Affinage

NLRP12

NACHT, LRR and PYD domains-containing protein 12 · UniProt P59046

Length
1061 aa
Mass
120.2 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NLRP12 (Monarch-1/PYPAF7) is a cytosolic NLR protein of myeloid-monocytic origin that functions predominantly as a negative regulator of inflammatory signaling, restraining both canonical and non-canonical NF-κB as well as MAPK pathways to limit inflammation and tumorigenesis (PMID:16203735, PMID:22503542, PMID:22094258). It dampens canonical TLR2/4 and TNFR signaling by associating with IRAK-1 and blocking its hyperphosphorylation (PMID:16203735), and suppresses the non-canonical pathway by binding NIK and TRAF3 to drive proteasomal degradation of NIK, thereby limiting p100-to-p52 processing (PMID:17237370, PMID:22503542). These inhibitory activities depend on intact Walker A/B motifs in the NACHT domain, which support ATP binding/hydrolysis and self-oligomerization, and on Hsp90, which stabilizes NLRP12 and enables NIK degradation (PMID:18160710, PMID:17947705). NLRP12 additionally restrains innate antiviral and nucleotide-sensing pathways by interacting with TRIM25 via its nucleotide-binding domain to block K63-ubiquitination of RIG-I and by promoting K48-linked degradation of NOD2 (PMID:30902577, PMID:30559449), and it suppresses Wnt/β-catenin signaling through an STK38–GSK3β–β-catenin axis in intestinal epithelium (PMID:37581937). Loss of NLRP12 in mice produces unchecked NF-κB/ERK signaling, colon inflammation and colorectal tumorigenesis, dysregulated osteoclastogenesis and bone loss, and aberrant T-cell responses, establishing its broad anti-inflammatory and tumor-suppressive role (PMID:22503542, PMID:22094258, PMID:26240332, PMID:32632939). In specific contexts NLRP12 instead acts as a pro-inflammatory sensor: triggered by heme plus PAMPs or TNF and induced upstream by TLR–IRF1 signaling, it assembles an inflammasome and a larger caspase-8/RIPK3 PANoptosome that drives IL-1β/IL-18 maturation and PANoptosis (PMID:37267949, PMID:37557956). In human cells NLRP12 also directly binds NLRP3 to inhibit ASC-dependent NLRP3 inflammasome assembly, and disease-associated NLRP12 mutations abolish this restraint, increasing IL-1β production in patient cells (PMID:38261657). Structural work defines the NLRP12 pyrin domain as a six-helical death-domain bundle that mediates a non-homotypic interaction with FAF-1 (PMID:21978668).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2002 Medium

    Established NLRP12 as an ASC-interacting NLR capable of engaging the caspase-1/NF-κB machinery, placing it within inflammatory signaling complexes.

    Evidence Mammalian two-hybrid and co-expression assays with NF-κB reporter and caspase-1 activity readouts

    PMID:12019269

    Open questions at the time
    • Did not define whether NLRP12 is a positive or negative regulator in primary cells
    • Overexpression-based, no endogenous validation
  2. 2003 Medium

    Identified NLRP12 as a myeloid-restricted gene regulating MHC class I expression, defining its expression niche.

    Evidence siRNA knockdown with microarray and promoter analysis in myeloid cells

    PMID:12759408

    Open questions at the time
    • Mechanism linking NLRP12 to MHC promoters not resolved
    • Single lab
  3. 2005 High

    Reframed NLRP12 as a negative regulator of canonical TLR/TNFR NF-κB signaling, identifying IRAK-1 as the target of inhibition.

    Evidence Co-IP, siRNA knockdown, NF-κB reporter and phosphorylation assays in myeloid cells

    PMID:16203735

    Open questions at the time
    • Did not establish how IRAK-1 phosphorylation is blocked biochemically
    • Did not address non-canonical pathway
  4. 2007 High

    Defined the non-canonical NF-κB target: NLRP12 binds NIK and drives its proteasomal degradation, with Hsp90 required for NLRP12 stability and ATPase activity required for function.

    Evidence Reciprocal Co-IP with NIK, proteasome/Hsp90 inhibitor dissection, shRNA, and in vitro ATP binding/ATPase assays with Walker A/B mutants

    PMID:17237370 PMID:17947705 PMID:18160710

    Open questions at the time
    • Identity of the E3 ligase mediating NIK degradation not defined
    • How ATP hydrolysis couples to partner engagement not resolved
  5. 2009 High

    Identified transcriptional control of NLRP12, showing Blimp-1/PRDM1 represses its expression downstream of TLR activation.

    Evidence ChIP, promoter reporter, RT-PCR, and Blimp-1-KO murine myeloid cells

    PMID:19234190

    Open questions at the time
    • Did not connect repression to a downstream inflammatory outcome in vivo
    • Other regulators of NLRP12 transcription not surveyed
  6. 2011 High

    Provided structural definition of the NLRP12 pyrin domain and a non-homotypic protein interaction, broadening its interactome beyond classical PYD-PYD partners.

    Evidence NMR structure of PYD with chemical-shift-mapped FAF-1 UBA interaction and W45 mutagenesis

    PMID:21978668

    Open questions at the time
    • Functional consequence of the FAF-1 interaction not established
    • No full-length protein structure
  7. 2011 High

    Demonstrated in vivo that NLRP12 restrains macrophage NF-κB/ERK to suppress colon inflammation and colorectal tumorigenesis, establishing tumor-suppressor function.

    Evidence Nlrp12-/- mouse colitis and tumorigenesis models with macrophage signaling/cytokine profiling

    PMID:22094258

    Open questions at the time
    • Did not pinpoint the molecular node bridging NLRP12 loss to ERK activation
  8. 2011 Medium

    Showed that disease-associated NLRP12 mutations can be gain-of-function for inflammasome assembly while leaving NF-κB inhibition intact, separating the protein's two activities.

    Evidence R352C mutant caspase-1/ASC-speck and NF-κB reporter assays in HEK293T; D294E mutant patient monocyte IL-1β/ROS assays

    PMID:21360512 PMID:21538323

    Open questions at the time
    • Structural basis of mutant inflammasome gain-of-function unresolved
    • Reconstituted cell-line readouts may not reflect endogenous neutrophil context
  9. 2012 High

    Confirmed and extended the non-canonical NF-κB mechanism, adding TRAF3 to the NIK-regulatory module and linking NLRP12 loss to ERK/AKT dysregulation in tumors.

    Evidence Reciprocal Co-IP (NIK, TRAF3) and Nlrp12-/- mice with quantified p100-to-p52 processing

    PMID:22503542

    Open questions at the time
    • Order of assembly within the NLRP12-NIK-TRAF3 module not defined
  10. 2010 High

    Revealed a cell-biological role beyond signaling: NLRP12 maintains dendritic cell and neutrophil migration competence, later traced to macrophage-autonomous CXCL1 production.

    Evidence Nlrp12-/- in vivo migration and chemotaxis assays; macrophage-specific rescue of a natural Nlrp12 missense mutation restoring neutrophil recruitment

    PMID:20861349 PMID:27779193

    Open questions at the time
    • Molecular link between NLRP12 and chemokine responsiveness incompletely defined
  11. 2015 Medium

    Extended NLRP12's negative regulation across tissues and lineages — osteoclast precursors, CD4+ T cells, and neutrophil differentiation — via non-canonical NF-κB, STAT3, and IL-4 control.

    Evidence Nlrp12-/- and overexpression models with RelB translocation, T-cell adoptive transfer, EAE, RANKL osteoclastogenesis, and RNA-seq/ERK-NIK signaling analyses

    PMID:25888258 PMID:26240332 PMID:29483833 PMID:30681895 PMID:32632939

    Open questions at the time
    • Whether direct NLRP12 binding or indirect signaling underlies each lineage phenotype not uniformly resolved
    • Context-dependence of NIK stabilization vs degradation unexplained
  12. 2013 Medium

    Established NLRP12 as a context-dependent restraint on antimicrobial responses, dampening NF-κB/ERK during Salmonella infection while contributing to inflammasome activation in Plasmodium infection.

    Evidence Nlrp12-/- infection models with macrophage signaling, bacterial burden, and patient monocyte pyroptosome imaging

    PMID:24347638 PMID:24453977

    Open questions at the time
    • What dictates the switch between inhibitory and inflammasome roles per pathogen unknown
    • Single-study findings per pathogen
  13. 2018 High

    Defined NLRP12 control of innate nucleotide sensing: it blocks TRIM25-mediated K63-ubiquitination of RIG-I and promotes K48-linked degradation of NOD2, dampening antiviral and MDP-driven inflammation.

    Evidence Co-IP with domain mapping, K63/K48 ubiquitination assays, and myeloid-specific Nlrp12-/- mice; R284X truncation loses NOD2 repression

    PMID:30559449 PMID:30902577

    Open questions at the time
    • How NLRP12 redirects ubiquitin-ligase activity mechanistically not resolved
    • Whether RIG-I and NOD2 regulation occur in the same cells unaddressed
  14. 2018 Medium

    Provided a crystal structure of the human NLRP12 PYD revealing a disulfide-linked dimer potentially relevant to redox-sensitive signaling.

    Evidence X-ray crystallography of MBP-fusion PYD at 1.70 Å

    PMID:29293680

    Open questions at the time
    • Functional relevance of the disulfide dimer not experimentally validated
    • No full-length structure
  15. 2019 Medium

    Linked NLRP12 to JNK control and microbiota-dependent hepatocarcinogenesis, reinforcing tumor-suppressor function in a third organ.

    Evidence Nlrp12-/- HCC model with JNK inhibition, NLRP12 overexpression rescue, and antibiotic treatment

    PMID:30990169

    Open questions at the time
    • Direct molecular target linking NLRP12 to JNK not identified
    • Microbiota mechanism only indirectly implicated
  16. 2021 Medium

    Identified a viral subversion mechanism: SARS-CoV-2 NSP5 protease directly cleaves human NLRP12, with the cleavage site absent in mouse, offering a species-specific route to dysregulated cytokine production.

    Evidence In vitro cleavage assay with recombinant NSP5 and sequence alignment of homologs

    PMID:33372854

    Open questions at the time
    • Functional consequence of cleavage in infected cells not demonstrated
    • No in vivo validation
  17. 2023 High

    Established NLRP12 as a bona fide cytosolic sensor that, under heme-plus-PAMP or TNF triggers and IRF1-driven induction, nucleates an inflammasome and a caspase-8/RIPK3 PANoptosome driving IL-1β/IL-18 maturation and PANoptosis.

    Evidence Multiple genetic KO models (Nlrp12, Irf1, Tlr2/4), PANoptosome component blots, live imaging, and a hemolytic acute kidney injury model

    PMID:37267949 PMID:37557956

    Open questions at the time
    • Direct ligand/sensing event upstream of assembly not biochemically defined
    • How the same protein switches between inhibitory and PANoptosome roles unresolved
  18. 2023 High

    Identified an STK38-dependent mechanism by which NLRP12 suppresses Wnt/β-catenin signaling, providing a molecular basis for its intestinal tumor-suppressor role.

    Evidence Co-IP/MS identifying STK38, conditional KO mice, intestinal organoids, and GSK3β/β-catenin signaling analysis

    PMID:37581937

    Open questions at the time
    • How NLRP12 engages STK38 structurally not defined
    • Integration with NLRP12's NF-κB roles in epithelium unclear
  19. 2024 High

    Demonstrated direct, species-specific inhibition of the NLRP3 inflammasome by NLRP12 binding NLRP3, with disease-associated mutants losing restraint — a unifying model for NLRP12-associated autoinflammation.

    Evidence ASC polymerization reconstitution screen, Co-IP, mutant comparisons, and patient PBMC IL-1β assays in human vs murine cells

    PMID:38261657

    Open questions at the time
    • Structural basis of the NLRP12-NLRP3 interface unresolved
    • Why inhibition is human-specific not explained
  20. 2024 Medium

    Extended NLRP12's regulatory repertoire to metabolism and additional inflammasome contexts — stabilizing HK2 to promote glycolysis, supporting a noncanonical NLRP12-ASC-caspase-8 axis in endothelial pyroptosis, and acting as a reconstitution-competent inflammasome in granulocytes.

    Evidence Co-IP of NLRP12-TRIM25-HK2 with ubiquitination/lysosome assays, AIP1-dependent endothelial inflammasome with GSDMD/NLRP12 KO, and in vitro inflammasome reconstitution with cell-type expression profiling

    PMID:39076995 PMID:39527457 PMID:40796546

    Open questions at the time
    • Generality of the HK2/glycolysis role beyond gastric cancer unknown
    • Reconciliation of NLRP12 expression in neutrophils/eosinophils vs macrophages across studies needed
  21. 2024 Medium

    Identified additional NLRP12 partners regulating its pro-death and antiviral functions — HCK as a PANoptosis regulator and an LRR/PYD-dependent recruitment of MARCH8 to degrade a viral glycoprotein.

    Evidence HCK knockdown with PANoptosis imaging and computational/domain-deletion binding; Co-IP with LRR/PYD domain mapping and K48 ubiquitination assays for GP2a degradation

    PMID:39362085 PMID:40408404

    Open questions at the time
    • HCK-NLRP12 interaction relies partly on computational modeling
    • GP2a finding is in a porcine virus/ortholog context
  22. 2023 Medium

    Positioned NLRP12 as an innate immune checkpoint on type I IFN, with RUNX1-dependent epigenetic suppression creating a feedback loop relevant to lupus.

    Evidence RUNX1 ChIP, NLRP12 promoter analysis, Nlrp12-/- lupus-prone and pristane models, and SLE monocyte signaling

    PMID:36719379

    Open questions at the time
    • Direct molecular target of NLRP12 in IFN-I suppression not defined
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what molecular switch determines whether NLRP12 acts as an inhibitor of NF-κB/inflammasome signaling or assembles its own inflammasome/PANoptosome, and no full-length structure explains how its NACHT, PYD, and LRR domains integrate ATP hydrolysis, partner binding, and oligomerization across these opposing modes.
  • No full-length NLRP12 structure
  • Direct ligand sensing event for inflammasome assembly undefined
  • Context determinants (cell type, stimulus, species) of dual function not unified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0060089 molecular transducer activity 2 GO:0140299 molecular sensor activity 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 2
Partners
ASCHSP90IRAK1NIKNLRP3STK38TRAF3TRIM25
Complex memberships
NLRP12 inflammasomeNLRP12-PANoptosome

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 NLRP12 (PYPAF7) co-expression with ASC recruits NLRP12 to distinct cytoplasmic loci and synergistically activates NF-κB; co-expression of NLRP12 and ASC also synergistically activates caspase-1 and increases IL-1β secretion, identifying pro-caspase-1 as a binding partner of ASC in this pathway. Mammalian two-hybrid screen, co-expression assays in cell lines, NF-κB reporter assay, caspase-1 activity assay The Journal of biological chemistry Medium 12019269
2003 Monarch-1/NLRP12 is expressed in cells of myeloid-monocytic origin and enhances nonclassical and classical MHC class I expression at the promoter, RNA, and protein levels, as determined by siRNA knockdown and Affymetrix microarray analysis. siRNA knockdown, Affymetrix microarrays, promoter assays Journal of immunology Medium 12759408
2005 Monarch-1/NLRP12 acts as a negative regulator of TLR (TLR2/TLR4) and TNF receptor signaling by associating with IRAK-1 (but not MyD88) and blocking IRAK-1 hyperphosphorylation; it reduces NFκB activation downstream of MyD88, IRAK-1, TRAF6, TRAF2, and RIP1 but not the NFκB subunit p65. siRNA knockdown in myeloid cells dramatically increased NFκB activation and cytokine expression. Co-immunoprecipitation, siRNA knockdown, NFκB reporter assay, phosphorylation analysis The Journal of biological chemistry High 16203735
2007 Monarch-1/NLRP12 inhibits the non-canonical NF-κB pathway in human monocytes by associating with NF-κB-inducing kinase (NIK) and inducing its proteasome-mediated degradation; shRNA silencing of Monarch-1 enhances p52-dependent chemokine expression. Co-immunoprecipitation, shRNA knockdown, proteasome inhibitor assay, NFκB reporter, chemokine expression analysis Journal of immunology High 17237370
2007 Purified NLRP12 specifically binds ATP and exhibits ATPase activity dependent on intact Walker A/B motifs. These motifs are required for NLRP12 self-oligomerization, TLR/CD40L-activated association with NIK and IRAK-1, NIK degradation, and inhibition of IRAK-1 phosphorylation; Walker A/B mutants behave equivalently to shRNA-silenced cells in promoting proinflammatory cytokine production. In vitro biochemical ATP binding assay, ATPase assay with purified protein, site-directed mutagenesis of Walker A/B motifs, Co-IP, THP-1 stable expression Molecular and cellular biology High 18160710
2007 Hsp90 associates with Monarch-1/NLRP12 in human monocytes, and this association is required for NLRP12 stability and its ability to promote NIK degradation. Hsp90 inhibitor treatment disrupts NLRP12-Hsp90 complexes, leading to rapid proteasomal degradation of NLRP12 and preventing NIK proteolysis. 2D gel/mass spectrometry, Co-IP, Hsp90 inhibitor treatment, proteasome inhibitor assay Journal of immunology High 17947705
2009 Blimp-1/PRDM1 binds the NLRP12 promoter and reduces NLRP12 promoter activity, mRNA expression, and histone H3 acetylation in a TLR-inducible manner. Blimp-1-deficient murine myeloid cells have higher NLRP12 gene expression, confirming that Blimp-1 is a transcriptional repressor of NLRP12. Promoter reporter assay, ChIP, siRNA/Blimp-1-KO murine cells, RT-PCR, western blot Journal of immunology High 19234190
2010 NLRP12 is required for dendritic cell (DC) and neutrophil migration competence; Nlrp12-deficient mice show attenuated contact hypersensitivity and Nlrp12-/- DCs have significantly reduced capacity to migrate to draining lymph nodes. Both DCs and neutrophils fail to respond to chemokines in vitro, indicating NLRP12 maintains cells in a migration-competent state. Nlrp12-/- mouse model, in vivo DC migration assay, in vitro chemotaxis assay, contact hypersensitivity model Journal of immunology High 20861349
2011 The NMR structure of the NLRP12 pyrin domain (PYD) reveals a six-helical bundle death domain fold. In vitro NMR interaction studies identified a non-homotypic PYD interaction between NLRP12 PYD and the UBA domain of pro-apoptotic FAF-1, with all interaction residues confined to the α2–α3 surface; tryptophan 45 is critical for this interaction. NMR structure determination, NMR chemical shift perturbation assays for protein interaction, mutagenesis Journal of molecular biology High 21978668
2011 The NLRP12 R352C missense mutation (in the nucleotide-binding site) does not alter NLRP12 inhibition of NF-κB activation but increases speck formation and activates caspase-1 signaling in HEK293T cells stably expressing ASC and procaspase-1, indicating a gain-of-function specifically for inflammasome assembly. Cell-based caspase-1 activity assay, ASC speck formation assay, NF-κB luciferase reporter, HEK293T stable expression Arthritis and rheumatism Medium 21538323
2012 NLRP12 negatively regulates the non-canonical NF-κB pathway by interacting with both NIK and TRAF3; Nlrp12-/- cells show constitutively elevated NIK, increased p100-to-p52 processing, and reduced TRAF3 levels. NLRP12 also negatively regulates ERK and AKT signaling in colonic tumor tissue. Co-immunoprecipitation (NIK and TRAF3), Nlrp12-/- mouse model, western blot for signaling intermediates, tumor tissue analysis Immunity High 22503542
2011 NLRP12 deficiency in macrophages leads to failure to dampen NF-κB and ERK activation, resulting in increased production of inflammatory cytokines and chemokines; this underlies enhanced colon inflammation and colorectal tumorigenesis in Nlrp12-/- mice. Nlrp12-/- mouse model, macrophage NF-κB/ERK signaling analysis, cytokine profiling, colitis and tumorigenesis models Cancer cell High 22094258
2014 NLRP12 mediates inflammasome-dependent caspase-1 activation during Plasmodium infection in a manner dependent on ASC, P2X7R, NLRP3, and/or NLRP12; NLRP12-containing pyroptosomes were identified in monocytes from malaria patients, and NLRP12/NLRP3-dependent caspase-1 activation drives IL-1β production and hypersensitivity to secondary bacterial infection. Mouse infection model (Plasmodium), caspase-1 activation assay, ASC-speck/pyroptosome immunofluorescence in patient monocytes, genetic KO analysis PLoS pathogens Medium 24453977
2013 During Salmonella infection, NLRP12 acts as a negative regulator by suppressing NF-κB (via IκBα phosphorylation) and ERK activation in macrophages, thereby down-regulating proinflammatory and antimicrobial molecules; NLRP12-deficient mice are highly resistant to S. typhimurium infection due to enhanced host immune signaling. Nlrp12-/- mouse infection model, macrophage NF-κB/ERK phosphorylation analysis, bacterial burden assay PNAS Medium 24347638
2015 NLRP12 negatively regulates T-cell-mediated immunity by suppressing NF-κB regulation and IL-4 production in CD4+ T cells; transfer of Nlrp12-/- CD4+CD45RBhi T cells into immunodeficient mice causes more severe colitis and atopic dermatitis, and enhanced IL-4 in Nlrp12-/- T cells promotes atypical EAE. T cell adoptive transfer, Nlrp12-/- mouse model, intracellular cytokine staining, EAE model Immunity Medium 25888258
2015 NLRP12 suppresses the non-canonical NF-κB pathway in osteoclast precursors; retroviral overexpression of NLRP12 suppresses RelB nuclear translocation and osteoclast formation, while Nlrp12-/- cells show enhanced NIK stabilization and RelB nuclear translocation. In vivo, NLRP12 deficiency leads to increased osteoclast numbers and significant decline in bone mass. Retroviral overexpression, Nlrp12-/- mouse model, radiation chimera, RelB nuclear translocation assay, RANKL stimulation, bone mass measurement PNAS Medium 26240332
2016 A missense mutation (p.D294E) in the NLRP12 ATP-binding site (NACHT domain) does not alter inhibitory activity on NF-κB (as tested in HEK293 cells) but accelerates PAMP-induced IL-1β secretion kinetics and causes elevated ROS production in patient monocytes. HEK293 NF-κB luciferase reporter, patient monocyte IL-1β ELISA, ROS assay Arthritis and rheumatism Medium 21360512
2018 The NLRP12 nucleotide-binding domain interacts with TRIM25 to prevent TRIM25-mediated Lys63-linked ubiquitination and activation of RIG-I; NLRP12 also enhances RNF125-mediated Lys48-linked degradative ubiquitination of RIG-I, thereby dampening RIG-I-MAVS anti-viral signaling. Co-immunoprecipitation, ubiquitination assays (K63 and K48 linkage), NLRP12 domain mapping, Nlrp12-/- myeloid-specific mouse model Cell host & microbe High 30902577
2018 NLRP12 promotes K48-linked ubiquitination and proteasomal degradation of NOD2 in response to muramyl dipeptide (MDP), an interaction mediated by the linker region proximal to the NLRP12 nucleotide-binding domain; NLRP12 also sequesters HSP90 as part of this mechanism. The disease-associated NLRP12 R284X truncation mutant fails to repress MDP-induced NF-κB and JAK/STAT signaling. Co-immunoprecipitation, ubiquitination assay (K48-linkage), domain mapping (linker region), NOD2 degradation assay, Nlrp12-/- mouse model, JAK/STAT and NF-κB signaling analysis Nature communications High 30559449
2018 Crystal structure of human NLRP12 PYD domain at 1.70 Å resolution (as MBP fusion) reveals that the PYD forms a dimeric configuration through a disulfide bond, potentially relevant to ROS-induced NF-κB activation. X-ray crystallography PloS one Medium 29293680
2019 NLRP12 negatively regulates JNK activation in hepatocytes; Nlrp12-/- mice show higher JNK activation during HCC development, and JNK inhibition or NLRP12 overexpression reduced proliferative and inflammatory responses in Nlrp12-/- hepatocytes. Antibiotic treatment abolishes tumorigenesis in Nlrp12-/- livers, implicating microbiota. Nlrp12-/- mouse HCC model (diethylnitrosamine), JNK phosphorylation analysis, NLRP12 overexpression in hepatocytes, JNK inhibitor treatment, antibiotic treatment eLife Medium 30990169
2020 NLRP12 negatively regulates IL-6-induced STAT3 phosphorylation in T cells, thereby inhibiting Th17 cell differentiation; NLRP12-/- T cells show markedly increased Th17 differentiation under skewing conditions, and STAT3 inhibition abrogates hyperinflammatory arthritis in Nlrp12-/- mice. Nlrp12-/- T cell differentiation assay, STAT3 phosphorylation western blot, adoptive transfer, anti-IL-17A neutralization, pharmacological STAT3 inhibition in vivo FASEB journal Medium 32632939
2021 SARS-CoV-2 NSP5 (3CLpro) directly cleaves NLRP12 in vitro; a cognate cleavage motif is absent in mouse NLRP12, explaining species differences. This cleavage mechanism may contribute to enhanced cytokine production in COVID-19. In vitro cleavage assay with recombinant NSP5 protease and NLRP12 substrate, comparative sequence alignment of NLRP12 homologs Emerging microbes & infections Medium 33372854
2023 NLRP12 functions as a cytosolic sensor that drives inflammasome formation and PANoptosome activation in response to heme plus PAMPs or TNF. TLR2/4-mediated signaling through IRF1 induces Nlrp12 expression. The NLRP12 inflammasome induces IL-1β and IL-18 maturation, and also serves as an integral component of a larger PANoptosome complex driving caspase-8/RIPK3-dependent inflammatory cell death (PANoptosis). Deletion of Nlrp12 protected mice from acute kidney injury in a hemolytic model. Nlrp12-/- mouse model, IRF1-/- and TLR2/4-/- genetic analysis, western blot for PANoptosome components (caspase-8, RIPK3), cytokine ELISA, live cell imaging, hemolytic in vivo model Cell High 37267949
2023 NLRP12 interacts with STK38 kinase to inhibit GSK3β phosphorylation, leading to β-catenin degradation and suppression of the Wnt/β-catenin pathway in intestinal epithelial cells; Nlrp12-/- intestinal organoids and CRC cells show increased β-catenin activation and proliferation. Proteomic interaction studies (Co-IP/MS identifying STK38), Nlrp12 conditional KO mice, intestinal organoids, western blot for GSK3β phosphorylation and β-catenin, human/mouse tumor tissue analysis The Journal of clinical investigation High 37581937
2023 IRF1 acts as an upstream transcriptional inducer of NLRP12 expression and contributes to NLRP12-PANoptosome activation and PANoptosis; IRF1 deficiency impairs NLRP12-PANoptosome-driven cell death but is dispensable for inflammasomes that drive pyroptosis independently of the PANoptosome. IRF1-/- primary murine macrophages, live cell imaging, western blot for PANoptosome components, ELISA The Journal of biological chemistry Medium 37557956
2024 Wild-type NLRP12 physically interacts with NLRP3 and inhibits ASC inflammasome assembly induced by wild-type and gain-of-function mutant NLRP3 in human (but not murine) cells. NLRP12 itself does not nucleate ASC polymerization. Disease-associated NLRP12 mutants lose this inhibitory capacity, and PBMCs from NLRP12-mutant patients produce increased IL-1β in response to NLRP3 stimulation. ASC polymerization reconstitution screen, Co-IP between NLRP12 and NLRP3, patient PBMC IL-1β assay, murine vs. human NLRP3 comparison Science signaling High 38261657
2024 NLRP12 interacts with TRIM25 via its nucleotide-binding domain to compete for binding to HK2, preventing TRIM25-mediated K63-linked ubiquitination of HK2 and protecting HK2 from autophagosome-lysosome degradation, thereby stabilizing HK2 and promoting glycolysis and H3K18 lactylation in gastric cancer cells. Co-IP (NLRP12-TRIM25-HK2 complex), ubiquitination assay (K63-linkage), lysosome inhibitor assay, NLRP12 overexpression/knockdown Cell death & disease Medium 40796546
2025 Hematopoietic cell kinase (HCK) is a regulator of NLRP12-mediated PANoptosis; HCK expression is upregulated by NLRP12-PANoptosome triggers, Hck knockdown inhibits NLRP12-PANoptosis, and computational modeling plus in vitro binding assays suggest HCK interacts with NLRP12 in the region between its NACHT domain and PYD; removal of the PYD domain abrogated this interaction. HCK knockdown, live cell imaging for PANoptosis, computational interaction modeling, in vitro domain deletion binding assay PNAS Medium 40408404
2024 Full-length NLRP12 forms an inflammasome in vitro; its PYD domain activates caspase-1 to induce IL-1β cleavage and GSDMD cleavage in reconstitution assays. NLRP12 is specifically expressed in neutrophils and eosinophils (not macrophages), and several patient NLRP12 mutations cause spontaneous caspase-1 activation in vitro. Inflammasome reconstitution assay (in vitro), caspase-1 and GSDMD cleavage assay, cell type expression profiling, patient mutation functional testing Frontiers in immunology Medium 39076995
2024 NLRP12 interacts with GP2a (a PRRSV glycoprotein) via its LRR domain and recruits the E3 ubiquitin ligase MARCH8 via its PYD domain, facilitating K48-linked polyubiquitination of GP2a at K128 and lysosomal degradation of GP2a via the MARCH8-NDP52 pathway, thereby inhibiting PRRSV replication. Co-immunoprecipitation, domain deletion mapping (LRR and PYD), K48 ubiquitination assay, lysosome degradation assay, NLRP12 overexpression/silencing Veterinary microbiology Medium 39362085
2016 A C57BL/6J-specific missense mutation in Nlrp12 causes defective macrophage CXCL1 production; the neutrophil recruitment defect in C57BL/6J mice is rescued by restoration of macrophage NLRP12, establishing a macrophage-cell-autonomous role for NLRP12 in chemokine-driven neutrophil recruitment. Nlrp12 missense mutation identification, bone marrow chimera/macrophage reconstitution, CXCL1 ELISA, neutrophil migration assay Nature communications High 27779193
2023 NLRP12 acts as an innate immune checkpoint suppressing IFN-I production; RUNX1-dependent epigenetic regulation transcriptionally suppresses NLRP12 expression under IFN-I stimulation, creating a negative feedback loop. Reduced NLRP12 in SLE monocytes is linked to spontaneous innate immune signaling activation and hyperresponsiveness to nucleic acid stimulation. RUNX1 ChIP, NLRP12 promoter analysis, Nlrp12-/- lupus-prone mouse model, pristane model, monocyte signaling assays, autoantibody and kidney function measurements The Journal of clinical investigation Medium 36719379
2018 NLRP12 promotes neutrophil differentiation through non-canonical NF-κB signaling: NLRP12 inhibits ERK1/2 activity, relieving ERK1/2-mediated suppression of NIK protein levels, thereby enhancing NIK stabilization and RelB nuclear translocation to drive neutrophil differentiation. Nlrp12-/- cells, genome-wide RNA-seq, ERK1/2 and NIK phosphorylation/protein-level assays, RelB nuclear translocation assay International journal of biological sciences Medium 29483833
2019 NLRP12 deficiency results in elevated RANKL-induced IκB-α degradation and p65 phosphorylation in preosteoclasts, and NLRP12-/- preosteoclasts show higher RANKL-induced osteoclastogenesis, which is synergistically amplified by IL-1β and TNF-α, demonstrating that NLRP12 negatively regulates NF-κB during osteoclastogenesis. Nlrp12-/- mouse model, RANKL stimulation, western blot for IκB-α and p65, TRAP staining, micro-CT bone analysis Journal of dental research Medium 30681895
2024 In retinal vascular endothelial cells, decreased AIP1 promotes assembly of a noncanonical NLRP12-ASC-caspase-8 inflammasome complex, which drives GSDMD-dependent endothelial pyroptosis, VEGF and IL-1β release, and pathological ocular angiogenesis. Suppression of the NLRP12-CASP8-GSDMD axis reduces VEGF signaling and new vessel formation. scRNA-seq (AIP1 identification), genetic deletion of GSDMD and NLRP12, Co-IP for inflammasome complex, western blot for caspase-8/GSDMD cleavage, OIR mouse model Advanced science Medium 39527457

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-κB signaling. Immunity 427 22503542
2011 The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer cell 347 22094258
2023 NLRP12-PANoptosome activates PANoptosis and pathology in response to heme and PAMPs. Cell 333 37267949
2002 PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing. The Journal of biological chemistry 317 12019269
2017 NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth. Nature immunology 255 28288099
2021 SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species. Emerging microbes & infections 214 33372854
2005 The CATERPILLER protein monarch-1 is an antagonist of toll-like receptor-, tumor necrosis factor alpha-, and Mycobacterium tuberculosis-induced pro-inflammatory signals. The Journal of biological chemistry 193 16203735
2007 Monarch-1 suppresses non-canonical NF-kappaB activation and p52-dependent chemokine expression in monocytes. Journal of immunology (Baltimore, Md. : 1950) 183 17237370
2018 The Inhibitory Innate Immune Sensor NLRP12 Maintains a Threshold against Obesity by Regulating Gut Microbiota Homeostasis. Cell host & microbe 173 30212649
2011 Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis and rheumatism 151 21360512
2014 Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection. PLoS pathogens 147 24453977
2020 NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma. Molecular neurodegeneration 139 32295623
2010 Cutting edge: NLRP12 controls dendritic and myeloid cell migration to affect contact hypersensitivity. Journal of immunology (Baltimore, Md. : 1950) 121 20861349
2013 Salmonella exploits NLRP12-dependent innate immune signaling to suppress host defenses during infection. Proceedings of the National Academy of Sciences of the United States of America 120 24347638
2020 NLRP12 in innate immunity and inflammation. Molecular aspects of medicine 117 32838963
2015 The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells. Immunity 95 25888258
2007 ATP binding by monarch-1/NLRP12 is critical for its inhibitory function. Molecular and cellular biology 92 18160710
2023 Immune regulator IRF1 contributes to ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosome activation and inflammatory cell death (PANoptosis). The Journal of biological chemistry 91 37557956
2011 Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes. Arthritis and rheumatism 83 21538323
2019 NLRP12 Regulates Anti-viral RIG-I Activation via Interaction with TRIM25. Cell host & microbe 82 30902577
2003 Cutting edge: Monarch-1: a pyrin/nucleotide-binding domain/leucine-rich repeat protein that controls classical and nonclassical MHC class I genes. Journal of immunology (Baltimore, Md. : 1950) 82 12759408
2011 Role of interleukin-1β in NLRP12-associated autoinflammatory disorders and resistance to anti-interleukin-1 therapy. Arthritis and rheumatism 79 21480187
2016 Nlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment. Nature communications 73 27779193
2020 NLRP12- and NLRC4-mediated corneal epithelial pyroptosis is driven by GSDMD cleavage accompanied by IL-33 processing in dry eye. The ocular surface 72 32735949
2014 The multifaceted nature of NLRP12. Journal of leukocyte biology 66 25249449
2011 The NLRP12 pyrin domain: structure, dynamics, and functional insights. Journal of molecular biology 60 21978668
2014 Role of Nlrp6 and Nlrp12 in the maintenance of intestinal homeostasis. European journal of immunology 59 24338634
2007 Heat shock protein 90 associates with monarch-1 and regulates its ability to promote degradation of NF-kappaB-inducing kinase. Journal of immunology (Baltimore, Md. : 1950) 58 17947705
2019 NLRP3, NLRP12, and IFI16 Inflammasomes Induction and Caspase-1 Activation Triggered by Virulent HSV-1 Strains Are Associated With Severe Corneal Inflammatory Herpetic Disease. Frontiers in immunology 55 31367214
2017 Expression analysis of inflammasome sensors and implication of NLRP12 inflammasome in prostate cancer. Scientific reports 54 28663562
2019 NLRP12 suppresses hepatocellular carcinoma via downregulation of cJun N-terminal kinase activation in the hepatocyte. eLife 45 30990169
2016 NLRP12 autoinflammatory disease: a Chinese case series and literature review. Clinical rheumatology 45 27633793
2018 Proteasomal degradation of NOD2 by NLRP12 in monocytes promotes bacterial tolerance and colonization by enteropathogens. Nature communications 44 30559449
2018 Multigene sequencing reveals heterogeneity of NLRP12-related autoinflammatory disorders. Rheumatology international 40 29500522
2016 Involvement of EGF receptor signaling and NLRP12 inflammasome in fine particulate matter-induced lung inflammation in mice. Environmental toxicology 40 27377055
2015 The nod-like receptor, Nlrp12, plays an anti-inflammatory role in experimental autoimmune encephalomyelitis. Journal of neuroinflammation 40 26521018
2015 NLRP12 modulates host defense through IL-17A-CXCL1 axis. Mucosal immunology 38 26349659
2022 NLRP12-associated systemic autoinflammatory diseases in children. Pediatric rheumatology online journal 36 35123508
2024 NLRP12 interacts with NLRP3 to block the activation of the human NLRP3 inflammasome. Science signaling 32 38261657
2007 Monarch-1/PYPAF7 and other CATERPILLER (CLR, NOD, NLR) proteins with negative regulatory functions. Microbes and infection 32 17418609
2015 NLRP12 is a neutrophil-specific, negative regulator of in vitro cell migration but does not modulate LPS- or infection-induced NF-κB or ERK signalling. Immunobiology 31 26514298
2014 Novel NLRP12 mutations associated with intestinal amyloidosis in a patient diagnosed with common variable immunodeficiency. Clinical immunology (Orlando, Fla.) 30 25064839
2009 Blimp-1/PRDM1 mediates transcriptional suppression of the NLR gene NLRP12/Monarch-1. Journal of immunology (Baltimore, Md. : 1950) 30 19234190
2019 NLRP12 Attenuates Inflammatory Bone Loss in Experimental Apical Periodontitis. Journal of dental research 29 30681895
2023 NLRP12 is an innate immune checkpoint for repressing IFN signatures and attenuating lupus nephritis progression. The Journal of clinical investigation 28 36719379
2023 NLRP12 drives PANoptosis in response to heme. Trends in immunology 28 37423881
2019 Gut Microbiota-Mediated NLRP12 Expression Drives the Attenuation of Dextran Sulphate Sodium-Induced Ulcerative Colitis by Qingchang Wenzhong Decoction. Evidence-based complementary and alternative medicine : eCAM 28 31061672
2018 Epigenetic hypomethylation and upregulation of NLRC4 and NLRP12 in Kawasaki disease. Oncotarget 28 29721174
2017 Nlrp12 Mediates Adverse Neutrophil Recruitment during Influenza Virus Infection. Journal of immunology (Baltimore, Md. : 1950) 28 29282312
2015 Kaurenoic Acid Possesses Leishmanicidal Activity by Triggering a NLRP12/IL-1β/cNOS/NO Pathway. Mediators of inflammation 28 26074677
2023 NLRP12 downregulates the Wnt/β-catenin pathway via interaction with STK38 to suppress colorectal cancer. The Journal of clinical investigation 27 37581937
2020 NLRP12 negatively regulates EtOH-induced liver macrophage activation via NF-κB pathway and mediates hepatocyte apoptosis in alcoholic liver injury. International immunopharmacology 27 33182058
2018 The Dual Immunoregulatory function of Nlrp12 in T Cell-Mediated Immune Response: Lessons from Experimental Autoimmune Encephalomyelitis. Cells 24 30150571
2016 Identification of a Novel NLRP12 Nonsense Mutation (Trp408X) in the Extremely Rare Disease FCAS by Exome Sequencing. PloS one 23 27314497
2021 NLRP12 reduces proliferation and inflammation of rheumatoid arthritis fibroblast-like synoviocytes by regulating the NF-κB and MAPK pathways. European cytokine network 21 34369379
2020 Crosstalk between NLRP12 and JNK during Hepatocellular Carcinoma. International journal of molecular sciences 21 31941025
2020 Serum exosomes derived from Hp-positive gastritis patients inhibit MCP-1 and MIP-1α expression via NLRP12-Notch signaling pathway in intestinal epithelial cells and improve DSS-induced colitis in mice. International immunopharmacology 21 33182033
2019 The clinical phenotype and genotype of NLRP12-autoinflammatory disease: a Chinese case series with literature review. World journal of pediatrics : WJP 21 31820221
2015 NLRP12 provides a critical checkpoint for osteoclast differentiation. Proceedings of the National Academy of Sciences of the United States of America 21 26240332
2023 The role of NLRP12 in inflammatory diseases. European journal of pharmacology 20 37572944
2017 Innate Immune Cell Recovery Is Positively Regulated by NLRP12 during Emergency Hematopoiesis. Journal of immunology (Baltimore, Md. : 1950) 20 28159904
2020 NLRP12 gene mutations and auto-inflammatory diseases: ever-changing evidence. Rheumatology (Oxford, England) 19 32725138
2024 NLRP3, NLRP6, and NLRP12 are inflammasomes with distinct expression patterns. Frontiers in immunology 18 39076995
2016 Inflammasome-independent role of NLRP12 in suppressing colonic inflammation regulated by Blimp-1. Oncotarget 18 27105524
2018 Membrane microdomains regulate NLRP10- and NLRP12-dependent signalling in A549 cells challenged with cigarette smoke extract. Archives of toxicology 17 29623357
2021 A Novel Role for the Regulatory Nod-Like Receptor NLRP12 in Anti-Dengue Virus Response. Frontiers in immunology 16 34956178
2021 Contrasting role of NLRP12 in autoinflammation: evidence from a case report and mouse models. RMD open 15 34725261
2020 NLRP12 controls arthritis severity by acting as a checkpoint inhibitor of Th17 cell differentiation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 15 32632939
2019 NLRP12 negatively modulates inducible nitric oxide synthase (iNOS) expression and tumor necrosis factor-α production in Porphyromonas gingivalis LPS-treated mouse macrophage cell line (RAW264.7). Inflammation research : official journal of the European Histamine Research Society ... [et al.] 15 31292668
2018 NLRP12 promotes host resistance against Pseudomonas aeruginosa keratitis inflammatory responses through the negative regulation of NF-κB signaling. European review for medical and pharmacological sciences 15 30556841
2022 Clinical heterogeneity of NLRP12-associated autoinflammatory diseases. Genes & diseases 14 37396539
2019 Novel Deleterious Sequence Change in the NLRP12 Gene in a Child with the Autoinflammatory Syndrome, Joint Hypermobility and Cutis Laxa from India. Mediterranean journal of hematology and infectious diseases 13 30858956
2018 NLRP12 Promotes Mouse Neutrophil Differentiation through Regulation of Non-canonical NF-κB and MAPKERK1/2 Signaling. International journal of biological sciences 13 29483833
2025 Short-Chain Chlorinated Paraffins May Induce Ovarian Damage in Mice via AIM2- and NLRP12-PANoptosome. Environmental science & technology 12 39754571
2024 Overexpression of NLRP12 enhances antiviral immunity and alleviates herpes simplex keratitis via pyroptosis/IL-18/IFN-γ signaling. International immunopharmacology 12 38908077
2024 AIP1 Regulates Ocular Angiogenesis Via NLRP12-ASC-Caspase-8 Inflammasome-Mediated Endothelial Pyroptosis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 12 39527457
2023 NLRP12-expressing dendritic cells mediate both dissemination of infection and adaptive immune responses in visceral leishmaniasis. iScience 12 36879824
2023 NLRP12-associated autoinflammatory disease in Chinese adult patients: a single-centre study. RMD open 12 38123482
2019 Peripheral blood miR-372 as a biomarker for ulcerative colitis via direct targeting of NLRP12. Experimental and therapeutic medicine 12 31363381
2018 C3 glomerulopathy in NLRP12-related autoinflammatory disorder: case-based review. Rheumatology international 12 29951964
2014 The immunomodulatory molecule pidotimod induces the expression of the NOD-like receptor NLRP12 and attenuates TLR-induced inflammation. Journal of biological regulators and homeostatic agents 12 25620184
2023 NLRP12-associated autoinflammatory disease: much more than the FCAS phenotype. Clinical and experimental rheumatology 11 37877365
2022 Rare mutations in NLRP3 and NLRP12 associated with familial cold autoinflammatory syndrome: two Chinese pedigrees. Clinical rheumatology 11 35852776
2021 A rare case of an NLRP12-associated autoinflammatory disease. European journal of medical genetics 11 33676062
2020 Persistent DNA damage-induced NLRP12 improves hematopoietic stem cell function. JCI insight 11 32434992
2025 HCK regulates NLRP12-mediated PANoptosis. Proceedings of the National Academy of Sciences of the United States of America 10 40408404
2023 NLRP12 senses heme and PAMPs to drive necrotic cell death and inflammation. Molecular cell 10 37541218
2022 The innate immune receptor Nlrp12 suppresses autoimmunity to the retina. Journal of neuroinflammation 10 35313917
2019 Generalized Cytokine Increase in the Setting of a Multisystem Clinical Disorder and Carcinoid Syndrome Associated with a Novel NLRP12 Variant. Digestive diseases and sciences 10 30788684
2017 NLRP12 Inflammasome Expression in the Rat Brain in Response to LPS during Morphine Tolerance. Brain sciences 10 28178176
2016 Understanding chemical allergen potency: role of NLRP12 and Blimp-1 in the induction of IL-18 in human keratinocytes. Archives of toxicology 10 27585668
2025 NLRP12 decreases TRIM25-mediated HK2 degradation to promote glycolysis and H3K18la in gastric cancer. Cell death & disease 9 40796546
2024 Genetic variations in NLRP3 and NLRP12 genes in adult-onset patients with autoinflammatory diseases: a comparative study. Frontiers in immunology 9 38343435
2024 NLRP12 inhibits PRRSV-2 replication by promoting GP2a degradation via MARCH8. Veterinary microbiology 9 39362085
2022 7-O-(2- (Propylamino)-2-oxoethyl) hesperetin attenuates inflammation and protects against alcoholic liver injury by NLRP12. International immunopharmacology 9 35792270
2022 Mechanism of LSD1 in oxygen-glucose deprivation/reoxygenation-induced pyroptosis of retinal ganglion cells via the miR-21-5p/NLRP12 axis. BMC neuroscience 9 36357913
2019 Toll-like receptor 3 (TLR3) variant and NLRP12 mutation confer susceptibility to a complex clinical presentation. Clinical immunology (Orlando, Fla.) 9 31445170
2018 Crystal structure of human NLRP12 PYD domain and implication in homotypic interaction. PloS one 9 29293680
2015 Desflurane preconditioning protects human umbilical vein endothelial cells against anoxia/reoxygenation by upregulating NLRP12 and inhibiting non-canonical nuclear factor-κB signaling. International journal of molecular medicine 9 26329693
2024 Overexpression of NLRP12 enhances macrophage immune response and alleviates herpes simplex keratitis. Frontiers in cellular and infection microbiology 8 39119293

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