradation of TAB1, thereby suppressing NF-κB signaling; NLRP6 deletion promotes platelet NF-κB signaling via sustained TAB1 expression independently of the inflammasome; TLR4/MyD88 signaling in platelets triggers this NLRP6/TRIM21/TAB1 axis.","method":"Platelet-specific Nlrp6-/- mice; cecal ligation and puncture sepsis model; Co-IP of NLRP6-TRIM21-TAB1; K48-ubiquitination assay; NF-κB inhibitor rescue; platelet aggregation/activation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP + ubiquitination assay + cell-type-specific KO + pharmacological rescue + in vivo model; multiple orthogonal approaches","pmids":["40373277"],"is_preprint":false},{"year":2024,"finding":"BRCC3 (BRCC36 homolog) physically interacts with NLRP6 (both N- and C-terminals), reduces NLRP6 ubiquitination, and affects the NLRP6-ASC interaction, thereby promoting NLRP6 inflammasome activation; BRCC3 knockdown reduces NLRP6-dependent caspase-1 cleavage and IL-1β in cerebral I/R injury.","method":"Co-immunoprecipitation (BRCC3-NLRP6); ubiquitination assay; BRCC3 siRNA in MCAO and OGD/R models; NLRP6-ASC interaction assay","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + ubiquitination assay + siRNA with in vivo and in vitro validation; single lab","pmids":["38544474"],"is_preprint":false},{"year":2024,"finding":"NLRP6 deficiency in microglia blocks multiple NLR inflammasome activations by reducing pro-caspase-1 protein levels through induction of proteasomal degradation of pro-caspase-1, thereby preventing neuroinflammation in ischemic stroke.","method":"Nlrp6-/- mice; MCAO model; OGD/R co-culture model; proteasome inhibitor assay; pro-caspase-1 protein stability assay; multiple inflammasome activation markers","journal":"Neurobiology of disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vivo KO with proteasome inhibitor experiment; indirect evidence for proteasomal mechanism; single lab","pmids":["38341160"],"is_preprint":false},{"year":2024,"finding":"NLRP3, NLRP6, and NLRP12 PYD domains activate caspase-1 to induce IL-1β cleavage and GSDMD cleavage; full-length NLRP6 reconstituted in vitro forms a functional inflammasome and is more prone to auto-activation than NLRP12; NLRP6 is specifically expressed in intestinal epithelial cells but not immune cells.","method":"In vitro inflammasome reconstitution; PYD domain screen for caspase-1 activation; cell fractionation/expression profiling; IL-1β and GSDMD cleavage assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution confirms inflammasome formation; single study, limited replication","pmids":["39076995"],"is_preprint":false}],"current_model":"NLRP6 is a cytosolic NLR family sensor that, upon activation by ligands including lipoteichoic acid (LTA) or dsRNA, undergoes liquid-liquid phase separation and assembles PYD filaments that recruit ASC (via PYD-PYD interactions) and caspase-1/caspase-11 to form a functional inflammasome that cleaves IL-1β and IL-18 and activates gasdermin D-dependent pyroptosis; independently of inflammasome assembly, NLRP6 interacts with DHX15 and MAVS to induce antiviral interferon signaling, negatively regulates TLR-driven NF-κB and MAPK signaling (partly via promoting TAB2/3 lysosomal degradation), controls goblet cell Muc2 mucin exocytosis through autophagy regulation, and is itself post-translationally regulated by CYLD-mediated deubiquitination (inhibitory) and TRIM29/TRIM21-mediated K48-ubiquitination (degradative); its expression is tissue-restricted through alternative promoter usage that silences translation outside the intestine."},"narrative":{"mechanistic_narrative":"NLRP6 is a cytosolic NLR-family pattern sensor that nucleates an ASC/caspase-1 inflammasome and operates predominantly in the intestinal epithelium, where it links microbial sensing to IL-18 maturation, mucosal defense, and host–microbiota homeostasis [PMID:21565393, PMID:30392956, PMID:39076995]. Upon engagement by ligands such as Gram-positive lipoteichoic acid or double-stranded RNA, NLRP6 undergoes liquid-liquid phase separation driven by an intrinsically disordered poly-lysine segment (K350-354) and assembles PYD filaments that recruit ASC through PYD-PYD interactions; ASC oligomerization solidifies the condensate and recruits caspase-1 (and caspase-11/caspase-4) to drive IL-1β/IL-18 processing and gasdermin-D-dependent pyroptosis [PMID:30392956, PMID:30674671, PMID:34678144, PMID:29791256, PMID:33377178]. Through this inflammasome-IL-18 axis NLRP6 shapes colonic microbial ecology, controls goblet-cell autophagy and Muc2 mucin exocytosis, and mediates enterocyte-intrinsic defense against enteric pathogens including Cryptosporidium [PMID:21565393, PMID:24581500, PMID:27339979, PMID:33372132]. Independently of inflammasome assembly, NLRP6 senses viral RNA via the helicase DHX15 and engages MAVS to induce type I/III interferon responses, and it functions as a negative regulator of TLR-driven NF-κB and MAPK signaling, in part by promoting lysosomal or ubiquitin-dependent degradation of TAB2/3 and TAB1 [PMID:22763455, PMID:26494172, PMID:33857628, PMID:40373277]. NLRP6 activity is set by post-translational control—CYLD-mediated deubiquitination restrains inflammasome activity while TRIM29- and TRIM21-directed K48 ubiquitination targets it for degradation—and its tissue-restricted expression is enforced by alternative promoter usage that silences translation outside the intestine [PMID:32424362, PMID:33376129, PMID:39396665, PMID:40373277]. Beyond these core functions, NLRP6 has been linked to scaffolding roles in PI3K/AKT signaling and substrate degradation in non-intestinal tissues [PMID:37770465].","teleology":[{"year":2002,"claim":"Established the first functional placement of NLRP6, showing it cooperates with the adaptor ASC to drive both NF-κB and caspase-1 activation, positioning it upstream in inflammatory signaling.","evidence":"Co-expression with ASC, NF-κB reporter, caspase-1 activity, and colocalization imaging in cells","pmids":["12387869"],"confidence":"Medium","gaps":["No endogenous ligand identified","Overexpression-based; physiological context unknown","No structural basis for ASC recruitment"]},{"year":2011,"claim":"Defined NLRP6 as an in vivo regulator of colonic IL-18 maturation and microbiota composition, connecting the inflammasome to host–microbe homeostasis and colitis susceptibility.","evidence":"Nlrp6-/- mice with IL-18 ELISA, 16S microbiome sequencing, cohousing/cross-fostering, and DSS colitis; bone marrow chimeras for compartment mapping","pmids":["21565393","21543645"],"confidence":"High","gaps":["Direct activating ligand not yet defined","Mechanism linking IL-18 to microbiota composition unresolved","Relative epithelial vs hematopoietic contribution debated across studies"]},{"year":2012,"claim":"Revealed an inflammasome-independent function: NLRP6 selectively dampens TLR-triggered NF-κB and MAPK signaling, establishing a negative-regulatory role distinct from inflammasome assembly.","evidence":"Nlrp6-/- macrophages with TLR vs NOD ligand stimulation, cytokine measurement, and phospho-MAPK/NF-κB blots","pmids":["22763455"],"confidence":"High","gaps":["Molecular target of suppression not yet identified in this study","Reconciliation with pro-inflammasome role unclear"]},{"year":2014,"claim":"Linked NLRP6 to goblet-cell biology, showing it controls autophagy-dependent Muc2 mucin exocytosis required to clear enteric pathogens.","evidence":"Nlrp6-/- mice with electron microscopy, exocytosis assays, autophagy markers, and pathogen clearance","pmids":["24581500"],"confidence":"High","gaps":["How inflammasome activity couples to autophagy machinery not defined","Direct molecular link to exocytic machinery unknown"]},{"year":2015,"claim":"Identified a non-inflammasome antiviral function, showing NLRP6 binds viral RNA via DHX15 and engages MAVS to induce interferons; a parallel study showed inflammasome-independent promotion of peripheral nerve recovery.","evidence":"Nlrp6-/- mice, reciprocal Co-IP of NLRP6-DHX15-MAVS, virus models; sciatic nerve crush in Nlrp6/ASC/Casp1-11 KO lines","pmids":["26494172","26253422"],"confidence":"High","gaps":["Structural basis of DHX15/MAVS engagement not resolved","Mechanism of nerve-recovery role beyond ERK association unknown"]},{"year":2016,"claim":"Defined the cellular circuitry of mucin secretion: a sentinel goblet cell activates the Nlrp6 inflammasome downstream of TLR-MyD88-Nox/Duox ROS to trigger calcium-dependent compound Muc2 exocytosis and gap-junction signaling; inflammatory monocytes were also shown to require NLRP6 for protective autocrine IL-18/TNFα responses.","evidence":"Live colonic-tissue imaging, pathway inhibition, calcium assays, Nlrp6-/- mice; Ly6C-hi monocyte adoptive transfer with cytokine measurement","pmids":["27339979","27353251"],"confidence":"High","gaps":["Direct upstream activating ligand in sentinel cells not biochemically defined","How ROS connects to NLRP6 activation unresolved"]},{"year":2017,"claim":"Provided a molecular mechanism for NF-κB suppression in a peripheral tissue, showing NLRP6 bridges TAB2/3 to the E3 ligase TRIM38 for lysosomal degradation.","evidence":"Co-IP, NLRP6 overexpression in RA-FLS, NF-κB reporter and TAB2/3 degradation assays; overexpression/knockdown in HPDLCs","pmids":["28295271","30712265"],"confidence":"Medium","gaps":["Overexpression-based; endogenous relevance not fully established","Tissue specificity of the TAB2/3-TRIM38 axis unclear"]},{"year":2018,"claim":"Identified lipoteichoic acid as a direct NLRP6 ligand and defined caspase recruitment, providing the first biochemical agonist for the inflammasome and demonstrating IL-18-dependent host defense.","evidence":"LTA binding assay, Nlrp6-/- and Casp11-/- infection models, caspase processing, and IL-18 rescue; overexpression-induced pyroptosis in gingival fibroblasts","pmids":["30392956","29791256"],"confidence":"High","gaps":["Stoichiometry and structural details of LTA binding not resolved","Selectivity for caspase-11 vs caspase-1 across cell types unclear"]},{"year":2019,"claim":"Resolved the structural basis of inflammasome nucleation, showing NLRP6 PYD self-assembles into filaments that recruit ASC PYD, and full-length NLRP6 forms wider PYD-core filaments; a parallel study extended NLRP6's MAPK-suppressive role to renal tubular inflammation.","evidence":"Cryo-EM, X-ray crystallography, MD simulations, in vitro filament assembly; Nlrp6-/- AKI models with phospho-MAPK and inhibitor experiments","pmids":["30674671","31504777"],"confidence":"High","gaps":["Trigger that converts inactive NLRP6 to filament-competent state in vivo not defined","Renal phenotype later complicated by tissue-restricted translation findings"]},{"year":2020,"claim":"Established post-translational and transcriptional control of NLRP6: CYLD deubiquitination restrains the inflammasome, and alternative-promoter usage translationally silences NLRP6 outside the intestine, explaining its tissue-restricted activity; additional work linked NLRP6 to GRP78 degradation and T-cell survival.","evidence":"CYLD-NLRP6 Co-IP, ubiquitination assays, Cyld-/- colitis, patient correlation; promoter reporters, 5' RACE, polysome profiling; LC-MS interactome with GRP78 and xenografts; CD4+ T cell adoptive transfer","pmids":["32424362","33376129","32682010","31152078"],"confidence":"High","gaps":["How CYLD-targeted ubiquitin marks gate filament assembly unclear","Reconciling functional reports in non-intestinal tissues with translational silencing remains open"]},{"year":2021,"claim":"Demonstrated that NLRP6 activation proceeds through liquid-liquid phase separation driven by a poly-lysine segment and ligand binding (dsRNA, LTA), unifying ligand sensing, condensate formation, and ASC/caspase recruitment into a single activation mechanism; the enterocyte-intrinsic NLRP6-caspase-1-IL-18 axis was shown sufficient for anti-Cryptosporidium defense.","evidence":"In vitro LLPS with purified NLRP6 and dsRNA, K350-354A knock-in mice, virus models, cryo-EM of ASC assembly; enterocyte-specific caspase-1 KO and germ-free/IL-18 rescue","pmids":["34678144","33372132","33377178","33918100"],"confidence":"High","gaps":["How distinct ligands converge on the same condensate not fully mapped","In vivo regulation of condensate dissolution unknown"]},{"year":2022,"claim":"Connected NLRP6 to hormonal and autophagic regulation, showing ERβ transcriptionally induces and physically binds NLRP6 to drive autophagy-coupled K48 ubiquitination and degradation of inflammatory components.","evidence":"ChIP, Co-IP, autophagy flux and ubiquitination assays, ERβ/NLRP6 KO colitis models","pmids":["36223738"],"confidence":"Medium","gaps":["Direct vs indirect ubiquitination of multiple substrates unresolved","Generalizability beyond colitis context unclear"]},{"year":2023,"claim":"Revealed a scaffolding role in growth signaling, showing NLRP6 recruits RBX1 to ubiquitinate PI3K p85α at K256 for OPTN-dependent autophagic degradation, thereby activating AKT in tumor cells.","evidence":"Co-IP, K256 site mutagenesis, OPTN pulldown, autophagic flux, glioblastoma KO, in vivo tumor model, and Pep9 peptide disruption; NSC studies on ECRG4/mitochondrial function","pmids":["37770465","37250149"],"confidence":"High","gaps":["How this scaffolding activity relates to NLR sensing domains unclear","Tissue contexts permitting NLRP6 expression for this role not reconciled with translational silencing"]},{"year":2025,"claim":"Extended NLRP6's ubiquitin-adaptor logic to negative regulation of NF-κB in platelets, showing it bridges TRIM21 to TAB1 for K48 degradation independently of the inflammasome.","evidence":"Platelet-specific Nlrp6-/- mice, CLP sepsis model, Co-IP of NLRP6-TRIM21-TAB1, K48-ubiquitination and NF-κB inhibitor rescue; TRIM29/BRCC3 regulation and microglial caspase-1 control in earlier reports","pmids":["40373277","39396665","38544474","38341160"],"confidence":"High","gaps":["Whether platelet NLRP6 expression escapes intestinal translational restriction not addressed","Common structural determinant for the various ubiquitin-ligase bridging functions undefined"]},{"year":null,"claim":"It remains unresolved how a single NLRP6 protein reconciles its tissue-restricted intestinal translation with the wide range of functions reported in non-intestinal tissues, and what unified structural switch governs its choice between inflammasome assembly, antiviral signaling, and ubiquitin-adaptor scaffolding.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of full-length ligand-bound NLRP6 in an activated complex","Mechanism partitioning inflammasome vs non-inflammasome outputs unknown","Endogenous expression in non-intestinal tissues not reconciled with translational silencing data"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8,33]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[5,13]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[8,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[25,30]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,30]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,13]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,8,5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[13,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,30,25]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4,25]}],"complexes":["NLRP6-ASC-caspase-1 inflammasome","NLRP6-DHX15-MAVS antiviral complex"],"partners":["ASC","DHX15","MAVS","CYLD","TRIM29","TRIM21","PPM1A","GRP78"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P59044","full_name":"NACHT, LRR and PYD domains-containing protein 6","aliases":["Angiotensin II/vasopressin receptor","PYRIN-containing APAF1-like protein 5"],"length_aa":892,"mass_kda":98.8,"function":"Acts as the sensor component of the NLRP6 inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to maturation and secretion of IL1B and IL18 (PubMed:30392956, PubMed:34678144). Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation (PubMed:30674671). Acts as a recognition receptor (PRR): recognizes and binds specific pathogens and other damage-associated signals, such as lipoteichoic acid (LTA), a cell-wall component of Gram-positive bacteria, or double stranded RNA (dsRNA) (PubMed:30392956, PubMed:33377178, PubMed:34678144). May also recognize and bind lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria; however, LPS is probably not a major activator of the NLRP6 inflammasome (PubMed:31932628, PubMed:34678144). Following LTA- or dsRNA-binding, NLRP6 undergoes liquid-liquid phase separation (LLPS), enhancing multivalent interactions, an essential step for the formation of the NLRP6 inflammasome polymeric complex (PubMed:34678144). The NLRP6 inflammasome acts by promoting recruitment of effector pro-inflammatory caspases (CASP1 and/or CASP4) that catalyze maturation and secretion of IL1B and IL18 in the extracellular milieu (PubMed:12387869, PubMed:30392956, PubMed:30674671, PubMed:34678144). The NLRP6 inflammasome plays a central role in the maintenance of epithelial integrity and host defense against microbial infections in the intestine (PubMed:30392956). Required to restrict infection against Gram-positive bacteria by recognizing lipoteichoic acid (LTA), leading to recruitment of CASP4 and CASP1, and subsequent maturation and secretion of IL1B and IL18 (PubMed:30392956, PubMed:33377178). Involved in intestinal antiviral innate immunity together with DHX15: recognizes and binds viral dsRNA to restrict infection by enteric viruses through the interferon pathway and GSDMD-dependent release of IL18 (PubMed:34161762, PubMed:34678144). Required to prevent infection by the apicomplexan parasite Cryptosporidium in enterocytes by promoting GSDMD-dependent release of IL18 (By similarity). The NLRP6 inflammasome may also regulate the gut microbiota composition by acting as a sensor of microbiota-associated metabolites to form a PYCARD/ASC-dependent inflammasome for downstream IL18 release and secretion of antimicrobial peptides (By similarity). Essential for gut mucosal self-renewal and proliferation (By similarity). Regulate mucus secretion in an inflammasome- and autophagy-dependent manner to prevent invasion by enteric bacteria, (By similarity). During systemic bacterial infections, the NLRP6 inflammasome negatively regulates neutrophil recruitment and neutrophil extracellular traps (NETs) formation (By similarity). May promote peripheral nerve recovery following injury via an inflammasome-independent mechanism (By similarity)","subcellular_location":"Cytoplasm, cytosol; Inflammasome; Cell membrane; Nucleus membrane","url":"https://www.uniprot.org/uniprotkb/P59044/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NLRP6","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDX6","stoichiometry":0.2},{"gene":"GSPT1","stoichiometry":0.2},{"gene":"PABPC4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NLRP6","total_profiled":1310},"omim":[{"mim_id":"613282","title":"FATTY LIVER DISEASE, SUSCEPTIBILITY TO, 1; FLD1","url":"https://www.omim.org/entry/613282"},{"mim_id":"609650","title":"NLR FAMILY, PYRIN DOMAIN-CONTAINING 6; NLRP6","url":"https://www.omim.org/entry/609650"},{"mim_id":"606838","title":"PYD AND CARD DOMAIN-CONTAINING PROTEIN; PYCARD","url":"https://www.omim.org/entry/606838"},{"mim_id":"606648","title":"INTERLEUKIN 22 RECEPTOR, ALPHA-2; IL22RA2","url":"https://www.omim.org/entry/606648"},{"mim_id":"605330","title":"INTERLEUKIN 22; IL22","url":"https://www.omim.org/entry/605330"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"intestine","ntpm":37.8}],"url":"https://www.proteinatlas.org/search/NLRP6"},"hgnc":{"alias_symbol":["PYPAF5","PAN3","CLR11.4"],"prev_symbol":["NALP6"]},"alphafold":{"accession":"P59044","domains":[{"cath_id":"1.10.533.10","chopping":"12-106","consensus_level":"high","plddt":84.1899,"start":12,"end":106},{"cath_id":"3.40.50.300","chopping":"136-156_175-350","consensus_level":"high","plddt":81.3977,"start":136,"end":350},{"cath_id":"-","chopping":"428-476_487-517_532-584","consensus_level":"high","plddt":79.6256,"start":428,"end":584},{"cath_id":"1.10.1900","chopping":"352-413","consensus_level":"medium","plddt":87.7411,"start":352,"end":413}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P59044","model_url":"https://alphafold.ebi.ac.uk/files/AF-P59044-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P59044-F1-predicted_aligned_error_v6.png","plddt_mean":78.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NLRP6","jax_strain_url":"https://www.jax.org/strain/search?query=NLRP6"},"sequence":{"accession":"P59044","fasta_url":"https://rest.uniprot.org/uniprotkb/P59044.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P59044/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P59044"}},"corpus_meta":[{"pmid":"21565393","id":"PMC_21565393","title":"NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis.","date":"2011","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/21565393","citation_count":1601,"is_preprint":false},{"pmid":"24581500","id":"PMC_24581500","title":"NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/24581500","citation_count":589,"is_preprint":false},{"pmid":"27339979","id":"PMC_27339979","title":"A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-dependent Muc2 secretion.","date":"2016","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/27339979","citation_count":455,"is_preprint":false},{"pmid":"21543645","id":"PMC_21543645","title":"A functional role for Nlrp6 in intestinal inflammation and tumorigenesis.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21543645","citation_count":358,"is_preprint":false},{"pmid":"22763455","id":"PMC_22763455","title":"NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22763455","citation_count":341,"is_preprint":false},{"pmid":"21593405","id":"PMC_21593405","title":"Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21593405","citation_count":301,"is_preprint":false},{"pmid":"28445725","id":"PMC_28445725","title":"NLRP6 Protects Il10-/- Mice from Colitis by Limiting Colonization of Akkermansia muciniphila.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28445725","citation_count":282,"is_preprint":false},{"pmid":"30392956","id":"PMC_30392956","title":"The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection.","date":"2018","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/30392956","citation_count":252,"is_preprint":false},{"pmid":"12387869","id":"PMC_12387869","title":"Functional screening of five PYPAF family members identifies PYPAF5 as a novel regulator of NF-kappaB and caspase-1.","date":"2002","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/12387869","citation_count":245,"is_preprint":false},{"pmid":"26494172","id":"PMC_26494172","title":"Nlrp6 regulates intestinal antiviral innate immunity.","date":"2015","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/26494172","citation_count":227,"is_preprint":false},{"pmid":"34678144","id":"PMC_34678144","title":"Phase separation drives RNA virus-induced activation of the NLRP6 inflammasome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/34678144","citation_count":187,"is_preprint":false},{"pmid":"23470617","id":"PMC_23470617","title":"Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome inhibition and transmissible enteritis in mice.","date":"2013","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/23470617","citation_count":126,"is_preprint":false},{"pmid":"28214100","id":"PMC_28214100","title":"NLRP6: A Multifaceted Innate Immune Sensor.","date":"2017","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28214100","citation_count":106,"is_preprint":false},{"pmid":"31420376","id":"PMC_31420376","title":"The Nlrp6 inflammasome is not required for baseline colonic inner mucus layer formation or function.","date":"2019","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31420376","citation_count":106,"is_preprint":false},{"pmid":"31988468","id":"PMC_31988468","title":"The NLRP6 inflammasome in health and disease.","date":"2020","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31988468","citation_count":104,"is_preprint":false},{"pmid":"30674671","id":"PMC_30674671","title":"Molecular mechanism for NLRP6 inflammasome assembly and activation.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30674671","citation_count":99,"is_preprint":false},{"pmid":"28238526","id":"PMC_28238526","title":"Mitochondrial DNA oxidation induces imbalanced activity of NLRP3/NLRP6 inflammasomes by activation of caspase-8 and BRCC36 in dry eye.","date":"2017","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/28238526","citation_count":97,"is_preprint":false},{"pmid":"33314083","id":"PMC_33314083","title":"The NLRP6 inflammasome.","date":"2020","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33314083","citation_count":94,"is_preprint":false},{"pmid":"32424362","id":"PMC_32424362","title":"Deubiquitination of NLRP6 inflammasome by Cyld critically regulates intestinal inflammation.","date":"2020","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32424362","citation_count":93,"is_preprint":false},{"pmid":"29281815","id":"PMC_29281815","title":"The NLR Protein NLRP6 Does Not Impact Gut Microbiota Composition.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29281815","citation_count":86,"is_preprint":false},{"pmid":"30248149","id":"PMC_30248149","title":"NLRP6 negatively regulates pulmonary host defense in Gram-positive bacterial infection through modulating neutrophil recruitment and function.","date":"2018","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/30248149","citation_count":83,"is_preprint":false},{"pmid":"21088234","id":"PMC_21088234","title":"Developmental control of the Nlrp6 inflammasome and a substrate, IL-18, in mammalian intestine.","date":"2010","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21088234","citation_count":79,"is_preprint":false},{"pmid":"29791256","id":"PMC_29791256","title":"NLRP6 Induces Pyroptosis by Activation of Caspase-1 in Gingival Fibroblasts.","date":"2018","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/29791256","citation_count":77,"is_preprint":false},{"pmid":"32386845","id":"PMC_32386845","title":"NLRP6 inflammasome.","date":"2020","source":"Molecular aspects of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32386845","citation_count":76,"is_preprint":false},{"pmid":"22503597","id":"PMC_22503597","title":"Aggregatibacter actinomycetemcomitans targets NLRP3 and NLRP6 inflammasome expression in human mononuclear leukocytes.","date":"2012","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/22503597","citation_count":69,"is_preprint":false},{"pmid":"36270983","id":"PMC_36270983","title":"NLRP6 is required for cancer-derived exosome-modified macrophage M2 polarization and promotes metastasis in small cell lung cancer.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36270983","citation_count":63,"is_preprint":false},{"pmid":"33372132","id":"PMC_33372132","title":"The intestinal parasite Cryptosporidium is controlled by an enterocyte intrinsic inflammasome that depends on NLRP6.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33372132","citation_count":61,"is_preprint":false},{"pmid":"31528095","id":"PMC_31528095","title":"Effect of mild moxibustion on intestinal microbiota and NLRP6 inflammasome signaling in rats with post-inflammatory irritable bowel syndrome.","date":"2019","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/31528095","citation_count":60,"is_preprint":false},{"pmid":"24338634","id":"PMC_24338634","title":"Role of Nlrp6 and Nlrp12 in the maintenance of intestinal homeostasis.","date":"2014","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24338634","citation_count":59,"is_preprint":false},{"pmid":"29139477","id":"PMC_29139477","title":"A dietary flavone confers communicable protection against colitis through NLRP6 signaling independently of inflammasome activation.","date":"2017","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29139477","citation_count":58,"is_preprint":false},{"pmid":"26253422","id":"PMC_26253422","title":"Nlrp6 promotes recovery after peripheral nerve injury independently of inflammasomes.","date":"2015","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/26253422","citation_count":52,"is_preprint":false},{"pmid":"27353251","id":"PMC_27353251","title":"NLRP6 function in inflammatory monocytes reduces susceptibility to chemically induced intestinal injury.","date":"2016","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27353251","citation_count":51,"is_preprint":false},{"pmid":"35369462","id":"PMC_35369462","title":"Intestinal Candida albicans Promotes Hepatocarcinogenesis by Up-Regulating NLRP6.","date":"2022","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/35369462","citation_count":51,"is_preprint":false},{"pmid":"31927506","id":"PMC_31927506","title":"NLRP6 expressed in astrocytes aggravates neurons injury after OGD/R through activating the inflammasome and inducing pyroptosis.","date":"2020","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31927506","citation_count":48,"is_preprint":false},{"pmid":"30712265","id":"PMC_30712265","title":"NLRP6 suppresses the inflammatory response of human periodontal ligament cells by inhibiting NF-κB and ERK signal pathways.","date":"2019","source":"International endodontic journal","url":"https://pubmed.ncbi.nlm.nih.gov/30712265","citation_count":46,"is_preprint":false},{"pmid":"33910012","id":"PMC_33910012","title":"NLRP6 in host defense and intestinal inflammation.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33910012","citation_count":44,"is_preprint":false},{"pmid":"33230225","id":"PMC_33230225","title":"NLRP6 modulates neutrophil homeostasis in bacterial pneumonia-derived sepsis.","date":"2020","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33230225","citation_count":42,"is_preprint":false},{"pmid":"36150347","id":"PMC_36150347","title":"Qing-Chang-Hua-Shi granule ameliorates DSS-induced colitis by activating NLRP6 signaling and regulating Th17/Treg balance.","date":"2022","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36150347","citation_count":42,"is_preprint":false},{"pmid":"29329362","id":"PMC_29329362","title":"Clostridium butyricum regulates visceral hypersensitivity of irritable bowel syndrome by inhibiting colonic mucous low grade inflammation through its action on NLRP6.","date":"2018","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/29329362","citation_count":41,"is_preprint":false},{"pmid":"31267316","id":"PMC_31267316","title":"Effects of NLRP6 in Cerebral Ischemia/Reperfusion (I/R) Injury in Rats.","date":"2019","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/31267316","citation_count":40,"is_preprint":false},{"pmid":"30858572","id":"PMC_30858572","title":"Host NLRP6 exacerbates graft-versus-host disease independent of gut microbial composition.","date":"2019","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30858572","citation_count":39,"is_preprint":false},{"pmid":"31504777","id":"PMC_31504777","title":"Loss of NLRP6 expression increases the severity of acute kidney injury.","date":"2020","source":"Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association","url":"https://pubmed.ncbi.nlm.nih.gov/31504777","citation_count":38,"is_preprint":false},{"pmid":"32783081","id":"PMC_32783081","title":"NLRP6 contributes to inflammation and brain injury following intracerebral haemorrhage by activating autophagy.","date":"2020","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/32783081","citation_count":35,"is_preprint":false},{"pmid":"31219209","id":"PMC_31219209","title":"Long noncoding RNA OIP5-AS1 aggravates cell proliferation, migration in gastric cancer by epigenetically silencing NLRP6 expression via binding EZH2.","date":"2019","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31219209","citation_count":35,"is_preprint":false},{"pmid":"30515917","id":"PMC_30515917","title":"The protective roles of NLRP6 in intestinal epithelial cells.","date":"2018","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/30515917","citation_count":33,"is_preprint":false},{"pmid":"33114531","id":"PMC_33114531","title":"Nicotine Causes Nephrotoxicity through the Induction of NLRP6 Inflammasome and Alpha7 Nicotinic Acetylcholine Receptor.","date":"2020","source":"Toxics","url":"https://pubmed.ncbi.nlm.nih.gov/33114531","citation_count":33,"is_preprint":false},{"pmid":"28295271","id":"PMC_28295271","title":"NLRP6 facilitates the interaction between TAB2/3 and TRIM38 in rheumatoid arthritis fibroblast-like synoviocytes.","date":"2017","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/28295271","citation_count":33,"is_preprint":false},{"pmid":"23811097","id":"PMC_23811097","title":"NLRP6 in infection and inflammation.","date":"2013","source":"Microbes and infection","url":"https://pubmed.ncbi.nlm.nih.gov/23811097","citation_count":32,"is_preprint":false},{"pmid":"34147913","id":"PMC_34147913","title":"SP1 transcriptionally activates NLRP6 inflammasome and induces immune evasion and radioresistance in glioma cells.","date":"2021","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34147913","citation_count":32,"is_preprint":false},{"pmid":"35650327","id":"PMC_35650327","title":"Physiological and pathophysiological functions of NLRP6: pro- and anti-inflammatory roles.","date":"2022","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/35650327","citation_count":31,"is_preprint":false},{"pmid":"35093492","id":"PMC_35093492","title":"Defects in NLRP6, autophagy and goblet cell homeostasis are associated with reduced duodenal CRH receptor 2 expression in patients with functional dyspepsia.","date":"2022","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/35093492","citation_count":31,"is_preprint":false},{"pmid":"37842661","id":"PMC_37842661","title":"Ginsenoside Rk2, a dehydroprotopanaxadiol saponin, alleviates alcoholic liver disease via regulating NLRP3 and NLRP6 inflammasome signaling pathways in mice.","date":"2023","source":"Journal of pharmaceutical analysis","url":"https://pubmed.ncbi.nlm.nih.gov/37842661","citation_count":31,"is_preprint":false},{"pmid":"39396665","id":"PMC_39396665","title":"TRIM29 controls enteric RNA virus-induced intestinal inflammation by targeting NLRP6 and NLRP9b signaling pathways.","date":"2024","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39396665","citation_count":29,"is_preprint":false},{"pmid":"36223738","id":"PMC_36223738","title":"Estrogen receptor β activation inhibits colitis by promoting NLRP6-mediated autophagy.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36223738","citation_count":29,"is_preprint":false},{"pmid":"32507279","id":"PMC_32507279","title":"NLRP6 exerts a protective role via NF-kB with involvement of CCL20 in a mouse model of alcoholic hepatitis.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32507279","citation_count":29,"is_preprint":false},{"pmid":"32596340","id":"PMC_32596340","title":"miR-331-3p Inhibits Inflammatory Response after Intracerebral Hemorrhage by Directly Targeting NLRP6.","date":"2020","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/32596340","citation_count":29,"is_preprint":false},{"pmid":"35524333","id":"PMC_35524333","title":"AIP1 suppresses neovascularization by inhibiting the NOX4-induced NLRP3/NLRP6 imbalance in a murine corneal alkali burn model.","date":"2022","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/35524333","citation_count":28,"is_preprint":false},{"pmid":"37250149","id":"PMC_37250149","title":"Neuron stem cell NLRP6 sustains hippocampal neurogenesis to resist stress-induced depression.","date":"2023","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/37250149","citation_count":26,"is_preprint":false},{"pmid":"32682010","id":"PMC_32682010","title":"NLRP6 suppresses gastric cancer growth via GRP78 ubiquitination.","date":"2020","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32682010","citation_count":26,"is_preprint":false},{"pmid":"33918100","id":"PMC_33918100","title":"The Critical Role of NLRP6 Inflammasome in Streptococcus pneumoniae Infection In Vitro and In Vivo.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33918100","citation_count":26,"is_preprint":false},{"pmid":"28798666","id":"PMC_28798666","title":"NLRP6 Inflammasome Ameliorates Brain Injury after Intracerebral Hemorrhage.","date":"2017","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28798666","citation_count":26,"is_preprint":false},{"pmid":"37770465","id":"PMC_37770465","title":"NLRP6 potentiates PI3K/AKT signalling by promoting autophagic degradation of p85α to drive tumorigenesis.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37770465","citation_count":25,"is_preprint":false},{"pmid":"30008389","id":"PMC_30008389","title":"TLR4-MyD88 pathway promotes the imbalanced activation of NLRP3/NLRP6 via caspase-8 stimulation after alkali burn injury.","date":"2018","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/30008389","citation_count":25,"is_preprint":false},{"pmid":"38772149","id":"PMC_38772149","title":"Nlrp6 protects from corticosterone-induced NSPC ferroptosis by modulating RIG-1/MAVS-mediated mitophagy.","date":"2024","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/38772149","citation_count":24,"is_preprint":false},{"pmid":"33857628","id":"PMC_33857628","title":"Hepatocyte-specific deletion of Nlrp6 in mice exacerbates the development of non-alcoholic steatohepatitis.","date":"2021","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33857628","citation_count":24,"is_preprint":false},{"pmid":"31561077","id":"PMC_31561077","title":"Is NLRP3 or NLRP6 inflammasome activation associated with inflammation-related lung tumorigenesis induced by benzo(a)pyrene and lipopolysaccharide?","date":"2019","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/31561077","citation_count":24,"is_preprint":false},{"pmid":"30568504","id":"PMC_30568504","title":"NLRP6, decreased in gastric cancer, suppresses tumorigenicity of gastric cancer cells.","date":"2018","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/30568504","citation_count":24,"is_preprint":false},{"pmid":"38544474","id":"PMC_38544474","title":"BRCC3 mediates inflammation and pyroptosis in cerebral ischemia/reperfusion injury by activating the NLRP6 inflammasome.","date":"2024","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/38544474","citation_count":23,"is_preprint":false},{"pmid":"29103703","id":"PMC_29103703","title":"Anti-inflammatory capacity of Lactobacillus rhamnosus GG in monophasic variant Salmonella infected piglets is correlated with impeding NLRP6-mediated host inflammatory responses.","date":"2017","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/29103703","citation_count":23,"is_preprint":false},{"pmid":"38315242","id":"PMC_38315242","title":"Decreased expression of the NLRP6 inflammasome is associated with increased intestinal permeability and inflammation in obesity with type 2 diabetes.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/38315242","citation_count":22,"is_preprint":false},{"pmid":"29966662","id":"PMC_29966662","title":"Effects of NLRP6 on the proliferation and activation of human hepatic stellate cells.","date":"2018","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/29966662","citation_count":22,"is_preprint":false},{"pmid":"31301646","id":"PMC_31301646","title":"NLRP6 deficiency aggravates liver injury after allogeneic hematopoietic stem cell transplantation.","date":"2019","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31301646","citation_count":22,"is_preprint":false},{"pmid":"31629100","id":"PMC_31629100","title":"Candida albicans SC5314 inhibits NLRP3/NLRP6 inflammasome expression and dampens human intestinal barrier activity in Caco-2 cell monolayer model.","date":"2019","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/31629100","citation_count":22,"is_preprint":false},{"pmid":"33377178","id":"PMC_33377178","title":"NLRP6-caspase 4 inflammasome activation in response to cariogenic bacterial lipoteichoic acid in human dental pulp inflammation.","date":"2021","source":"International endodontic journal","url":"https://pubmed.ncbi.nlm.nih.gov/33377178","citation_count":21,"is_preprint":false},{"pmid":"35053298","id":"PMC_35053298","title":"NLRP6 Inflammasome Modulates Disease Progression in a Chronic-Plus-Binge Mouse Model of Alcoholic Liver Disease.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35053298","citation_count":20,"is_preprint":false},{"pmid":"32431709","id":"PMC_32431709","title":"NLRP6 Plays an Important Role in Early Hepatic Immunopathology Caused by Schistosoma mansoni Infection.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32431709","citation_count":20,"is_preprint":false},{"pmid":"39076995","id":"PMC_39076995","title":"NLRP3, NLRP6, and NLRP12 are inflammasomes with distinct expression patterns.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39076995","citation_count":18,"is_preprint":false},{"pmid":"36845152","id":"PMC_36845152","title":"Vitamin D3 alleviates inflammation in ulcerative colitis by activating the VDR-NLRP6 signaling pathway.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36845152","citation_count":18,"is_preprint":false},{"pmid":"36211635","id":"PMC_36211635","title":"The latest breakthrough on NLRP6 inflammasome.","date":"2022","source":"Precision clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36211635","citation_count":16,"is_preprint":false},{"pmid":"33979701","id":"PMC_33979701","title":"BRCC3 promotes activation of the NLRP6 inflammasome following cerebral ischemia/reperfusion (I/R) injury in rats.","date":"2021","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/33979701","citation_count":16,"is_preprint":false},{"pmid":"40373277","id":"PMC_40373277","title":"Platelet NLRP6 protects against microvascular thrombosis in sepsis.","date":"2025","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/40373277","citation_count":15,"is_preprint":false},{"pmid":"36016685","id":"PMC_36016685","title":"Baicalin Ameliorates DSS-Induced Colitis by Protecting Goblet Cells through Activating NLRP6 Inflammasomes.","date":"2022","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/36016685","citation_count":15,"is_preprint":false},{"pmid":"31602628","id":"PMC_31602628","title":"Upregulation of Intestinal NLRP6 Inflammasomes After Roux-en-Y Gastric Bypass Promotes Gut Immune Homeostasis.","date":"2020","source":"Obesity surgery","url":"https://pubmed.ncbi.nlm.nih.gov/31602628","citation_count":14,"is_preprint":false},{"pmid":"33617596","id":"PMC_33617596","title":"NLRP6-associated host microbiota composition impacts in the intestinal barrier to systemic dissemination of Brucella abortus.","date":"2021","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/33617596","citation_count":14,"is_preprint":false},{"pmid":"31399193","id":"PMC_31399193","title":"microRNA-650 promotes inflammation induced apoptosis of intestinal epithelioid cells by targeting NLRP6.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31399193","citation_count":14,"is_preprint":false},{"pmid":"38341160","id":"PMC_38341160","title":"NLRP6 deficiency inhibits neuroinflammation and ameliorates brain injury in ischemic stroke by blocking NLRs inflammasomes activation through proteasomal degradation of pro-caspase-1.","date":"2024","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38341160","citation_count":13,"is_preprint":false},{"pmid":"38278335","id":"PMC_38278335","title":"NLRP6 deficiency suppresses colorectal cancer liver metastasis growth by modulating M-MDSC-induced immunosuppressive microenvironment.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38278335","citation_count":13,"is_preprint":false},{"pmid":"24147025","id":"PMC_24147025","title":"Sex-specific effects of NLRP6/AVR and ADM loci on susceptibility to essential hypertension in a Sardinian population.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24147025","citation_count":13,"is_preprint":false},{"pmid":"31152078","id":"PMC_31152078","title":"NLRP6 Deficiency in CD4 T Cells Decreases T Cell Survival Associated with Increased Cell Death.","date":"2019","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/31152078","citation_count":12,"is_preprint":false},{"pmid":"38146368","id":"PMC_38146368","title":"NLRP6 controls pulmonary inflammation from cigarette smoke in a gut microbiota-dependent manner.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38146368","citation_count":11,"is_preprint":false},{"pmid":"18413781","id":"PMC_18413781","title":"Overlapping genes in Nalp6/PYPAF5 locus encode two V2-type vasopressin isoreceptors: angiotensin-vasopressin receptor (AVR) and non-AVR.","date":"2008","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/18413781","citation_count":10,"is_preprint":false},{"pmid":"35615773","id":"PMC_35615773","title":"NLRP6 negatively regulates type 2 immune responses in mice.","date":"2022","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/35615773","citation_count":10,"is_preprint":false},{"pmid":"30663229","id":"PMC_30663229","title":"Corticotropin-releasing factor induces inflammatory cytokines via the NLRP6-inflammatory cytokine axis in a murine model of irritable bowel syndrome.","date":"2019","source":"Journal of digestive diseases","url":"https://pubmed.ncbi.nlm.nih.gov/30663229","citation_count":10,"is_preprint":false},{"pmid":"39879739","id":"PMC_39879739","title":"Methamphetamine-mediated astrocytic pyroptosis and neuroinflammation involves miR-152-NLRP6 inflammasome signaling axis.","date":"2025","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/39879739","citation_count":9,"is_preprint":false},{"pmid":"33376129","id":"PMC_33376129","title":"Tissue-selective alternate promoters guide NLRP6 expression.","date":"2020","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/33376129","citation_count":9,"is_preprint":false},{"pmid":"12633874","id":"PMC_12633874","title":"Identification of mammalian orthologs associates PYPAF5 with distinct functional roles.","date":"2003","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/12633874","citation_count":9,"is_preprint":false},{"pmid":"36911699","id":"PMC_36911699","title":"NLRP6 deficiency expands a novel CD103+ B cell population that confers immune tolerance in NOD mice.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36911699","citation_count":9,"is_preprint":false},{"pmid":"35694317","id":"PMC_35694317","title":"NLRP6 Serves as a Negative Regulator of Neutrophil Recruitment and Function During Streptococcus pneumoniae Infection.","date":"2022","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/35694317","citation_count":9,"is_preprint":false},{"pmid":"30262203","id":"PMC_30262203","title":"Reduced expression of the NLRP6 inflammasome in the colon of patients with Hirschsprung's disease.","date":"2018","source":"Journal of pediatric surgery","url":"https://pubmed.ncbi.nlm.nih.gov/30262203","citation_count":9,"is_preprint":false},{"pmid":"39522566","id":"PMC_39522566","title":"Ethanol modulates astrocyte activation and neuroinflammation via miR-339/NLRP6 inflammasome signaling.","date":"2024","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39522566","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51579,"output_tokens":9064,"usd":0.145348,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18946,"output_tokens":5514,"usd":0.11629,"stage2_stop_reason":"end_turn"},"total_usd":0.261638,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"NLRP6 (PYPAF5) co-expressed with the adaptor ASC synergistically activates NF-κB and recruits NLRP6 to punctate cytoplasmic structures; it also synergistically activates caspase-1-dependent cytokine processing when co-expressed with ASC, placing NLRP6 upstream of both NF-κB and caspase-1 in inflammatory signaling.\",\n      \"method\": \"Co-expression/overexpression assays in cells; NF-κB reporter assay; caspase-1 activity assay; subcellular colocalization imaging\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts (NF-κB, caspase-1, localization) in a single study; single lab, no in vitro reconstitution\",\n      \"pmids\": [\"12387869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NLRP6 inflammasome deficiency in colonic epithelial cells reduces IL-18 levels and alters fecal microbiota composition, establishing that NLRP6—acting together with ASC and caspase-1—controls IL-18 maturation and microbial ecology in the colon.\",\n      \"method\": \"Nlrp6-/- mouse model; IL-18 ELISA; 16S microbiome sequencing; cohousing/cross-fostering experiments; DSS colitis model\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods in vivo (KO, microbiome, cytokine measurement, cohousing transfer), replicated across genetic contexts\",\n      \"pmids\": [\"21565393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NLRP6 activity in hematopoietic cells is critical for protection against DSS-induced colitis and colitis-associated tumorigenesis, demonstrated by bone marrow chimera experiments.\",\n      \"method\": \"Nlrp6-/- mouse model; bone marrow chimera experiments; DSS colitis and azoxymethane/DSS tumorigenesis models\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chimera experiments define cellular compartment; single lab\",\n      \"pmids\": [\"21543645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NLRP6 negatively regulates TLR-triggered MAPK and canonical NF-κB signaling in macrophages and other cells; Nlrp6-deficient cells produce increased NF-κB- and MAPK-dependent cytokines/chemokines after TLR ligation but not after NOD1/2 ligation, placing NLRP6 specifically as an inhibitor of TLR-driven inflammatory signaling.\",\n      \"method\": \"Nlrp6-/- mouse model; in vitro TLR/NOD ligand stimulation assays; cytokine/chemokine measurement; phospho-MAPK/NF-κB western blot\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo and in vitro experiments; pathway specificity established by NOD1/2 negative control; published in Nature\",\n      \"pmids\": [\"22763455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The NLRP6 inflammasome controls goblet cell mucin granule exocytosis (Muc2 secretion) into the large intestinal lumen; NLRP6 deficiency leads to defective autophagy in goblet cells and abrogated mucus secretion, rendering mice unable to clear enteric pathogens from the mucosal surface.\",\n      \"method\": \"Nlrp6-/- mouse model; electron microscopy; goblet cell exocytosis assays; autophagy markers; enteric pathogen clearance assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct cellular phenotype (exocytosis, autophagy) linked to NLRP6 with multiple methods; replicated across infection models\",\n      \"pmids\": [\"24581500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NLRP6 binds viral RNA via the RNA helicase DHX15 and interacts with mitochondrial antiviral signaling protein (MAVS) to induce type I/III interferons and interferon-stimulated genes in intestinal cells, functioning as a viral RNA sensor independently of inflammasome activation.\",\n      \"method\": \"Nlrp6-/- mouse model; co-immunoprecipitation (NLRP6-DHX15-MAVS interaction); viral load measurement (EMCV, MNV); interferon/ISG measurement\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying binding partners, in vivo KO with defined phenotype, multiple virus models\",\n      \"pmids\": [\"26494172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A 'sentinel' goblet cell at the colonic crypt entrance activates the Nlrp6 inflammasome downstream of TLR- and MyD88-dependent Nox/Duox reactive oxygen species synthesis in response to TLR2/1, TLR4, and TLR5 ligands; this triggers calcium ion-dependent compound exocytosis of Muc2 mucin and propagates an intercellular gap junction signal to adjacent goblet cells.\",\n      \"method\": \"Live imaging of colonic tissue; TLR ligand stimulation; MyD88/Nox/Duox pathway inhibition; calcium signaling assays; Nlrp6-/- mice\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (imaging, genetic KO, pharmacological inhibition, pathway epistasis) in a rigorous single study\",\n      \"pmids\": [\"27339979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NLRP6 facilitates the interaction between TAB2/3 and the E3 ligase TRIM38 in rheumatoid arthritis fibroblast-like synoviocytes, promoting lysosome-dependent degradation of TAB2/3 and thereby suppressing NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation; NLRP6 overexpression in RA-FLS; NF-κB reporter assay; cytokine measurement; TAB2/3 degradation assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional overexpression with defined molecular mechanism; single lab\",\n      \"pmids\": [\"28295271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Lipoteichoic acid (LTA) from Gram-positive bacteria directly binds and activates NLRP6; cytosolic LTA triggers NLRP6 to recruit caspase-11 and caspase-1 via the adaptor ASC, leading to caspase-11 processing, caspase-1 activation, and IL-1β/IL-18 maturation in macrophages.\",\n      \"method\": \"LTA binding assay; Nlrp6-/- and Casp11-/- mouse infection models; caspase-1/11 processing assays; IL-18 reconstitution experiment (IL-18 administration rescuing susceptibility phenotype)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct ligand binding established, caspase recruitment complex defined biochemically, in vivo rescue with IL-18 confirms pathway; published in Cell\",\n      \"pmids\": [\"30392956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NLRP6 PYD alone self-assembles into filamentous structures with large conformational changes and recruits ASC via PYD-PYD interactions; full-length NLRP6 assembles into wider filaments with a PYD core surrounded by NBD and LRR domains; MD simulations identified the surface used by NLRP6 PYD filaments to recruit ASC PYD.\",\n      \"method\": \"Cryo-EM; X-ray crystallography of NLRP6 PYD; molecular dynamics simulations; in vitro filament assembly assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure + cryo-EM + in vitro reconstitution of filament assembly, multiple complementary structural methods in one study\",\n      \"pmids\": [\"30674671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NLRP6 deficiency in kidney tubular epithelial cells results in upregulation of ERK1/2 and p38 MAPK phosphorylation and increased chemokine expression; MAPK inhibition prevented the inflammatory response in Nlrp6-deficient cells, establishing NLRP6 as a suppressor of MAP kinase signaling in sterile renal inflammation.\",\n      \"method\": \"Nlrp6-/- mice; cisplatin/folic acid AKI models; siRNA knockdown in cultured tubular cells; phospho-MAPK western blot; MAPK inhibitor experiments\",\n      \"journal\": \"Nephrology, dialysis, transplantation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO and in vitro siRNA with pharmacological rescue; single lab, two model systems\",\n      \"pmids\": [\"31504777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The deubiquitinase CYLD deubiquitinates NLRP6, and this deubiquitination inhibits the NLRP6-ASC inflammasome complex, reducing IL-18 maturation; CYLD deficiency leads to elevated active IL-18 and severe colonic inflammation.\",\n      \"method\": \"Co-immunoprecipitation of CYLD-NLRP6; ubiquitination assays; Cyld-/- mouse colitis model; IL-18 ELISA; patient samples (CYLD/IL-18 inverse correlation)\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, in vivo KO with defined phenotype, and human correlative validation; multiple orthogonal approaches\",\n      \"pmids\": [\"32424362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NLRP6 deficiency in CD4+ T cells increases caspase-1 activation and cell death following adoptive transfer, indicating that NLRP6 promotes T cell survival in an inflammasome-dependent manner.\",\n      \"method\": \"Nlrp6-/- CD4+ T cell adoptive transfer into Rag2-/- mice; caspase-1 activation assay; cell death measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — adoptive transfer with defined cellular phenotype; single lab, single method for mechanism\",\n      \"pmids\": [\"31152078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NLRP6 undergoes liquid-liquid phase separation (LLPS) upon interaction with double-stranded RNA (dsRNA) in vitro and in cells; an intrinsically disordered poly-lysine sequence (K350-354) is required for multivalent interactions, phase separation, and inflammasome activation. Recruitment of ASC via helical assembly solidifies NLRP6 condensates, and ASC further recruits and activates caspase-1. LTA also promotes NLRP6 LLPS, and DHX15 co-forms condensates with NLRP6 and dsRNA.\",\n      \"method\": \"In vitro LLPS assay with purified NLRP6 and dsRNA; live-cell imaging of condensate formation; Nlrp6K350-354A knock-in mice; mouse hepatitis virus and rotavirus infection models; cryo-EM/structural analysis of ASC helical assembly\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of LLPS, mutagenesis (K350-354A knock-in), multiple ligands tested, in vivo validation; published in Cell\",\n      \"pmids\": [\"34678144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NLRP6 is the only NLR required for inflammasome-dependent innate control of Cryptosporidium infection in enterocytes; enterocyte-specific caspase-1 deletion phenocopies whole-body KO, and the response is sufficient in germ-free mice, establishing an enterocyte-intrinsic NLRP6-caspase-1-IL-18 axis for anti-parasite defense.\",\n      \"method\": \"Nlrp6-/- mouse infection model with C. tyzzeri; conditional caspase-1 KO in enterocytes; germ-free mouse experiments; IL-18 KO and recombinant IL-18 rescue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO, germ-free control, cytokine rescue experiment; multiple orthogonal genetic approaches\",\n      \"pmids\": [\"33372132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of Nlrp6 leads to strongly impaired nerve function upon sciatic nerve crush, but loss of the inflammasome adaptor ASC and caspase-1/11 did not affect nerve function, establishing that Nlrp6 promotes recovery after peripheral nerve injury independently of inflammasomes; Nlrp6 deficiency was associated with increased pro-inflammatory ERK signaling.\",\n      \"method\": \"Nlrp6-/-, ASC-/-, Casp1/11-/- mouse sciatic nerve crush models; functional nerve assessment; ERK phosphorylation western blot; IL-1β measurement\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple KO lines establishes inflammasome independence; single lab\",\n      \"pmids\": [\"26253422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NLRP6 is upregulated in Ly6C-hi inflammatory monocytes infiltrating the colon during DSS-induced inflammation; adoptive transfer of WT Ly6C-hi monocytes into Nlrp6-/- mice protects from mortality and reduces intestinal permeability; NLRP6-deficient monocytes are defective in TNFα production, which depends on autocrine IL-18 signaling.\",\n      \"method\": \"Flow cytometry; adoptive transfer of Ly6C-hi monocytes; Nlrp6-/- mice; IL-18 and TNFα measurement; intestinal permeability assay\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — adoptive transfer rescue, autocrine signaling mechanism defined; single lab\",\n      \"pmids\": [\"27353251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NLRP6 overexpression in rheumatoid arthritis fibroblast-like synoviocytes inhibits NF-κB and ERK signaling, reducing IL-6 and TNF-α production; NLRP6 knockdown enhances NF-κB and ERK activation and upregulates NLRP3 and Pro-IL-1β while downregulating ASC.\",\n      \"method\": \"NLRP6 overexpression and siRNA knockdown in HPDLCs; NF-κB and ERK western blot; cytokine ELISA; qRT-PCR\",\n      \"journal\": \"International endodontic journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method set (overexpression/knockdown with reporter assays), no in vitro reconstitution\",\n      \"pmids\": [\"30712265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NLRP6 overexpression in gingival fibroblasts activates caspase-1 and gasdermin-D and induces pyroptosis with release of IL-1β and IL-18; Porphyromonas gingivalis triggers NLRP6-dependent pyroptosis.\",\n      \"method\": \"NLRP6 overexpression in human gingival fibroblasts; caspase-1 and GSDMD activation assays; IL-1β/IL-18 ELISA; P. gingivalis infection\",\n      \"journal\": \"Journal of dental research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression without loss-of-function confirmation or in vitro reconstitution\",\n      \"pmids\": [\"29791256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NLRP6 suppresses gastric cancer cell growth by binding GRP78 through its Pyrin domain (while the SBD domain of GRP78 mediates binding to NLRP6) and promoting polyubiquitination and degradation of GRP78; GRP78 overexpression abolishes NLRP6-mediated growth suppression.\",\n      \"method\": \"Flag-tagged immunoprecipitation + LC-MS proteomics to identify GRP78 as NLRP6 interactor; domain mapping by co-IP; ubiquitination assay; GRP78 overexpression/knockdown rescue experiments; xenograft tumor model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interactome + Co-IP domain mapping + functional rescue; single lab\",\n      \"pmids\": [\"32682010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Alternative promoter utilization determines NLRP6 expression in a tissue-selective manner: human NLRP6 contains an internal alternative promoter within exon 2 of the PYD resulting in a truncated, translationally silenced mRNA in non-intestinal tissue; in mice, a proximal promoter expands the 5' leader sequence restricting nuclear export and abolishing translational efficiency.\",\n      \"method\": \"Promoter reporter assays; 5' RACE; polysome profiling; nuclear/cytoplasmic fractionation; Nlrp6-/- mice in kidney disease models (negative functional result outside intestine)\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple molecular biology methods defining promoter usage and translational control; single lab\",\n      \"pmids\": [\"33376129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In inflamed dental pulp cells, cytosolic Streptococcus mutans LTA activates an NLRP6-caspase-4 inflammasome complex (distinct from NLRP3); knockdown of NLRP6 or CASP4, or the caspase-4 inhibitor Ac-FLTD-CMK (but not the NLRP3 inhibitor MCC950), suppresses this LTA-triggered inflammasome activation.\",\n      \"method\": \"siRNA knockdown of NLRP6 and CASP4; pharmacological inhibitors (Ac-FLTD-CMK, MCC950); western blot and ELISA for inflammasome activation; LTA cytosolic delivery assay\",\n      \"journal\": \"International endodontic journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA + pharmacological inhibitor epistasis identifying NLRP6-caspase-4 as the relevant complex; single lab\",\n      \"pmids\": [\"33377178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The E3 ligase TRIM29 promotes K48-linked ubiquitination of NLRP6 (and NLRP9b), leading to their proteasomal degradation and decreased IFN-λ and IL-18 production by intestinal epithelial cells; TRIM29-deficient mice show increased NLRP6 and NLRP9b protein levels and restricted intestinal inflammation upon enteric RNA virus challenge.\",\n      \"method\": \"TRIM29-/- mice; rotavirus and EMCV intestinal infection models; K48-ubiquitination assay; Co-IP of TRIM29-NLRP6; IFN-λ and IL-18 measurement\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + ubiquitination assay + in vivo KO with defined phenotype; single lab\",\n      \"pmids\": [\"39396665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Estrogen receptor β (ERβ) directly activates NLRP6 gene expression by binding to estrogen responsive elements in the Nlrp6 promoter and also physically interacts with the NLRP6 nucleotide-binding domain to promote inflammasome assembly; the ERβ-NLRP6 axis then interacts with autophagy-related proteins (ULK1, BECN1, ATG16L1, LC3B, p62) and promotes K48-linked polyubiquitination and degradation of ASC, Casp-1 p20, IL-1β, TNF-α, and prohibitin-2 to suppress inflammation.\",\n      \"method\": \"ChIP assay (ERβ binding to Nlrp6 promoter); Co-IP (ERβ-NLRP6 NDB interaction); autophagy flux assays; ubiquitination assays; ERβ/NLRP6 KO mouse colitis models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + Co-IP + ubiquitination assay + in vivo KO; single lab, multiple methods\",\n      \"pmids\": [\"36223738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NLRP6 inflammasome activation leads to caspase-1 activation, GSDMD cleavage, ASC oligomerization, and IL-1β/IL-18 maturation in macrophages infected with Streptococcus pneumoniae; NLRP6 activation simultaneously reduces NF-κB and ERK signaling in S. pneumoniae-infected macrophages.\",\n      \"method\": \"Nlrp6-/- macrophages; caspase-1/11 and GSDMD western blot; ASC oligomerization assay; NF-κB/ERK western blot; IL-1β maturation assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical readouts in KO macrophages; single lab\",\n      \"pmids\": [\"33918100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NLRP6 potentiates PI3K/AKT signaling by binding p85α (the regulatory subunit of PI3K) and recruiting the E3 ligase RBX1 to ubiquitinate p85α at lysine 256; ubiquitinated p85α is recognized by the autophagy cargo receptor OPTN, causing selective autophagic degradation of p85α and subsequent AKT activation with reduced PTEN stability.\",\n      \"method\": \"Co-IP of NLRP6-p85α-RBX1; K256 ubiquitination site mutagenesis; OPTN pulldown; autophagic flux assays; NLRP6 KO in glioblastoma cells; in vivo tumor growth; Pep9 peptide disruption of NLRP6/p85α interaction\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-specific mutagenesis, Co-IP, cargo receptor identification, in vivo tumor model, peptide inhibitor; multiple orthogonal methods in one study\",\n      \"pmids\": [\"37770465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NLRP6 deficiency in hippocampal neural stem cells (NSCs) causes increased expression of ECRG4 and mitochondrial dysfunction; corticosterone downregulates NLRP6 and promotes ECRG4-mediated mitochondrial dysfunction and NSC proliferation suppression; NLRP6 is required for NSC proliferation and hippocampal neurogenesis to sustain stress resilience.\",\n      \"method\": \"Nlrp6-/- and NSC-conditional Nlrp6CKO mice; ECRG4 knockdown rescue; mitochondrial function assays; NSC proliferation assays; corticosterone treatment; NLRP6 overexpression rescue\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO + genetic rescue + mechanistic pathway delineation; single lab\",\n      \"pmids\": [\"37250149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nlrp6 acts as a sensor for RIG-1/MAVS-mediated mitophagy in hippocampal NSCs; Nlrp6 deficiency suppresses RIG-1/MAVS-mediated autophagy and drives ferroptotic cell death; short-chain fatty acids (SCFAs) upregulate Nlrp6 and promote RIG-1/MAVS-mediated mitophagy, preventing corticosterone-induced NSPC ferroptosis.\",\n      \"method\": \"siNlrp6 transfection; RIG-1/MAVS pathway assays; mitophagy/autophagy flux assays; ferroptosis markers; SCFA treatment\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — siRNA knockdown with pathway assays; single lab, limited mechanistic validation of direct NLRP6-RIG-1/MAVS interaction\",\n      \"pmids\": [\"38772149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NLRP6 in hepatic stellate cells (LX-2) suppresses TGF-β1/Smad2/3 signaling by forming a complex with the Smad2/3 phosphatase PPM1A; NLRP6 overexpression enhances PPM1A expression and reduces p-Smad2/3; PPM1A knockdown abolishes the anti-fibrotic effects of NLRP6 overexpression.\",\n      \"method\": \"Co-immunoprecipitation (NLRP6-PPM1A complex); NLRP6 overexpression/knockdown in LX-2 cells; p-Smad2/3 western blot; PPM1A siRNA rescue experiment\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + genetic epistasis (siRNA rescue) defines PPM1A-dependent mechanism; single lab\",\n      \"pmids\": [\"29966662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nlrp6 deficiency in hepatocytes promotes CD36-mediated lipid uptake and increases NF-κB phosphorylation; Nlrp6 promotes lysosomal-dependent degradation of TAB2/3 to suppress NF-κB activation; CD36 inhibition blocks the enhanced fatty acid uptake caused by Nlrp6 deficiency.\",\n      \"method\": \"Hepatocyte-specific Nlrp6-/- mice; HFD/MCD diet models; CD36 inhibitor experiment; TAB2/3 lysosomal degradation assay; NF-κB phosphorylation western blot\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO + pharmacological rescue + lysosomal degradation mechanism; single lab\",\n      \"pmids\": [\"33857628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In platelets, NLRP6 facilitates the interaction between TRIM21 and TAB1, resulting in K48-linked polyubiquitination and degradation of TAB1, thereby suppressing NF-κB signaling; NLRP6 deletion promotes platelet NF-κB signaling via sustained TAB1 expression independently of the inflammasome; TLR4/MyD88 signaling in platelets triggers this NLRP6/TRIM21/TAB1 axis.\",\n      \"method\": \"Platelet-specific Nlrp6-/- mice; cecal ligation and puncture sepsis model; Co-IP of NLRP6-TRIM21-TAB1; K48-ubiquitination assay; NF-κB inhibitor rescue; platelet aggregation/activation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP + ubiquitination assay + cell-type-specific KO + pharmacological rescue + in vivo model; multiple orthogonal approaches\",\n      \"pmids\": [\"40373277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BRCC3 (BRCC36 homolog) physically interacts with NLRP6 (both N- and C-terminals), reduces NLRP6 ubiquitination, and affects the NLRP6-ASC interaction, thereby promoting NLRP6 inflammasome activation; BRCC3 knockdown reduces NLRP6-dependent caspase-1 cleavage and IL-1β in cerebral I/R injury.\",\n      \"method\": \"Co-immunoprecipitation (BRCC3-NLRP6); ubiquitination assay; BRCC3 siRNA in MCAO and OGD/R models; NLRP6-ASC interaction assay\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + ubiquitination assay + siRNA with in vivo and in vitro validation; single lab\",\n      \"pmids\": [\"38544474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NLRP6 deficiency in microglia blocks multiple NLR inflammasome activations by reducing pro-caspase-1 protein levels through induction of proteasomal degradation of pro-caspase-1, thereby preventing neuroinflammation in ischemic stroke.\",\n      \"method\": \"Nlrp6-/- mice; MCAO model; OGD/R co-culture model; proteasome inhibitor assay; pro-caspase-1 protein stability assay; multiple inflammasome activation markers\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vivo KO with proteasome inhibitor experiment; indirect evidence for proteasomal mechanism; single lab\",\n      \"pmids\": [\"38341160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NLRP3, NLRP6, and NLRP12 PYD domains activate caspase-1 to induce IL-1β cleavage and GSDMD cleavage; full-length NLRP6 reconstituted in vitro forms a functional inflammasome and is more prone to auto-activation than NLRP12; NLRP6 is specifically expressed in intestinal epithelial cells but not immune cells.\",\n      \"method\": \"In vitro inflammasome reconstitution; PYD domain screen for caspase-1 activation; cell fractionation/expression profiling; IL-1β and GSDMD cleavage assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution confirms inflammasome formation; single study, limited replication\",\n      \"pmids\": [\"39076995\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NLRP6 is a cytosolic NLR family sensor that, upon activation by ligands including lipoteichoic acid (LTA) or dsRNA, undergoes liquid-liquid phase separation and assembles PYD filaments that recruit ASC (via PYD-PYD interactions) and caspase-1/caspase-11 to form a functional inflammasome that cleaves IL-1β and IL-18 and activates gasdermin D-dependent pyroptosis; independently of inflammasome assembly, NLRP6 interacts with DHX15 and MAVS to induce antiviral interferon signaling, negatively regulates TLR-driven NF-κB and MAPK signaling (partly via promoting TAB2/3 lysosomal degradation), controls goblet cell Muc2 mucin exocytosis through autophagy regulation, and is itself post-translationally regulated by CYLD-mediated deubiquitination (inhibitory) and TRIM29/TRIM21-mediated K48-ubiquitination (degradative); its expression is tissue-restricted through alternative promoter usage that silences translation outside the intestine.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NLRP6 is a cytosolic NLR-family pattern sensor that nucleates an ASC/caspase-1 inflammasome and operates predominantly in the intestinal epithelium, where it links microbial sensing to IL-18 maturation, mucosal defense, and host–microbiota homeostasis [#1, #8, #33]. Upon engagement by ligands such as Gram-positive lipoteichoic acid or double-stranded RNA, NLRP6 undergoes liquid-liquid phase separation driven by an intrinsically disordered poly-lysine segment (K350-354) and assembles PYD filaments that recruit ASC through PYD-PYD interactions; ASC oligomerization solidifies the condensate and recruits caspase-1 (and caspase-11/caspase-4) to drive IL-1β/IL-18 processing and gasdermin-D-dependent pyroptosis [#8, #9, #13, #18, #21]. Through this inflammasome-IL-18 axis NLRP6 shapes colonic microbial ecology, controls goblet-cell autophagy and Muc2 mucin exocytosis, and mediates enterocyte-intrinsic defense against enteric pathogens including Cryptosporidium [#1, #4, #6, #14]. Independently of inflammasome assembly, NLRP6 senses viral RNA via the helicase DHX15 and engages MAVS to induce type I/III interferon responses, and it functions as a negative regulator of TLR-driven NF-κB and MAPK signaling, in part by promoting lysosomal or ubiquitin-dependent degradation of TAB2/3 and TAB1 [#3, #5, #29, #30]. NLRP6 activity is set by post-translational control—CYLD-mediated deubiquitination restrains inflammasome activity while TRIM29- and TRIM21-directed K48 ubiquitination targets it for degradation—and its tissue-restricted expression is enforced by alternative promoter usage that silences translation outside the intestine [#11, #20, #22, #30]. Beyond these core functions, NLRP6 has been linked to scaffolding roles in PI3K/AKT signaling and substrate degradation in non-intestinal tissues [#25].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the first functional placement of NLRP6, showing it cooperates with the adaptor ASC to drive both NF-κB and caspase-1 activation, positioning it upstream in inflammatory signaling.\",\n      \"evidence\": \"Co-expression with ASC, NF-κB reporter, caspase-1 activity, and colocalization imaging in cells\",\n      \"pmids\": [\"12387869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No endogenous ligand identified\", \"Overexpression-based; physiological context unknown\", \"No structural basis for ASC recruitment\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined NLRP6 as an in vivo regulator of colonic IL-18 maturation and microbiota composition, connecting the inflammasome to host–microbe homeostasis and colitis susceptibility.\",\n      \"evidence\": \"Nlrp6-/- mice with IL-18 ELISA, 16S microbiome sequencing, cohousing/cross-fostering, and DSS colitis; bone marrow chimeras for compartment mapping\",\n      \"pmids\": [\"21565393\", \"21543645\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct activating ligand not yet defined\", \"Mechanism linking IL-18 to microbiota composition unresolved\", \"Relative epithelial vs hematopoietic contribution debated across studies\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed an inflammasome-independent function: NLRP6 selectively dampens TLR-triggered NF-κB and MAPK signaling, establishing a negative-regulatory role distinct from inflammasome assembly.\",\n      \"evidence\": \"Nlrp6-/- macrophages with TLR vs NOD ligand stimulation, cytokine measurement, and phospho-MAPK/NF-κB blots\",\n      \"pmids\": [\"22763455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target of suppression not yet identified in this study\", \"Reconciliation with pro-inflammasome role unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked NLRP6 to goblet-cell biology, showing it controls autophagy-dependent Muc2 mucin exocytosis required to clear enteric pathogens.\",\n      \"evidence\": \"Nlrp6-/- mice with electron microscopy, exocytosis assays, autophagy markers, and pathogen clearance\",\n      \"pmids\": [\"24581500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How inflammasome activity couples to autophagy machinery not defined\", \"Direct molecular link to exocytic machinery unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a non-inflammasome antiviral function, showing NLRP6 binds viral RNA via DHX15 and engages MAVS to induce interferons; a parallel study showed inflammasome-independent promotion of peripheral nerve recovery.\",\n      \"evidence\": \"Nlrp6-/- mice, reciprocal Co-IP of NLRP6-DHX15-MAVS, virus models; sciatic nerve crush in Nlrp6/ASC/Casp1-11 KO lines\",\n      \"pmids\": [\"26494172\", \"26253422\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of DHX15/MAVS engagement not resolved\", \"Mechanism of nerve-recovery role beyond ERK association unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the cellular circuitry of mucin secretion: a sentinel goblet cell activates the Nlrp6 inflammasome downstream of TLR-MyD88-Nox/Duox ROS to trigger calcium-dependent compound Muc2 exocytosis and gap-junction signaling; inflammatory monocytes were also shown to require NLRP6 for protective autocrine IL-18/TNFα responses.\",\n      \"evidence\": \"Live colonic-tissue imaging, pathway inhibition, calcium assays, Nlrp6-/- mice; Ly6C-hi monocyte adoptive transfer with cytokine measurement\",\n      \"pmids\": [\"27339979\", \"27353251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct upstream activating ligand in sentinel cells not biochemically defined\", \"How ROS connects to NLRP6 activation unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided a molecular mechanism for NF-κB suppression in a peripheral tissue, showing NLRP6 bridges TAB2/3 to the E3 ligase TRIM38 for lysosomal degradation.\",\n      \"evidence\": \"Co-IP, NLRP6 overexpression in RA-FLS, NF-κB reporter and TAB2/3 degradation assays; overexpression/knockdown in HPDLCs\",\n      \"pmids\": [\"28295271\", \"30712265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression-based; endogenous relevance not fully established\", \"Tissue specificity of the TAB2/3-TRIM38 axis unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified lipoteichoic acid as a direct NLRP6 ligand and defined caspase recruitment, providing the first biochemical agonist for the inflammasome and demonstrating IL-18-dependent host defense.\",\n      \"evidence\": \"LTA binding assay, Nlrp6-/- and Casp11-/- infection models, caspase processing, and IL-18 rescue; overexpression-induced pyroptosis in gingival fibroblasts\",\n      \"pmids\": [\"30392956\", \"29791256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural details of LTA binding not resolved\", \"Selectivity for caspase-11 vs caspase-1 across cell types unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the structural basis of inflammasome nucleation, showing NLRP6 PYD self-assembles into filaments that recruit ASC PYD, and full-length NLRP6 forms wider PYD-core filaments; a parallel study extended NLRP6's MAPK-suppressive role to renal tubular inflammation.\",\n      \"evidence\": \"Cryo-EM, X-ray crystallography, MD simulations, in vitro filament assembly; Nlrp6-/- AKI models with phospho-MAPK and inhibitor experiments\",\n      \"pmids\": [\"30674671\", \"31504777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger that converts inactive NLRP6 to filament-competent state in vivo not defined\", \"Renal phenotype later complicated by tissue-restricted translation findings\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established post-translational and transcriptional control of NLRP6: CYLD deubiquitination restrains the inflammasome, and alternative-promoter usage translationally silences NLRP6 outside the intestine, explaining its tissue-restricted activity; additional work linked NLRP6 to GRP78 degradation and T-cell survival.\",\n      \"evidence\": \"CYLD-NLRP6 Co-IP, ubiquitination assays, Cyld-/- colitis, patient correlation; promoter reporters, 5' RACE, polysome profiling; LC-MS interactome with GRP78 and xenografts; CD4+ T cell adoptive transfer\",\n      \"pmids\": [\"32424362\", \"33376129\", \"32682010\", \"31152078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CYLD-targeted ubiquitin marks gate filament assembly unclear\", \"Reconciling functional reports in non-intestinal tissues with translational silencing remains open\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that NLRP6 activation proceeds through liquid-liquid phase separation driven by a poly-lysine segment and ligand binding (dsRNA, LTA), unifying ligand sensing, condensate formation, and ASC/caspase recruitment into a single activation mechanism; the enterocyte-intrinsic NLRP6-caspase-1-IL-18 axis was shown sufficient for anti-Cryptosporidium defense.\",\n      \"evidence\": \"In vitro LLPS with purified NLRP6 and dsRNA, K350-354A knock-in mice, virus models, cryo-EM of ASC assembly; enterocyte-specific caspase-1 KO and germ-free/IL-18 rescue\",\n      \"pmids\": [\"34678144\", \"33372132\", \"33377178\", \"33918100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How distinct ligands converge on the same condensate not fully mapped\", \"In vivo regulation of condensate dissolution unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected NLRP6 to hormonal and autophagic regulation, showing ERβ transcriptionally induces and physically binds NLRP6 to drive autophagy-coupled K48 ubiquitination and degradation of inflammatory components.\",\n      \"evidence\": \"ChIP, Co-IP, autophagy flux and ubiquitination assays, ERβ/NLRP6 KO colitis models\",\n      \"pmids\": [\"36223738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect ubiquitination of multiple substrates unresolved\", \"Generalizability beyond colitis context unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a scaffolding role in growth signaling, showing NLRP6 recruits RBX1 to ubiquitinate PI3K p85α at K256 for OPTN-dependent autophagic degradation, thereby activating AKT in tumor cells.\",\n      \"evidence\": \"Co-IP, K256 site mutagenesis, OPTN pulldown, autophagic flux, glioblastoma KO, in vivo tumor model, and Pep9 peptide disruption; NSC studies on ECRG4/mitochondrial function\",\n      \"pmids\": [\"37770465\", \"37250149\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How this scaffolding activity relates to NLR sensing domains unclear\", \"Tissue contexts permitting NLRP6 expression for this role not reconciled with translational silencing\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended NLRP6's ubiquitin-adaptor logic to negative regulation of NF-κB in platelets, showing it bridges TRIM21 to TAB1 for K48 degradation independently of the inflammasome.\",\n      \"evidence\": \"Platelet-specific Nlrp6-/- mice, CLP sepsis model, Co-IP of NLRP6-TRIM21-TAB1, K48-ubiquitination and NF-κB inhibitor rescue; TRIM29/BRCC3 regulation and microglial caspase-1 control in earlier reports\",\n      \"pmids\": [\"40373277\", \"39396665\", \"38544474\", \"38341160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether platelet NLRP6 expression escapes intestinal translational restriction not addressed\", \"Common structural determinant for the various ubiquitin-ligase bridging functions undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single NLRP6 protein reconciles its tissue-restricted intestinal translation with the wide range of functions reported in non-intestinal tissues, and what unified structural switch governs its choice between inflammasome assembly, antiviral signaling, and ubiquitin-adaptor scaffolding.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of full-length ligand-bound NLRP6 in an activated complex\", \"Mechanism partitioning inflammasome vs non-inflammasome outputs unknown\", \"Endogenous expression in non-intestinal tissues not reconciled with translational silencing data\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8, 33]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [5, 13]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [25, 30]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 8, 5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [13, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 30, 25]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4, 25]}\n    ],\n    \"complexes\": [\n      \"NLRP6-ASC-caspase-1 inflammasome\",\n      \"NLRP6-DHX15-MAVS antiviral complex\"\n    ],\n    \"partners\": [\n      \"ASC\",\n      \"DHX15\",\n      \"MAVS\",\n      \"CYLD\",\n      \"TRIM29\",\n      \"TRIM21\",\n      \"PPM1A\",\n      \"GRP78\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}