Affinage

NLRP12

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

Length
1061 aa
Mass
120.2 kDa
Annotated
2026-04-29
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NLRP12 is a cytosolic NLR family member that functions as a broad negative regulator of inflammatory signaling while also serving as a scaffold for inflammasome and PANoptosome assembly under specific stimuli. As an anti-inflammatory checkpoint, NLRP12 binds ATP via Walker A/B motifs required for self-oligomerization, associates with NIK and TRAF3 to promote proteasomal NIK degradation and suppress noncanonical NF-κB, interacts with IRAK-1 to block canonical NF-κB/TNFR signaling, engages TRIM25 and RNF125 to regulate K63/K48-ubiquitination of RIG-I, promotes HSP90-dependent K48-ubiquitination of NOD2, and interacts with STK38 to inhibit GSK3β phosphorylation and Wnt/β-catenin signaling (PMID:18160710, PMID:22503542, PMID:16203735, PMID:30902577, PMID:30559449, PMID:37581937). Under hemolytic or TNF-driven conditions, IRF1-induced NLRP12 assembles a PANoptosome with caspase-8 and RIPK3 to drive PANoptosis, and its PYD domain can directly inhibit human NLRP3 inflammasome assembly, with disease-associated mutations disrupting this suppression and causing gain-of-function inflammasome activation (PMID:37267949, PMID:38261657, PMID:21538323). Loss-of-function mutations in NLRP12 are linked to familial cold autoinflammatory syndrome and periodic fever syndromes characterized by dysregulated NF-κB and inflammasome signaling (PMID:30559449, PMID:38261657).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2002 High

    The initial identification of NLRP12 as an NLR capable of activating NF-κB and caspase-1 through ASC established it as a potential inflammasome-forming sensor, framing the central question of whether its primary role is pro- or anti-inflammatory.

    Evidence Mammalian two-hybrid, co-expression with ASC, NF-κB reporter, caspase-1 and IL-1β assays in HEK293 cells

    PMID:12019269

    Open questions at the time
    • Endogenous stimuli for NLRP12 activation unknown
    • Whether NLRP12 forms a bona fide inflammasome in physiological settings untested
    • In vivo relevance not addressed
  2. 2005 High

    Discovery that NLRP12 associates with IRAK-1 to block its hyperphosphorylation and suppresses both TLR and TNFR signaling reversed the initial pro-inflammatory framing and established NLRP12 as a negative regulator of canonical NF-κB.

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

    PMID:16203735

    Open questions at the time
    • Mechanism by which NLRP12 prevents IRAK-1 phosphorylation unresolved
    • Whether IRAK-1 interaction requires ATP binding unknown
  3. 2007 High

    Demonstration that NLRP12 binds and hydrolyzes ATP through Walker A/B motifs, and that these motifs are required for NIK degradation, IRAK-1 interaction, and self-oligomerization, provided the biochemical basis for NLRP12's enzymatic activity and its dual suppression of canonical and noncanonical NF-κB.

    Evidence Purified protein ATP-binding/hydrolysis assays, Walker A/B mutagenesis, Co-IP for NIK, stable THP-1 expression

    PMID:17237370 PMID:18160710

    Open questions at the time
    • Structure of the NACHT domain in ATP-bound versus hydrolyzed state not determined
    • Whether oligomerization is required for anti-inflammatory function or only for inflammasome assembly unclear
  4. 2007 High

    Identification of HSP90 as a stabilizing partner whose association protects NLRP12 from proteasomal degradation and is required for NLRP12-mediated NIK proteolysis revealed a chaperone-dependent regulatory layer governing NLRP12 activity.

    Evidence 2D gel/mass spectrometry identification, Co-IP, HSP90 inhibitor treatment, Western blot for NIK

    PMID:17947705

    Open questions at the time
    • Whether HSP90 binding is direct or part of a larger chaperone complex not determined
    • Stoichiometry and domain requirements for HSP90 interaction unmapped
  5. 2011 High

    NMR structure of the NLRP12 PYD revealed a six-helical death domain fold and an unexpected non-homotypic interaction with FAF-1 UBA domain, expanding the repertoire of PYD interactions beyond classical homotypic binding and identifying a potential apoptotic crosstalk point.

    Evidence NMR structure determination, in vitro binding assays, Trp45 mutagenesis

    PMID:21978668

    Open questions at the time
    • Physiological relevance of FAF-1 interaction in cell death pathways untested
    • Full-length NLRP12 structure unavailable
  6. 2011 High

    Nlrp12-knockout mouse studies demonstrated that NLRP12 deficiency unleashes NF-κB and ERK hyperactivation in macrophages, driving increased inflammatory cytokines and susceptibility to colitis and colorectal tumorigenesis, establishing NLRP12 as a tumor suppressor in the colon through inflammatory pathway restraint.

    Evidence Nlrp12-/- mice with colitis/tumor induction, Western blot for NF-κB/ERK, bone marrow chimeras, ELISA

    PMID:22094258 PMID:22503542

    Open questions at the time
    • Whether tumor-suppressive role is cell-intrinsic to epithelium or immune-mediated not fully resolved
    • Direct substrates for NLRP12's anti-ERK activity not identified
  7. 2011 Medium

    The R352C NACHT domain mutation was shown to be a gain-of-function for inflammasome assembly (increased ASC specks and caspase-1 activation) without altering NF-κB suppression, demonstrating that NLRP12's anti-inflammatory and inflammasome functions are genetically separable.

    Evidence HEK293T co-transfection, ASC speck assay, caspase-1 activity, NF-κB reporter

    PMID:21538323

    Open questions at the time
    • Whether R352C alters ATP hydrolysis kinetics untested
    • Patient phenotype–genotype correlation limited
  8. 2015 High

    Extension of NLRP12's anti-inflammatory role to T cells showed it restrains NF-κB-driven IL-4 production, with deficiency causing atypical neuroinflammation, and to osteoclast progenitors where it suppresses NIK-dependent osteoclastogenesis, broadening the cell types governed by NLRP12.

    Evidence Nlrp12-/- EAE model with T cell transfer; Nlrp12-/- RANKL osteolysis model with radiation chimeras

    PMID:25888258 PMID:26240332

    Open questions at the time
    • Mechanism of NLRP12 action in T cells versus myeloid cells may differ but is not directly compared
    • Whether NLRP12 directly targets NIK in osteoclast precursors or acts indirectly not resolved
  9. 2018 High

    Discovery that NLRP12 dampens RIG-I antiviral signaling through dual ubiquitin ligase manipulation — blocking TRIM25-mediated K63-ubiquitination while enhancing RNF125-mediated K48-ubiquitination of RIG-I — established NLRP12 as a regulator of innate antiviral immunity beyond NF-κB.

    Evidence Co-IP and ubiquitination assays, myeloid-specific Nlrp12-/- mice with VSV infection, IFN measurement

    PMID:30902577

    Open questions at the time
    • Whether NLRP12 directly bridges TRIM25 and RIG-I or competes for binding not structurally resolved
    • Relevance to human viral infections beyond VSV not tested
  10. 2018 High

    NLRP12 was shown to promote K48-ubiquitination and degradation of NOD2 via its linker-NACHT region and HSP90 sequestration, directly linking NLRP12 to regulation of a second NLR; the disease-causing R284X truncation failed to suppress MDP-induced signaling, connecting loss-of-function to autoinflammatory disease.

    Evidence Co-IP, ubiquitination assays, Nlrp12-/- monocytes, Citrobacter model, NF-κB/STAT reporter

    PMID:30559449

    Open questions at the time
    • Identity of the E3 ligase mediating K48-ubiquitination of NOD2 in the NLRP12 complex not identified
    • Whether HSP90 sequestration model applies to all NLRP12 anti-inflammatory targets unclear
  11. 2023 High

    A paradigm shift came with the discovery that under hemolytic or TNF conditions, IRF1-induced NLRP12 assembles a PANoptosome containing caspase-8 and RIPK3, driving simultaneous pyroptosis, apoptosis, and necroptosis — establishing that NLRP12 can switch from anti-inflammatory regulator to cell death scaffold depending on context.

    Evidence Nlrp12-/- hemolytic disease model, caspase-8/RIPK3/IRF1 KO, Western blot, live cell imaging, ELISA

    PMID:37267949 PMID:37557956

    Open questions at the time
    • Structural basis for PANoptosome assembly unknown
    • What determines the switch from anti-inflammatory to PANoptotic function not defined
    • Whether PANoptosome forms in human cells not shown
  12. 2023 High

    NLRP12 was found to suppress Wnt/β-catenin signaling by interacting with STK38 to inhibit GSK3β phosphorylation, identifying a non-immune tumor-suppressive mechanism in intestinal epithelial cells independent of NF-κB.

    Evidence Proteomics-identified interactome, Co-IP with STK38, conditional Nlrp12-KO intestinal organoids, Western blot for p-GSK3β/β-catenin

    PMID:37581937

    Open questions at the time
    • Whether STK38 interaction requires ATP binding or specific NLRP12 domains not mapped
    • Relevance of this pathway in immune cells not examined
  13. 2023 High

    The PYD domain of NLRP12 was shown to directly interact with and inhibit human NLRP3 inflammasome assembly; disease-associated NLRP12 mutations lost this suppressive capacity, providing a molecular explanation for autoinflammatory symptoms in patients carrying NLRP12 mutations.

    Evidence ASC polymerization screen, Co-IP with NLRP3, PBMCs from NLRP12-mutant patients, IL-1β measurement

    PMID:38261657

    Open questions at the time
    • Structural basis of PYD-NLRP3 interaction not resolved
    • Species specificity (human but not mouse NLRP3) mechanism unclear
    • Whether this interaction occurs in neutrophils where NLRP12 is most expressed not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for how NLRP12 switches between anti-inflammatory NF-κB suppression and pro-death PANoptosome assembly, the full-length structure of NLRP12 in active and autoinhibited states, and the physiological triggers and cell-type-specific contexts that determine which of its multiple effector functions predominate.
  • No full-length NLRP12 structure available
  • Context-dependent switch mechanism between anti-inflammatory and PANoptotic functions uncharacterized
  • Relative contribution of neutrophil versus macrophage NLRP12 to in vivo phenotypes incompletely resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 8 GO:0016787 hydrolase activity 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005829 cytosol 3
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 5 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1643685 Disease 2
Partners
HSP90IRAK1NIKPYCARDRNF125STK38TRAF3TRIM25
Complex memberships
NLRP12-ASC inflammasomeNLRP12-PANoptosome

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 NLRP12 (then called PYPAF7) co-expressed 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 downstream of NLRP12 signaling. Mammalian two-hybrid screen, co-expression assays, NF-κB luciferase reporter, caspase-1 activity assays, IL-1β ELISA The Journal of Biological Chemistry High 12019269
2003 NLRP12 (Monarch-1) enhances nonclassical and classical MHC class I expression at the promoter, RNA, and protein level in myeloid-monocytic cells, as revealed by Affymetrix microarrays combined with siRNA knockdown. Affymetrix microarrays, siRNA knockdown, reporter assays Journal of Immunology Medium 12759408
2005 NLRP12 (Monarch-1) associates with IRAK-1 (but not MyD88) and blocks IRAK-1 hyperphosphorylation, thereby suppressing both TLR and TNFR (via TRAF2/RIP1) signaling pathways; siRNA knockdown in myeloid cells dramatically increased NF-κB activation and cytokine expression. Co-immunoprecipitation, siRNA knockdown, NF-κB reporter, kinase phosphorylation assays The Journal of Biological Chemistry High 16203735
2007 NLRP12 (Monarch-1) specifically binds ATP and exhibits ATP hydrolysis activity; intact Walker A/B motifs are required for ATP binding, self-oligomerization, TLR/CD40L-activated association with NIK and IRAK-1, degradation of NIK, and inhibition of IRAK-1 phosphorylation. Walker A/B mutants fail to suppress inflammatory cytokines. In vitro ATP-binding and hydrolysis assays with purified protein, Walker A/B mutagenesis, Co-IP, stable THP-1 cell expression, cytokine measurement Molecular and Cellular Biology High 18160710
2007 NLRP12 (Monarch-1) inhibits CD40-mediated noncanonical NF-κB activation in human monocytes by associating with NF-κB-inducing kinase (NIK) and inducing its proteasome-mediated degradation; shRNA silencing of NLRP12 enhances p52-dependent chemokine expression. Co-immunoprecipitation, shRNA knockdown, NF-κB reporter, proteasome inhibitor experiments, chemokine expression analysis Journal of Immunology High 17237370
2007 Hsp90 associates with NLRP12 (Monarch-1) in human monocytes; disruption of Hsp90-NLRP12 complexes leads to rapid proteasomal degradation of NLRP12 and prevents NLRP12-induced proteolysis of NIK, demonstrating that Hsp90 is a critical regulator of NLRP12 anti-inflammatory activity. 2D gel/mass spectrometry, Co-IP, Hsp90 inhibitor treatment, Western blot for NIK degradation Journal of Immunology High 17947705
2009 Blimp-1/PRDM1 transcriptionally suppresses NLRP12 expression by binding to a novel site in the NLRP12 promoter in a TLR-inducible manner; Blimp-1-/- murine myeloid cells show elevated NLRP12 expression, confirming inverse correlation in vivo. Promoter-reporter assays, ChIP, Blimp-1 KO mouse myeloid cells, RT-PCR, histone acetylation analysis Journal of Immunology High 19234190
2010 NLRP12 is required for dendritic cell and neutrophil migration competence; Nlrp12-deficient DCs exhibit significantly reduced capacity to migrate to draining lymph nodes and both DCs and neutrophils fail to respond to chemokines in vitro. Nlrp12-/- mouse model, contact hypersensitivity models, in vitro chemotaxis assays, lymph node migration assays Journal of Immunology High 20861349
2011 The NLRP12 pyrin domain (PYD) adopts a six-helical bundle death domain fold; NMR spectroscopy revealed a non-homotypic PYD interaction between NLRP12-PYD and the pro-apoptotic protein FAF-1 UBA domain, confined to the α2-α3 surface with Trp45 playing a key role. NMR spectroscopy structure determination, in vitro binding assays, mutagenesis of Trp45 Journal of Molecular Biology High 21978668
2011 The NLRP12 R352C missense mutation (in the NBS/NACHT domain) does not alter the inhibitory effect on NF-κB but increases inflammasome speck formation and activates caspase-1 signaling, representing a gain-of-function for inflammasome assembly. HEK293T co-transfection assays, ASC speck formation assay, caspase-1 activity assay, NF-κB luciferase reporter Arthritis and Rheumatism Medium 21538323
2012 NLRP12 interacts with both NIK and TRAF3 in vivo; Nlrp12-/- cells have constitutively elevated NIK and increased p100 processing to p52 with reduced TRAF3, establishing NLRP12 as a checkpoint of noncanonical NF-κB signaling. NLRP12 also negatively regulates ERK and AKT signaling in tumor tissues. Co-immunoprecipitation, Nlrp12-/- mouse model (colitis/tumorigenesis), Western blot for NIK/TRAF3/p100/p52, bone marrow chimeras Immunity High 22503542
2011 NLRP12 deficiency in mice results in failure to dampen NF-κB and ERK activation in macrophages, leading to increased production of inflammatory cytokines, chemokines, and tumorigenic factors and heightened susceptibility to colitis and colorectal tumorigenesis. Nlrp12-/- mouse model, colitis/tumorigenesis induction, Western blot for NF-κB/ERK, ELISA for cytokines Cancer Cell High 22094258
2013 NLRP12 mediates inhibition of NF-κB and ERK activation in Salmonella-infected macrophages by suppressing phosphorylation of IκBα and ERK; NLRP12-mediated down-regulation of antimicrobial molecules prevents efficient bacterial clearance. Nlrp12-/- mouse model, S. typhimurium infection, Western blot for pIκBα and pERK, bacterial burden assays Proceedings of the National Academy of Sciences High 24347638
2014 Plasmodium infection drives NLRP12/NLRP3-dependent caspase-1 activation in macrophages, requiring IFN-γ priming and ASC, P2X7R expression; NLRP12-containing pyroptosomes were identified in monocytes from malaria patients. Nlrp12-/- and Nlrp3-/- mouse infection models, caspase-1 activity assays, flow cytometry for caspase-1+ monocytes, IL-1β measurement PLoS Pathogens Medium 24453977
2015 NLRP12 deficiency in T cells leads to hyperinflammatory T cell responses with elevated NF-κB activity; specifically, NLRP12 negatively regulates IL-4 production in T cells, and enhanced IL-4 drives atypical EAE neuroinflammatory disease in Nlrp12-/- mice. Nlrp12-/- mouse model, CD4+ T cell transfer into immunodeficient mice, EAE model, intracellular cytokine staining, NF-κB reporter Immunity High 25888258
2015 NLRP12 suppresses noncanonical NF-κB-induced osteoclastogenesis; retroviral overexpression of NLRP12 suppressed RelB nuclear translocation and osteoclast formation, while Nlrp12-/- cells showed NIK stabilization, RelB nuclear translocation, and increased osteoclastogenesis in vitro and increased osteoclast numbers with bone mass loss in vivo. Retroviral overexpression, Nlrp12-/- mouse model, radiation chimeras, RANKL injection osteolysis model, Western blot for NIK/RelB, histomorphometry Proceedings of the National Academy of Sciences High 26240332
2018 NLRP12 dampens RIG-I-mediated antiviral signaling by: (1) its nucleotide-binding domain interacting with the E3 ubiquitin ligase TRIM25 to prevent TRIM25-mediated K63-linked ubiquitination of RIG-I; and (2) enhancing RNF125-mediated K48-linked degradative ubiquitination of RIG-I, thereby controlling RIG-I's association with MAVS. Co-immunoprecipitation, ubiquitination assays, VSV infection of myeloid-specific Nlrp12-/- mice, IFN/TNF measurement Cell Host & Microbe High 30902577
2018 NLRP12 promotes K48-linked ubiquitination and proteasomal degradation of NOD2 in response to bacterial MDP, mediated through the linker region proximal to the NACHT domain of NLRP12; it also sequesters HSP90 to facilitate this process. Disease-causing R284X mutation fails to repress MDP-induced NF-κB and JAK/STAT signaling. Co-immunoprecipitation, ubiquitination assays, Nlrp12-/- mouse/monocyte model, MDP stimulation, NF-κB/STAT reporter, Citrobacter colonization model Nature Communications High 30559449
2018 Crystal structure of human NLRP12 PYD domain at 1.70 Å resolution reveals a dimeric configuration through a disulfide bond, suggesting a role for ROS-induced NF-κB activation. X-ray crystallography (MBP-fusion construct) PLoS One Medium 29293680
2019 NLRP12 negatively regulates hepatocellular carcinoma via downregulation of JNK activation in hepatocytes; JNK inhibition or NLRP12 overexpression reduced proliferative and inflammatory responses in Nlrp12-/- hepatocytes stimulated with microbial PAMPs. Nlrp12-/- mouse DEN-induced HCC model, JNK inhibitor, NLRP12 overexpression, Western blot for pJNK, proliferation assays eLife Medium 30990169
2020 NLRP12 negatively regulates RANKL-induced osteoclastogenesis through inhibition of NF-κB; NLRP12-/- preosteoclasts show elevated IκB-α degradation and p65 phosphorylation upon RANKL stimulation. Nlrp12-/- mouse-derived preosteoclasts, RANKL stimulation, Western blot for pIκB-α and pp65, TRAP staining, micro-CT Journal of Dental Research Medium 30681895
2020 NLRP12 negatively regulates IL-6-induced STAT3 phosphorylation in T cells, thereby acting as a checkpoint inhibitor of Th17 cell differentiation; pharmacological STAT3 inhibition abrogated hyperinflammatory arthritis in Nlrp12-/- mice. Nlrp12-/- mouse AIA model, adoptive T cell transfer, anti-IL-17A treatment, in vitro Th17 differentiation assay, Western blot for pSTAT3 FASEB Journal High 32632939
2021 SARS-CoV-2 NSP5 (3C-like protease) directly cleaves NLRP12 protein in vitro; a cleavage site present in human NLRP12 is absent in mouse NLRP12, potentially contributing to species-specific disease presentation. In vitro protease cleavage assay, comparative sequence alignment of NLRP12 homologs across species Emerging Microbes & Infections Medium 33372854
2023 NLRP12 drives PANoptosome formation and PANoptosis in response to heme plus PAMPs or TNF; TLR2/4-mediated IRF1 induction upregulates Nlrp12 expression, which leads to inflammasome assembly for IL-1β/IL-18 maturation and a larger NLRP12-PANoptosome complex driving caspase-8/RIPK3-dependent cell death. Deletion of Nlrp12 protected mice from acute kidney injury in a hemolytic model. Nlrp12-/- mouse model, hemolytic disease model, IRF1 KO, caspase-8/RIPK3 KO, Western blot for inflammasome components, ELISA, live cell imaging Cell High 37267949
2023 IRF1 regulates NLRP12-PANoptosome activation and PANoptosis; IRF1 contributed to NLRP12-PANoptosome-dependent cell death but was dispensable for inflammasomes that form independently of the PANoptosome. IRF1-/- primary murine macrophages, live cell imaging, Western blot, ELISA, NLRP12-PANoptosome trigger stimulation The Journal of Biological Chemistry Medium 37557956
2023 NLRP12 downregulates the Wnt/β-catenin pathway by interacting with STK38, which inhibits phosphorylation of GSK3β, leading to β-catenin degradation; conditional Nlrp12-KO in intestinal epithelial cells showed increased β-catenin activation and proliferation. Proteomics (NLRP12 interactome), Co-immunoprecipitation, Nlrp12 conditional KO mice, intestinal organoids, Western blot for p-GSK3β/β-catenin The Journal of Clinical Investigation High 37581937
2023 NLRP12 inhibits ASC inflammasome assembly induced by wild-type and gain-of-function NLRP3 via direct protein interaction; wild-type NLRP12 but not disease-associated NLRP12 mutants suppressed NLRP3 inflammasome assembly. This suppression was specific to human (not murine) NLRP3. NLR ASC polymerization screen, Co-immunoprecipitation, PBMCs from NLRP12-mutant patients (IL-1β measurement), NLRP12 disease mutant expression Science Signaling High 38261657
2023 NLRP12 suppresses type I IFN production and SLE progression; NLRP12 expression is transcriptionally suppressed by RUNX1-dependent epigenetic regulation under IFN-I treatment, creating a negative feedback loop. Nlrp12-/- lupus-prone mice showed augmented autoantibody production, glomerular IgG deposition, and kidney deterioration in an IFN-I-dependent manner. Nlrp12-/- pristane-treated mice, lupus-prone mouse models, ChIP for RUNX1, Western blot, ELISA, flow cytometry The Journal of Clinical Investigation Medium 36719379
2018 NLRP12 is predominantly expressed in neutrophils (not macrophages or DCs in mice); in the C57BL/6J substrain, a missense mutation in Nlrp12 causes defective CXCL1 production in macrophages and impaired neutrophil recruitment; restoration of macrophage NLRP12 rescues the neutrophil defect. C57BL/6J vs C57BL/6N comparison, Nlrp12-/- macrophage reconstitution, CXCL1 ELISA, neutrophil migration assays Nature Communications High 27779193
2024 Full-length NLRP12 can form an inflammasome in vitro, reconstituted by its PYD domain activating caspase-1 to induce IL-1β cleavage and GSDMD cleavage; NLRP12 is specifically expressed in neutrophils and eosinophils but not macrophages. Several patient-derived NLRP12 mutations caused spontaneous caspase-1 activation in vitro. Inflammasome reconstitution in vitro, PYD domain screen for caspase-1 activation, cell-type expression analysis, patient mutation functional assays Frontiers in Immunology Medium 39076995
2024 NLRP12 interacts with viral glycoprotein GP2a through its LRR domain and recruits E3 ubiquitin ligase MARCH8 via its PYD domain, facilitating K48-linked polyubiquitination of GP2a at K128 and lysosomal degradation via the MARCH8-NDP52 pathway to restrict PRRSV replication. Co-immunoprecipitation, domain mapping, ubiquitination assays, lysosome inhibitors, overexpression/silencing of NLRP12 Veterinary Microbiology Medium 39362085
2025 Hematopoietic cell kinase (HCK) was identified as a regulator of NLRP12-mediated PANoptosis; HCK knockdown inhibited NLRP12-PANoptosis and computational analysis suggests HCK binds NLRP12 in the region between the NACHT domain and PYD; removal of the NLRP12 PYD abrogated the HCK-NLRP12 interaction in vitro. Computational interaction modeling, in vitro binding assay with PYD deletion mutant, Hck knockdown in macrophages, cell death assays Proceedings of the National Academy of Sciences Medium 40408404
2018 NLRP12 promotes neutrophil differentiation through regulation of noncanonical NF-κB and MAPK/ERK1/2 signaling; NLRP12 inhibits ERK1/2 activity, which relieves ERK1/2-mediated suppression of NIK protein levels, thereby enhancing RelB nuclear translocation and neutrophil differentiation. RNA-seq, Nlrp12-/- in vitro differentiation assays, Western blot for NIK/RelB/pERK1/2 International Journal of Biological Sciences Medium 29483833
2019 NLRP12 inhibits DENV and other flavivirus replication via its NACHT domain; NLRP12 interacts with HSP90 in a Walker A/B-dependent manner and enhances type I IFN (IFN-α/β) and ISG production; HSP90 inhibition impairs NLRP12-induced type I IFN upregulation. NLRP12 overexpression/silencing, NACHT domain mutants, HSP90 inhibitor (17-DMAG), IFN-α/β ELISA, viral titer assays Frontiers in Immunology Medium 34956178
2020 NLRP12 colocalizes with NLRP3 and NLRC4 downstream of the caspase-8-HIF-1α axis in microglial cells to activate caspase-1, IL-1β maturation, and GSDMD-dependent pyroptosis; IL-1β in turn amplifies the CASP8-HIF-1α-NLRP12/NLRP3/NLRC4 circuit. Genetic deletion of GSDMD/CASP8/NLRP12/NLRP3/NLRC4 in retinal ischemia-reperfusion model, immunofluorescence, Western blot, IL-1β ELISA Molecular Neurodegeneration Medium 32295623
2024 AIP1 inhibits pathological ocular angiogenesis by preventing NLRP12-ASC-caspase-8 inflammasome assembly in retinal vascular endothelial cells; this noncanonical inflammasome drives GSDMD-dependent endothelial pyroptosis, releasing VEGF and IL-1β. Suppression of the NLRP12-CASP8-GSDMD axis reduced VEGF signaling and neovascularization. Single-cell RNA-seq (AIP1 identification), genetic knockdown of NLRP12/ASC/CASP8/GSDMD, OIR mouse model, Western blot, VEGF/IL-1β ELISA 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 421 22503542
2011 The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer cell 345 22094258
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 314 12019269
2023 NLRP12-PANoptosome activates PANoptosis and pathology in response to heme and PAMPs. Cell 302 37267949
2017 NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth. Nature immunology 249 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 208 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 189 16203735
2007 Monarch-1 suppresses non-canonical NF-kappaB activation and p52-dependent chemokine expression in monocytes. Journal of immunology (Baltimore, Md. : 1950) 180 17237370
2018 The Inhibitory Innate Immune Sensor NLRP12 Maintains a Threshold against Obesity by Regulating Gut Microbiota Homeostasis. Cell host & microbe 170 30212649
2011 Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis and rheumatism 147 21360512
2014 Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection. PLoS pathogens 145 24453977
2020 NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma. Molecular neurodegeneration 137 32295623
2010 Cutting edge: NLRP12 controls dendritic and myeloid cell migration to affect contact hypersensitivity. Journal of immunology (Baltimore, Md. : 1950) 120 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 119 24347638
2020 NLRP12 in innate immunity and inflammation. Molecular aspects of medicine 114 32838963
2015 The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells. Immunity 94 25888258
2007 ATP binding by monarch-1/NLRP12 is critical for its inhibitory function. Molecular and cellular biology 90 18160710
2019 NLRP12 Regulates Anti-viral RIG-I Activation via Interaction with TRIM25. Cell host & microbe 82 30902577
2023 Immune regulator IRF1 contributes to ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosome activation and inflammatory cell death (PANoptosis). The Journal of biological chemistry 81 37557956
2011 Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes. Arthritis and rheumatism 81 21538323
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) 80 12759408
2011 Role of interleukin-1β in NLRP12-associated autoinflammatory disorders and resistance to anti-interleukin-1 therapy. Arthritis and rheumatism 79 21480187
2020 NLRP12- and NLRC4-mediated corneal epithelial pyroptosis is driven by GSDMD cleavage accompanied by IL-33 processing in dry eye. The ocular surface 70 32735949
2016 Nlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment. Nature communications 70 27779193
2014 The multifaceted nature of NLRP12. Journal of leukocyte biology 61 25249449
2014 Role of Nlrp6 and Nlrp12 in the maintenance of intestinal homeostasis. European journal of immunology 59 24338634
2011 The NLRP12 pyrin domain: structure, dynamics, and functional insights. Journal of molecular biology 59 21978668
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) 57 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 51 28663562
2019 NLRP12 suppresses hepatocellular carcinoma via downregulation of cJun N-terminal kinase activation in the hepatocyte. eLife 44 30990169
2018 Proteasomal degradation of NOD2 by NLRP12 in monocytes promotes bacterial tolerance and colonization by enteropathogens. Nature communications 43 30559449
2016 NLRP12 autoinflammatory disease: a Chinese case series and literature review. Clinical rheumatology 43 27633793
2016 Involvement of EGF receptor signaling and NLRP12 inflammasome in fine particulate matter-induced lung inflammation in mice. Environmental toxicology 40 27377055
2018 Multigene sequencing reveals heterogeneity of NLRP12-related autoinflammatory disorders. Rheumatology international 39 29500522
2015 The nod-like receptor, Nlrp12, plays an anti-inflammatory role in experimental autoimmune encephalomyelitis. Journal of neuroinflammation 39 26521018
2015 NLRP12 modulates host defense through IL-17A-CXCL1 axis. Mucosal immunology 38 26349659
2007 Monarch-1/PYPAF7 and other CATERPILLER (CLR, NOD, NLR) proteins with negative regulatory functions. Microbes and infection 32 17418609
2022 NLRP12-associated systemic autoinflammatory diseases in children. Pediatric rheumatology online journal 31 35123508
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 30 26514298
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
2014 Novel NLRP12 mutations associated with intestinal amyloidosis in a patient diagnosed with common variable immunodeficiency. Clinical immunology (Orlando, Fla.) 29 25064839
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 is an innate immune checkpoint for repressing IFN signatures and attenuating lupus nephritis progression. The Journal of clinical investigation 27 36719379
2023 NLRP12 drives PANoptosis in response to heme. Trends in immunology 27 37423881
2023 NLRP12 downregulates the Wnt/β-catenin pathway via interaction with STK38 to suppress colorectal cancer. The Journal of clinical investigation 27 37581937
2024 NLRP12 interacts with NLRP3 to block the activation of the human NLRP3 inflammasome. Science signaling 26 38261657
2020 NLRP12 negatively regulates EtOH-induced liver macrophage activation via NF-κB pathway and mediates hepatocyte apoptosis in alcoholic liver injury. International immunopharmacology 26 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 22 27314497
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
2015 NLRP12 provides a critical checkpoint for osteoclast differentiation. Proceedings of the National Academy of Sciences of the United States of America 21 26240332
2021 NLRP12 reduces proliferation and inflammation of rheumatoid arthritis fibroblast-like synoviocytes by regulating the NF-κB and MAPK pathways. European cytokine network 20 34369379
2019 The clinical phenotype and genotype of NLRP12-autoinflammatory disease: a Chinese case series with literature review. World journal of pediatrics : WJP 20 31820221
2017 Innate Immune Cell Recovery Is Positively Regulated by NLRP12 during Emergency Hematopoiesis. Journal of immunology (Baltimore, Md. : 1950) 20 28159904
2023 The role of NLRP12 in inflammatory diseases. European journal of pharmacology 17 37572944
2018 Membrane microdomains regulate NLRP10- and NLRP12-dependent signalling in A549 cells challenged with cigarette smoke extract. Archives of toxicology 17 29623357
2016 Inflammasome-independent role of NLRP12 in suppressing colonic inflammation regulated by Blimp-1. Oncotarget 17 27105524
2024 NLRP3, NLRP6, and NLRP12 are inflammasomes with distinct expression patterns. Frontiers in immunology 16 39076995
2020 NLRP12 gene mutations and auto-inflammatory diseases: ever-changing evidence. Rheumatology (Oxford, England) 16 32725138
2021 A Novel Role for the Regulatory Nod-Like Receptor NLRP12 in Anti-Dengue Virus Response. Frontiers in immunology 15 34956178
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
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
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.] 14 31292668
2023 NLRP12-expressing dendritic cells mediate both dissemination of infection and adaptive immune responses in visceral leishmaniasis. iScience 12 36879824
2021 Contrasting role of NLRP12 in autoinflammation: evidence from a case report and mouse models. RMD open 12 34725261
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 12 30858956
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
2024 Overexpression of NLRP12 enhances antiviral immunity and alleviates herpes simplex keratitis via pyroptosis/IL-18/IFN-γ signaling. International immunopharmacology 11 38908077
2018 NLRP12 Promotes Mouse Neutrophil Differentiation through Regulation of Non-canonical NF-κB and MAPKERK1/2 Signaling. International journal of biological sciences 11 29483833
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 11 25620184
2025 Short-Chain Chlorinated Paraffins May Induce Ovarian Damage in Mice via AIM2- and NLRP12-PANoptosome. Environmental science & technology 10 39754571
2024 AIP1 Regulates Ocular Angiogenesis Via NLRP12-ASC-Caspase-8 Inflammasome-Mediated Endothelial Pyroptosis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 10 39527457
2023 NLRP12-associated autoinflammatory disease in Chinese adult patients: a single-centre study. RMD open 10 38123482
2022 Rare mutations in NLRP3 and NLRP12 associated with familial cold autoinflammatory syndrome: two Chinese pedigrees. Clinical rheumatology 10 35852776
2021 A rare case of an NLRP12-associated autoinflammatory disease. European journal of medical genetics 10 33676062
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
2024 NLRP12 inhibits PRRSV-2 replication by promoting GP2a degradation via MARCH8. Veterinary microbiology 9 39362085
2023 NLRP12 senses heme and PAMPs to drive necrotic cell death and inflammation. Molecular cell 9 37541218
2022 The innate immune receptor Nlrp12 suppresses autoimmunity to the retina. Journal of neuroinflammation 9 35313917
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
2020 Persistent DNA damage-induced NLRP12 improves hematopoietic stem cell function. JCI insight 9 32434992
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
2025 HCK regulates NLRP12-mediated PANoptosis. Proceedings of the National Academy of Sciences of the United States of America 8 40408404
2024 Overexpression of NLRP12 enhances macrophage immune response and alleviates herpes simplex keratitis. Frontiers in cellular and infection microbiology 8 39119293
2023 NLRP12-associated autoinflammatory disease: much more than the FCAS phenotype. Clinical and experimental rheumatology 8 37877365
2022 Clinical heterogeneity of NLRP12-associated autoinflammatory diseases. Genes & diseases 8 37396539
2021 Toxoplasma gondii activates NLRP12 inflammasome pathway in the BALB/c murine model. Acta tropica 8 34688629
2019 Toll-like receptor 3 (TLR3) variant and NLRP12 mutation confer susceptibility to a complex clinical presentation. Clinical immunology (Orlando, Fla.) 8 31445170
2018 Crystal structure of human NLRP12 PYD domain and implication in homotypic interaction. PloS one 8 29293680
2025 A Novel Protein NLRP12-119aa that Prevents Rhabdovirus Replication by Disrupting the RNP Complex Formation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 7 39754725