Affinage

NLRP6

NACHT, LRR and PYD domains-containing protein 6 · UniProt P59044

Length
892 aa
Mass
98.8 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2002 Medium

    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

    PMID:12387869

    Open questions at the time
    • No endogenous ligand identified
    • Overexpression-based; physiological context unknown
    • No structural basis for ASC recruitment
  2. 2011 High

    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

    PMID:21543645 PMID:21565393

    Open questions at the time
    • Direct activating ligand not yet defined
    • Mechanism linking IL-18 to microbiota composition unresolved
    • Relative epithelial vs hematopoietic contribution debated across studies
  3. 2012 High

    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

    PMID:22763455

    Open questions at the time
    • Molecular target of suppression not yet identified in this study
    • Reconciliation with pro-inflammasome role unclear
  4. 2014 High

    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

    PMID:24581500

    Open questions at the time
    • How inflammasome activity couples to autophagy machinery not defined
    • Direct molecular link to exocytic machinery unknown
  5. 2015 High

    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

    PMID:26253422 PMID:26494172

    Open questions at the time
    • Structural basis of DHX15/MAVS engagement not resolved
    • Mechanism of nerve-recovery role beyond ERK association unknown
  6. 2016 High

    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

    PMID:27339979 PMID:27353251

    Open questions at the time
    • Direct upstream activating ligand in sentinel cells not biochemically defined
    • How ROS connects to NLRP6 activation unresolved
  7. 2017 Medium

    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

    PMID:28295271 PMID:30712265

    Open questions at the time
    • Overexpression-based; endogenous relevance not fully established
    • Tissue specificity of the TAB2/3-TRIM38 axis unclear
  8. 2018 High

    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

    PMID:29791256 PMID:30392956

    Open questions at the time
    • Stoichiometry and structural details of LTA binding not resolved
    • Selectivity for caspase-11 vs caspase-1 across cell types unclear
  9. 2019 High

    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

    PMID:30674671 PMID:31504777

    Open questions at the time
    • Trigger that converts inactive NLRP6 to filament-competent state in vivo not defined
    • Renal phenotype later complicated by tissue-restricted translation findings
  10. 2020 High

    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

    PMID:31152078 PMID:32424362 PMID:32682010 PMID:33376129

    Open questions at the time
    • How CYLD-targeted ubiquitin marks gate filament assembly unclear
    • Reconciling functional reports in non-intestinal tissues with translational silencing remains open
  11. 2021 High

    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

    PMID:33372132 PMID:33377178 PMID:33918100 PMID:34678144

    Open questions at the time
    • How distinct ligands converge on the same condensate not fully mapped
    • In vivo regulation of condensate dissolution unknown
  12. 2022 Medium

    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

    PMID:36223738

    Open questions at the time
    • Direct vs indirect ubiquitination of multiple substrates unresolved
    • Generalizability beyond colitis context unclear
  13. 2023 High

    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

    PMID:37250149 PMID:37770465

    Open questions at the time
    • How this scaffolding activity relates to NLR sensing domains unclear
    • Tissue contexts permitting NLRP6 expression for this role not reconciled with translational silencing
  14. 2025 High

    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

    PMID:38341160 PMID:38544474 PMID:39396665 PMID:40373277

    Open questions at the time
    • Whether platelet NLRP6 expression escapes intestinal translational restriction not addressed
    • Common structural determinant for the various ubiquitin-ligase bridging functions undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0060089 molecular transducer activity 2 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 2
Partners
ASCCYLDDHX15GRP78MAVSPPM1ATRIM21TRIM29
Complex memberships
NLRP6-ASC-caspase-1 inflammasomeNLRP6-DHX15-MAVS antiviral complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 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. Co-expression/overexpression assays in cells; NF-κB reporter assay; caspase-1 activity assay; subcellular colocalization imaging FEBS letters Medium 12387869
2011 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. Nlrp6-/- mouse model; IL-18 ELISA; 16S microbiome sequencing; cohousing/cross-fostering experiments; DSS colitis model Cell High 21565393
2011 NLRP6 activity in hematopoietic cells is critical for protection against DSS-induced colitis and colitis-associated tumorigenesis, demonstrated by bone marrow chimera experiments. Nlrp6-/- mouse model; bone marrow chimera experiments; DSS colitis and azoxymethane/DSS tumorigenesis models Journal of immunology Medium 21543645
2012 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. Nlrp6-/- mouse model; in vitro TLR/NOD ligand stimulation assays; cytokine/chemokine measurement; phospho-MAPK/NF-κB western blot Nature High 22763455
2014 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. Nlrp6-/- mouse model; electron microscopy; goblet cell exocytosis assays; autophagy markers; enteric pathogen clearance assays Cell High 24581500
2015 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. Nlrp6-/- mouse model; co-immunoprecipitation (NLRP6-DHX15-MAVS interaction); viral load measurement (EMCV, MNV); interferon/ISG measurement Science High 26494172
2016 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. Live imaging of colonic tissue; TLR ligand stimulation; MyD88/Nox/Duox pathway inhibition; calcium signaling assays; Nlrp6-/- mice Science High 27339979
2017 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. Co-immunoprecipitation; NLRP6 overexpression in RA-FLS; NF-κB reporter assay; cytokine measurement; TAB2/3 degradation assay FEBS letters Medium 28295271
2018 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. LTA binding assay; Nlrp6-/- and Casp11-/- mouse infection models; caspase-1/11 processing assays; IL-18 reconstitution experiment (IL-18 administration rescuing susceptibility phenotype) Cell High 30392956
2019 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. Cryo-EM; X-ray crystallography of NLRP6 PYD; molecular dynamics simulations; in vitro filament assembly assays Proceedings of the National Academy of Sciences High 30674671
2019 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. Nlrp6-/- mice; cisplatin/folic acid AKI models; siRNA knockdown in cultured tubular cells; phospho-MAPK western blot; MAPK inhibitor experiments Nephrology, dialysis, transplantation Medium 31504777
2020 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. Co-immunoprecipitation of CYLD-NLRP6; ubiquitination assays; Cyld-/- mouse colitis model; IL-18 ELISA; patient samples (CYLD/IL-18 inverse correlation) Nature immunology High 32424362
2020 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. Nlrp6-/- CD4+ T cell adoptive transfer into Rag2-/- mice; caspase-1 activation assay; cell death measurement Journal of immunology Medium 31152078
2021 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. 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 Cell High 34678144
2021 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. 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 Proceedings of the National Academy of Sciences High 33372132
2015 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. Nlrp6-/-, ASC-/-, Casp1/11-/- mouse sciatic nerve crush models; functional nerve assessment; ERK phosphorylation western blot; IL-1β measurement Journal of neuroinflammation Medium 26253422
2016 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. Flow cytometry; adoptive transfer of Ly6C-hi monocytes; Nlrp6-/- mice; IL-18 and TNFα measurement; intestinal permeability assay Mucosal immunology Medium 27353251
2017 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. NLRP6 overexpression and siRNA knockdown in HPDLCs; NF-κB and ERK western blot; cytokine ELISA; qRT-PCR International endodontic journal Low 30712265
2018 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. NLRP6 overexpression in human gingival fibroblasts; caspase-1 and GSDMD activation assays; IL-1β/IL-18 ELISA; P. gingivalis infection Journal of dental research Low 29791256
2020 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. 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 Experimental cell research Medium 32682010
2020 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. Promoter reporter assays; 5' RACE; polysome profiling; nuclear/cytoplasmic fractionation; Nlrp6-/- mice in kidney disease models (negative functional result outside intestine) Life science alliance Medium 33376129
2021 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. siRNA knockdown of NLRP6 and CASP4; pharmacological inhibitors (Ac-FLTD-CMK, MCC950); western blot and ELISA for inflammasome activation; LTA cytosolic delivery assay International endodontic journal Medium 33377178
2021 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. TRIM29-/- mice; rotavirus and EMCV intestinal infection models; K48-ubiquitination assay; Co-IP of TRIM29-NLRP6; IFN-λ and IL-18 measurement Mucosal immunology Medium 39396665
2022 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. ChIP assay (ERβ binding to Nlrp6 promoter); Co-IP (ERβ-NLRP6 NDB interaction); autophagy flux assays; ubiquitination assays; ERβ/NLRP6 KO mouse colitis models Cell reports Medium 36223738
2021 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. Nlrp6-/- macrophages; caspase-1/11 and GSDMD western blot; ASC oligomerization assay; NF-κB/ERK western blot; IL-1β maturation assay International journal of molecular sciences Medium 33918100
2023 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. 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 Nature communications High 37770465
2021 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. Nlrp6-/- and NSC-conditional Nlrp6CKO mice; ECRG4 knockdown rescue; mitochondrial function assays; NSC proliferation assays; corticosterone treatment; NLRP6 overexpression rescue Acta pharmaceutica Sinica. B Medium 37250149
2024 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. siNlrp6 transfection; RIG-1/MAVS pathway assays; mitophagy/autophagy flux assays; ferroptosis markers; SCFA treatment Redox biology Low 38772149
2021 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. Co-immunoprecipitation (NLRP6-PPM1A complex); NLRP6 overexpression/knockdown in LX-2 cells; p-Smad2/3 western blot; PPM1A siRNA rescue experiment Experimental cell research Medium 29966662
2021 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. Hepatocyte-specific Nlrp6-/- mice; HFD/MCD diet models; CD36 inhibitor experiment; TAB2/3 lysosomal degradation assay; NF-κB phosphorylation western blot Free radical biology & medicine Medium 33857628
2025 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. 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 Blood High 40373277
2024 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. Co-immunoprecipitation (BRCC3-NLRP6); ubiquitination assay; BRCC3 siRNA in MCAO and OGD/R models; NLRP6-ASC interaction assay CNS neuroscience & therapeutics Medium 38544474
2024 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. Nlrp6-/- mice; MCAO model; OGD/R co-culture model; proteasome inhibitor assay; pro-caspase-1 protein stability assay; multiple inflammasome activation markers Neurobiology of disease Low 38341160
2024 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. In vitro inflammasome reconstitution; PYD domain screen for caspase-1 activation; cell fractionation/expression profiling; IL-1β and GSDMD cleavage assays Frontiers in immunology Medium 39076995

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 1601 21565393
2014 NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 589 24581500
2016 A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-dependent Muc2 secretion. Science (New York, N.Y.) 455 27339979
2011 A functional role for Nlrp6 in intestinal inflammation and tumorigenesis. Journal of immunology (Baltimore, Md. : 1950) 358 21543645
2012 NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature 341 22763455
2011 Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury. Proceedings of the National Academy of Sciences of the United States of America 301 21593405
2017 NLRP6 Protects Il10-/- Mice from Colitis by Limiting Colonization of Akkermansia muciniphila. Cell reports 282 28445725
2018 The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection. Cell 252 30392956
2002 Functional screening of five PYPAF family members identifies PYPAF5 as a novel regulator of NF-kappaB and caspase-1. FEBS letters 245 12387869
2015 Nlrp6 regulates intestinal antiviral innate immunity. Science (New York, N.Y.) 227 26494172
2021 Phase separation drives RNA virus-induced activation of the NLRP6 inflammasome. Cell 187 34678144
2013 Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome inhibition and transmissible enteritis in mice. Gastroenterology 126 23470617
2019 The Nlrp6 inflammasome is not required for baseline colonic inner mucus layer formation or function. The Journal of experimental medicine 106 31420376
2017 NLRP6: A Multifaceted Innate Immune Sensor. Trends in immunology 106 28214100
2020 The NLRP6 inflammasome in health and disease. Mucosal immunology 104 31988468
2019 Molecular mechanism for NLRP6 inflammasome assembly and activation. Proceedings of the National Academy of Sciences of the United States of America 99 30674671
2017 Mitochondrial DNA oxidation induces imbalanced activity of NLRP3/NLRP6 inflammasomes by activation of caspase-8 and BRCC36 in dry eye. Journal of autoimmunity 97 28238526
2020 The NLRP6 inflammasome. Immunology 94 33314083
2020 Deubiquitination of NLRP6 inflammasome by Cyld critically regulates intestinal inflammation. Nature immunology 93 32424362
2017 The NLR Protein NLRP6 Does Not Impact Gut Microbiota Composition. Cell reports 86 29281815
2018 NLRP6 negatively regulates pulmonary host defense in Gram-positive bacterial infection through modulating neutrophil recruitment and function. PLoS pathogens 83 30248149
2010 Developmental control of the Nlrp6 inflammasome and a substrate, IL-18, in mammalian intestine. American journal of physiology. Gastrointestinal and liver physiology 79 21088234
2018 NLRP6 Induces Pyroptosis by Activation of Caspase-1 in Gingival Fibroblasts. Journal of dental research 77 29791256
2020 NLRP6 inflammasome. Molecular aspects of medicine 76 32386845
2012 Aggregatibacter actinomycetemcomitans targets NLRP3 and NLRP6 inflammasome expression in human mononuclear leukocytes. Cytokine 69 22503597
2022 NLRP6 is required for cancer-derived exosome-modified macrophage M2 polarization and promotes metastasis in small cell lung cancer. Cell death & disease 63 36270983
2021 The intestinal parasite Cryptosporidium is controlled by an enterocyte intrinsic inflammasome that depends on NLRP6. Proceedings of the National Academy of Sciences of the United States of America 61 33372132
2019 Effect of mild moxibustion on intestinal microbiota and NLRP6 inflammasome signaling in rats with post-inflammatory irritable bowel syndrome. World journal of gastroenterology 60 31528095
2014 Role of Nlrp6 and Nlrp12 in the maintenance of intestinal homeostasis. European journal of immunology 59 24338634
2017 A dietary flavone confers communicable protection against colitis through NLRP6 signaling independently of inflammasome activation. Mucosal immunology 58 29139477
2015 Nlrp6 promotes recovery after peripheral nerve injury independently of inflammasomes. Journal of neuroinflammation 52 26253422
2022 Intestinal Candida albicans Promotes Hepatocarcinogenesis by Up-Regulating NLRP6. Frontiers in microbiology 51 35369462
2016 NLRP6 function in inflammatory monocytes reduces susceptibility to chemically induced intestinal injury. Mucosal immunology 51 27353251
2020 NLRP6 expressed in astrocytes aggravates neurons injury after OGD/R through activating the inflammasome and inducing pyroptosis. International immunopharmacology 48 31927506
2019 NLRP6 suppresses the inflammatory response of human periodontal ligament cells by inhibiting NF-κB and ERK signal pathways. International endodontic journal 46 30712265
2021 NLRP6 in host defense and intestinal inflammation. Cell reports 44 33910012
2022 Qing-Chang-Hua-Shi granule ameliorates DSS-induced colitis by activating NLRP6 signaling and regulating Th17/Treg balance. Phytomedicine : international journal of phytotherapy and phytopharmacology 42 36150347
2020 NLRP6 modulates neutrophil homeostasis in bacterial pneumonia-derived sepsis. Mucosal immunology 42 33230225
2018 Clostridium butyricum regulates visceral hypersensitivity of irritable bowel syndrome by inhibiting colonic mucous low grade inflammation through its action on NLRP6. Acta biochimica et biophysica Sinica 41 29329362
2019 Effects of NLRP6 in Cerebral Ischemia/Reperfusion (I/R) Injury in Rats. Journal of molecular neuroscience : MN 40 31267316
2019 Host NLRP6 exacerbates graft-versus-host disease independent of gut microbial composition. Nature microbiology 39 30858572
2020 Loss of NLRP6 expression increases the severity of acute kidney injury. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 38 31504777
2020 NLRP6 contributes to inflammation and brain injury following intracerebral haemorrhage by activating autophagy. Journal of molecular medicine (Berlin, Germany) 35 32783081
2019 Long noncoding RNA OIP5-AS1 aggravates cell proliferation, migration in gastric cancer by epigenetically silencing NLRP6 expression via binding EZH2. Journal of cellular biochemistry 35 31219209
2020 Nicotine Causes Nephrotoxicity through the Induction of NLRP6 Inflammasome and Alpha7 Nicotinic Acetylcholine Receptor. Toxics 33 33114531
2018 The protective roles of NLRP6 in intestinal epithelial cells. Cell proliferation 33 30515917
2017 NLRP6 facilitates the interaction between TAB2/3 and TRIM38 in rheumatoid arthritis fibroblast-like synoviocytes. FEBS letters 33 28295271
2021 SP1 transcriptionally activates NLRP6 inflammasome and induces immune evasion and radioresistance in glioma cells. International immunopharmacology 32 34147913
2013 NLRP6 in infection and inflammation. Microbes and infection 32 23811097
2023 Ginsenoside Rk2, a dehydroprotopanaxadiol saponin, alleviates alcoholic liver disease via regulating NLRP3 and NLRP6 inflammasome signaling pathways in mice. Journal of pharmaceutical analysis 31 37842661
2022 Defects in NLRP6, autophagy and goblet cell homeostasis are associated with reduced duodenal CRH receptor 2 expression in patients with functional dyspepsia. Brain, behavior, and immunity 31 35093492
2022 Physiological and pathophysiological functions of NLRP6: pro- and anti-inflammatory roles. Communications biology 31 35650327
2024 TRIM29 controls enteric RNA virus-induced intestinal inflammation by targeting NLRP6 and NLRP9b signaling pathways. Mucosal immunology 29 39396665
2022 Estrogen receptor β activation inhibits colitis by promoting NLRP6-mediated autophagy. Cell reports 29 36223738
2020 NLRP6 exerts a protective role via NF-kB with involvement of CCL20 in a mouse model of alcoholic hepatitis. Biochemical and biophysical research communications 29 32507279
2020 miR-331-3p Inhibits Inflammatory Response after Intracerebral Hemorrhage by Directly Targeting NLRP6. BioMed research international 29 32596340
2022 AIP1 suppresses neovascularization by inhibiting the NOX4-induced NLRP3/NLRP6 imbalance in a murine corneal alkali burn model. Cell communication and signaling : CCS 28 35524333
2023 Neuron stem cell NLRP6 sustains hippocampal neurogenesis to resist stress-induced depression. Acta pharmaceutica Sinica. B 26 37250149
2021 The Critical Role of NLRP6 Inflammasome in Streptococcus pneumoniae Infection In Vitro and In Vivo. International journal of molecular sciences 26 33918100
2020 NLRP6 suppresses gastric cancer growth via GRP78 ubiquitination. Experimental cell research 26 32682010
2017 NLRP6 Inflammasome Ameliorates Brain Injury after Intracerebral Hemorrhage. Frontiers in cellular neuroscience 26 28798666
2023 NLRP6 potentiates PI3K/AKT signalling by promoting autophagic degradation of p85α to drive tumorigenesis. Nature communications 25 37770465
2018 TLR4-MyD88 pathway promotes the imbalanced activation of NLRP3/NLRP6 via caspase-8 stimulation after alkali burn injury. Experimental eye research 25 30008389
2024 Nlrp6 protects from corticosterone-induced NSPC ferroptosis by modulating RIG-1/MAVS-mediated mitophagy. Redox biology 24 38772149
2021 Hepatocyte-specific deletion of Nlrp6 in mice exacerbates the development of non-alcoholic steatohepatitis. Free radical biology & medicine 24 33857628
2019 Is NLRP3 or NLRP6 inflammasome activation associated with inflammation-related lung tumorigenesis induced by benzo(a)pyrene and lipopolysaccharide? Ecotoxicology and environmental safety 24 31561077
2018 NLRP6, decreased in gastric cancer, suppresses tumorigenicity of gastric cancer cells. Cancer management and research 24 30568504
2024 BRCC3 mediates inflammation and pyroptosis in cerebral ischemia/reperfusion injury by activating the NLRP6 inflammasome. CNS neuroscience & therapeutics 23 38544474
2017 Anti-inflammatory capacity of Lactobacillus rhamnosus GG in monophasic variant Salmonella infected piglets is correlated with impeding NLRP6-mediated host inflammatory responses. Veterinary microbiology 23 29103703
2024 Decreased expression of the NLRP6 inflammasome is associated with increased intestinal permeability and inflammation in obesity with type 2 diabetes. Cellular and molecular life sciences : CMLS 22 38315242
2019 NLRP6 deficiency aggravates liver injury after allogeneic hematopoietic stem cell transplantation. International immunopharmacology 22 31301646
2019 Candida albicans SC5314 inhibits NLRP3/NLRP6 inflammasome expression and dampens human intestinal barrier activity in Caco-2 cell monolayer model. Cytokine 22 31629100
2018 Effects of NLRP6 on the proliferation and activation of human hepatic stellate cells. Experimental cell research 22 29966662
2021 NLRP6-caspase 4 inflammasome activation in response to cariogenic bacterial lipoteichoic acid in human dental pulp inflammation. International endodontic journal 21 33377178
2022 NLRP6 Inflammasome Modulates Disease Progression in a Chronic-Plus-Binge Mouse Model of Alcoholic Liver Disease. Cells 20 35053298
2020 NLRP6 Plays an Important Role in Early Hepatic Immunopathology Caused by Schistosoma mansoni Infection. Frontiers in immunology 20 32431709
2024 NLRP3, NLRP6, and NLRP12 are inflammasomes with distinct expression patterns. Frontiers in immunology 18 39076995
2023 Vitamin D3 alleviates inflammation in ulcerative colitis by activating the VDR-NLRP6 signaling pathway. Frontiers in immunology 18 36845152
2022 The latest breakthrough on NLRP6 inflammasome. Precision clinical medicine 16 36211635
2021 BRCC3 promotes activation of the NLRP6 inflammasome following cerebral ischemia/reperfusion (I/R) injury in rats. Neuroscience letters 16 33979701
2025 Platelet NLRP6 protects against microvascular thrombosis in sepsis. Blood 15 40373277
2022 Baicalin Ameliorates DSS-Induced Colitis by Protecting Goblet Cells through Activating NLRP6 Inflammasomes. Evidence-based complementary and alternative medicine : eCAM 15 36016685
2021 NLRP6-associated host microbiota composition impacts in the intestinal barrier to systemic dissemination of Brucella abortus. PLoS neglected tropical diseases 14 33617596
2020 Upregulation of Intestinal NLRP6 Inflammasomes After Roux-en-Y Gastric Bypass Promotes Gut Immune Homeostasis. Obesity surgery 14 31602628
2019 microRNA-650 promotes inflammation induced apoptosis of intestinal epithelioid cells by targeting NLRP6. Biochemical and biophysical research communications 14 31399193
2024 NLRP6 deficiency suppresses colorectal cancer liver metastasis growth by modulating M-MDSC-induced immunosuppressive microenvironment. Biochimica et biophysica acta. Molecular basis of disease 13 38278335
2024 NLRP6 deficiency inhibits neuroinflammation and ameliorates brain injury in ischemic stroke by blocking NLRs inflammasomes activation through proteasomal degradation of pro-caspase-1. Neurobiology of disease 13 38341160
2013 Sex-specific effects of NLRP6/AVR and ADM loci on susceptibility to essential hypertension in a Sardinian population. PloS one 13 24147025
2019 NLRP6 Deficiency in CD4 T Cells Decreases T Cell Survival Associated with Increased Cell Death. Journal of immunology (Baltimore, Md. : 1950) 12 31152078
2023 NLRP6 controls pulmonary inflammation from cigarette smoke in a gut microbiota-dependent manner. Frontiers in immunology 11 38146368
2022 NLRP6 negatively regulates type 2 immune responses in mice. Allergy 10 35615773
2019 Corticotropin-releasing factor induces inflammatory cytokines via the NLRP6-inflammatory cytokine axis in a murine model of irritable bowel syndrome. Journal of digestive diseases 10 30663229
2008 Overlapping genes in Nalp6/PYPAF5 locus encode two V2-type vasopressin isoreceptors: angiotensin-vasopressin receptor (AVR) and non-AVR. Physiological genomics 10 18413781
2025 Methamphetamine-mediated astrocytic pyroptosis and neuroinflammation involves miR-152-NLRP6 inflammasome signaling axis. Redox biology 9 39879739
2024 Ethanol modulates astrocyte activation and neuroinflammation via miR-339/NLRP6 inflammasome signaling. Free radical biology & medicine 9 39522566
2023 NLRP6 deficiency expands a novel CD103+ B cell population that confers immune tolerance in NOD mice. Frontiers in immunology 9 36911699
2022 NLRP6 Serves as a Negative Regulator of Neutrophil Recruitment and Function During Streptococcus pneumoniae Infection. Frontiers in microbiology 9 35694317
2020 Tissue-selective alternate promoters guide NLRP6 expression. Life science alliance 9 33376129
2018 Reduced expression of the NLRP6 inflammasome in the colon of patients with Hirschsprung's disease. Journal of pediatric surgery 9 30262203
2003 Identification of mammalian orthologs associates PYPAF5 with distinct functional roles. FEBS letters 9 12633874

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