{"gene":"NLRP7","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2005,"finding":"NLRP7 (PYPAF3) inhibits caspase-1-dependent IL-1β secretion; stable expression of NLRP7 in THP-1 cells abrogated LPS-induced IL-1β production, and NLRP7 mRNA expression was induced by LPS or IL-1β stimulation, placing it as a feedback regulator of IL-1β secretion.","method":"Stable transfection in THP-1 monocytic cells, LPS/IL-1β stimulation, IL-1β secretion assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD/OE with defined cellular phenotype (IL-1β secretion) in THP-1 cells, single lab, two methods (stable expression + mRNA induction)","pmids":["15817483"],"is_preprint":false},{"year":2010,"finding":"The N-terminal pyrin domain (PYD) of NLRP7 adopts a six-alpha-helix bundle death domain fold; helix α3 and loop α2-α3 are stabilized by a strong hydrophobic cluster, and the electrostatic surface differs from NLRP1 PYD, providing a structural basis for differential inflammasome signaling specificity.","method":"NMR spectroscopy (3D structure determination of NLRP7 PYD)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional interpretation and comparison to other PYDs, single lab but structure-grade evidence","pmids":["20547486"],"is_preprint":false},{"year":2011,"finding":"NLRP7 co-localizes with the Golgi apparatus and the microtubule-organizing center (MTOC) and is associated with microtubules in peripheral blood mononuclear cells; cells from patients with NLRP7 mutations secrete low levels of IL-1β and TNF in response to LPS, and NLRP7 down-regulates pro-IL-1β synthesis; this inhibitory function is abolished by protein-truncating mutations after the Pyrin domain.","method":"Immunofluorescence co-localization, transient transfection with truncation mutants, ELISA for IL-1β/TNF from patient PBMCs","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence tied to functional consequence (cytokine secretion), mutant constructs, patient cells; single lab","pmids":["22025618"],"is_preprint":false},{"year":2012,"finding":"NLRP7 assembles an inflammasome complex in human macrophages in response to microbial acylated lipopeptides; this complex is ASC-dependent, activates caspase-1, drives maturation and release of IL-1β and IL-18, induces pyroptosis, and restricts intracellular bacterial replication; it does not affect caspase-1-independent secretion of IL-6 or TNF-α.","method":"Co-immunoprecipitation (ASC/caspase-1 complex), NLRP7 knockdown, IL-1β/IL-18/IL-6/TNF-α ELISA, bacterial replication assays in human macrophages","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP demonstrating complex assembly, KD with multiple cytokine readouts and bacterial restriction phenotype; single lab but multiple orthogonal methods","pmids":["22361007"],"is_preprint":false},{"year":2012,"finding":"NLRP7 and KHDC3L co-localize to a juxta-perinuclear signal consistent with the MTOC/Golgi in lymphoblastoid cell lines from normal subjects; KHDC3L mutations do not change the subcellular localization of KHDC3L but NLRP7 and KHDC3L proteins co-localize in this compartment.","method":"Immunofluorescence in lymphoblastoid cell lines","journal":"European journal of human genetics : EJHG","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (immunofluorescence), single lab, no functional consequence linked to co-localization","pmids":["23232697"],"is_preprint":false},{"year":2013,"finding":"NLRP7 interacts with YY1 (a chromatin-binding transcription factor) in human embryonic stem cells; reduced NLRP7 levels alter DNA methylation and accelerate trophoblast lineage differentiation, demonstrating a role in chromatin reprogramming and DNA methylation.","method":"Co-immunoprecipitation (NLRP7–YY1 interaction), NLRP7 knockdown in hESCs, DNA methylation analysis, trophoblast differentiation assays","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing interaction, KD with defined cellular phenotype (methylation + differentiation), single lab","pmids":["24105472"],"is_preprint":false},{"year":2014,"finding":"The NACHT-associated domain (NAD) of NLRP7 is central to its oligomeric assembly; upon activation, the NAD and part of the LRR of one NLRP7 molecule interact with the NACHT domain of a second molecule to form an oligomer. Disease-causing missense mutations L398R and R693W decrease oligomerization potential and increase aggresome formation.","method":"Yeast two-hybrid inter-domain interaction screen, in silico structural modeling, confocal microscopy of transiently transfected NLRP7 mutants in HEK293T cells","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus confocal microscopy with disease mutants, single lab, two orthogonal methods","pmids":["25082979"],"is_preprint":false},{"year":2015,"finding":"The NBD of NLRP7 is an ATP-binding domain with ATPase activity; an intact Walker A motif is required for nucleotide binding, hydrolysis, NLRP7 oligomerization, inflammasome formation, and activity. THP-1 cells expressing a Walker A mutant display defective NLRP7 inflammasome activation, IL-1β release, and pyroptosis in response to acylated lipopeptides and S. aureus infection.","method":"In vitro ATP binding and ATPase assays, Walker A motif mutagenesis, co-immunoprecipitation (oligomerization), IL-1β ELISA, pyroptosis assay in THP-1 cells","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay plus mutagenesis, multiple orthogonal methods (binding, hydrolysis, oligomerization, cell-based inflammasome activity), single lab","pmids":["26143398"],"is_preprint":false},{"year":2015,"finding":"NLRP7 interacts with the transcriptional repressor ZBTB16; this interaction was verified by yeast two-hybrid, co-immunoprecipitation, and confocal microscopy in mammalian cells; both proteins are found in a ~480 kDa complex and co-localize in cytoplasmic juxtanuclear aggregates; overexpressed NLRP7 sequesters ZBTB16 in the cytoplasm away from the nucleus.","method":"Yeast two-hybrid (ovarian library screen), co-immunoprecipitation, native PAGE (480 kDa complex), confocal microscopy","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Y2H, Co-IP, native complex, microscopy) establishing interaction, single lab","pmids":["26121690"],"is_preprint":false},{"year":2014,"finding":"NLRP7 and KHDC3L localize to the oocyte cytoskeleton and are predominant at the cortical region in growing oocytes; after first cell division they become asymmetrically confined to the outer cortical region and excluded from the cell-to-cell contact region until the blastocyst stage where they redistribute to the cytoplasm and nucleus respectively.","method":"High-resolution confocal immunofluorescence and electron microscopy on human oocytes and preimplantation embryos (n=164)","journal":"Human reproduction (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by confocal + electron microscopy in primary human material, large sample size, single lab","pmids":["25358348"],"is_preprint":false},{"year":2017,"finding":"NLRP7 protein is constitutively ubiquitinated and targeted to the endolysosome for degradation; upon TLR ligation (LPS or Pam3CSK4), the deubiquitinase STAMBP deubiquitinates NLRP7, prevents its lysosomal trafficking, and increases NLRP7 protein abundance, thereby potentiating inflammasome activation and IL-1β release. A small-molecule STAMBP inhibitor (BC-1471) reduces NLRP7 levels and suppresses IL-1β release.","method":"Ubiquitination assays, STAMBP knockdown, endolysosomal trafficking assays, small-molecule inhibitor (BC-1471), IL-1β ELISA","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (ubiquitination assay, KD, trafficking, pharmacological inhibition), single lab, clear mechanistic pathway established","pmids":["28492230"],"is_preprint":false},{"year":2017,"finding":"NLRP7 translocates to the nucleus of decidualized endometrial stromal cells and promotes progesterone receptor (PR) transcriptional activity and IGFBP-1 expression; knockdown of NLRP7 reduces decidualization markers while overexpression enhances them.","method":"Subcellular fractionation, confocal microscopy, siRNA knockdown and lentiviral overexpression in T-HESCs, PR reporter assay, ELISA for IGFBP-1 and prolactin","journal":"Reproductive biology and endocrinology : RB&E","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct nuclear translocation shown by fractionation and confocal, KD/OE with defined phenotype (PR activity, IGFBP-1), single lab, multiple orthogonal methods","pmids":["28810880"],"is_preprint":false},{"year":2016,"finding":"The NLRP7 inflammasome is activated by virulent Mycobacterium bovis Beijing strain in THP-1 macrophages, promoting IL-1β secretion, caspase-1 activation, pyroptosis induction, and upregulation of TNF-α, CCL3, and IL-1β mRNAs.","method":"NLRP7 knockdown (siRNA) in THP-1 macrophages, M. bovis infection, caspase-1 activity assay, IL-1β ELISA, pyroptosis assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KD with defined phenotypic readouts (caspase-1, IL-1β, pyroptosis), single lab, single method for each readout","pmids":["27043315"],"is_preprint":false},{"year":2021,"finding":"NLRP7 is deubiquitinated by USP10 in colorectal cancer cells; this stabilizes NLRP7 protein (K379 is an important lysine acceptor site for ubiquitination); NLRP7 promotes NF-κB nuclear translocation and CCL2 transcription, which induces polarization of pro-tumor M2-like macrophages.","method":"Co-immunoprecipitation/mass spectrometry, ubiquitination/deubiquitination assays, K379 mutagenesis, RNA sequencing, NF-κB reporter, ELISA for CCL2, flow cytometry for macrophage phenotype, in vivo tumor models","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS identifying USP10, mutagenesis of ubiquitination site, multiple downstream readouts; single lab","pmids":["33838681"],"is_preprint":false},{"year":2020,"finding":"NLRP7 deficiency in patient-derived trophoblasts (iPSC model) causes precocious downregulation of pluripotency factors and excessive trophoblast differentiation; these phenotypes are dependent on BMP4 signaling, as BMP pathway inhibition corrects the excessive differentiation.","method":"Patient-derived iPSC trophoblast differentiation model, whole transcriptome profiling, BMP pathway inhibition rescue experiment","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function (patient NLRP7 mutations in iPSCs) with defined cellular phenotype and pharmacological epistasis (BMP inhibition rescue), single lab","pmids":["32814763"],"is_preprint":false},{"year":2020,"finding":"NLRP7 inflammasome activation in trophoblast cells increases IL-1β secretion but not IL-18 secretion; NLRP7 controls trophoblast proliferation, differentiation towards syncytium, and invasive extravillous trophoblast differentiation, and has an anti-apoptotic role; NLRP7 expression is upregulated by hypoxia.","method":"NLRP7 knockdown/overexpression in primary trophoblasts and trophoblast cell lines, [3H]-thymidine proliferation assay, 2D/3D invasion cultures, xCELLigence, β-hCG/syncytin ELISA, IL-1β/IL-18 ELISA, hypoxia treatment","journal":"Journal of molecular medicine (Berlin, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple KD/OE experiments with defined functional readouts, single lab, multiple orthogonal methods","pmids":["30617930"],"is_preprint":false},{"year":2020,"finding":"NLRP7 inflammasome assembles around the nucleus in human amnion epithelial cells (AECs) upon stimulation with FSL-1 (a Mycoplasma salivarium-derived lipopeptide), leading to NLRP7–ASC co-localization, pro-caspase-1 and gasdermin D cleavage into mature forms.","method":"Immunofluorescence (NLRP7/ASC co-localization), Western blot (pro-caspase-1 and gasdermin D cleavage), RT-qPCR, FSL-1 stimulation of primary AECs","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct inflammasome assembly shown by co-localization and caspase/gasdermin D cleavage in primary cells, single lab","pmids":["32849565"],"is_preprint":false},{"year":2021,"finding":"NLRP7 promotes choriocarcinoma (CC) cell proliferation, 3D organization, and tumor growth in an inflammasome-independent manner; CC cells with NLRP7 invalidated generated smaller tumors with higher maternal immune response and less metastases in an orthotopic mouse model.","method":"NLRP7 knockdown in CC cell lines, in vitro proliferation/3D culture assays, orthotopic mouse CC model, immune phenotyping","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with defined tumor growth and immune phenotype, KD with multiple readouts; single lab","pmids":["34203890"],"is_preprint":false},{"year":2023,"finding":"In choriocarcinoma (JEG-3) cells, NLRP7 functions in an inflammasome-independent manner and differentially regulates NF-κB activity (compared to non-tumor HTR8/SVneo cells where it acts inflammasome-dependently); NLRP7 increases malignant cell survival, dedifferentiation, and immune camouflage, and facilitates tumor cell colonization of the lungs in a preclinical GC model.","method":"NLRP7 knockdown (shRNA) in JEG-3, NLRP7 overexpression in HTR8/SVneo, NF-κB activity assay, in vivo metastatic mouse model","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — parallel cell systems with KD/OE, in vivo validation, NF-κB pathway placement; single lab","pmids":["36980199"],"is_preprint":false},{"year":2024,"finding":"ELF3 transactivates NLRP7 while suppressing NLRP2 in extravillous trophoblast (EVT) JEG-3 cells by binding to their shared enhancer; NLRP7 and NLRP2 have opposing effects on HLA-C expression, with NLRP7 promoting HLA-C levels (likely through modulating IκBα degradation kinetics) and NLRP2 suppressing them, implicating this axis in maternal immune evasion.","method":"ELF3 knockout in JEG-3, ChIP-like analysis of ELF3 binding to NLRP2/NLRP7 enhancer, NLRP7/NLRP2 overexpression/knockdown with HLA-C expression readout, IκBα protein level measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus OE/KD with defined molecular readout (HLA-C, IκBα), single lab, multiple orthogonal approaches","pmids":["39052836"],"is_preprint":false},{"year":2025,"finding":"NLRP7 interacts with TCL1A (a DNMT3A inhibitor) and the cryo-EM structure of the NLRP7-TCL1A complex was determined; NLRP7 sequesters TCL1A in the cytoplasm, preventing its nuclear entry and consequent suppression of DNMT3A-mediated de novo methylation; most recurrent hydatidiform mole-causing NLRP7 variants impair the NLRP7-TCL1A interaction, providing a mechanistic explanation for oocyte hypomethylation.","method":"Cryo-EM structure determination of NLRP7-TCL1A complex, co-immunoprecipitation, subcellular fractionation (TCL1A cytoplasmic retention), interaction analysis of NLRP7 pathogenic variants, in silico pathogenicity predictions","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus multiple orthogonal methods (Co-IP, fractionation, variant interaction analysis), single lab but Tier 1 structural evidence with mechanistic validation","pmids":["41786744"],"is_preprint":false},{"year":2025,"finding":"NLRP7 knockout in human embryonic stem cells and blastoids increases DNA damage and apoptosis; mechanistically, NLRP7 interacts with alternative splicing factors and DNA damage response proteins (DDX39B, PRPF8, THRAP3, PARP1), and its loss causes abnormal alternative splicing of homologous recombination genes (BRCA1, RAD51), compromising genomic integrity during early embryogenesis.","method":"NLRP7 knockout in hESCs and blastoids, co-immunoprecipitation identifying DDX39B/PRPF8/THRAP3/PARP1 as binding partners, RNA-seq for alternative splicing analysis, DNA damage assays (γH2AX), apoptosis assay","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO phenotype plus Co-IP establishing binding partners plus RNA-seq mechanism, single lab, multiple orthogonal methods","pmids":["39865169"],"is_preprint":false},{"year":2020,"finding":"In NLRP7-mutated patient monocytes, homozygous or compound heterozygous mutations in different NLRP7 domains cause distinct defects: abnormal intracellular pro-IL-1β levels or impaired mature IL-1β processing; plasmids encoding NLRP7 non-synonymous variants affect pro-IL-1β processing and/or trafficking together with caspase-1 and ASC.","method":"Patient PBMC LPS stimulation, ELISA for secreted IL-1β, intracellular staining for pro-IL-1β and mature IL-1β, overexpression of NLRP7 variant plasmids in cell lines, ASC/caspase-1 co-expression","journal":"Clinical and experimental immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient cells plus reconstitution with mutant constructs, multiple readouts; single lab","pmids":["32484253"],"is_preprint":false}],"current_model":"NLRP7 is a cytoplasmic NLR protein whose PYD domain adopts a six-helix death-fold (NMR structure) and whose NACHT domain binds and hydrolyzes ATP (Walker A motif essential) to drive oligomerization and assembly of an ASC/caspase-1 inflammasome in response to microbial acylated lipopeptides, resulting in IL-1β/IL-18 maturation, pyroptosis, and bacterial restriction; NLRP7 protein stability is controlled by constitutive ubiquitination and lysosomal degradation, countered by the deubiquitinase STAMBP upon TLR ligation, while in cancer cells USP10 performs the same stabilizing deubiquitination at K379; the NAD mediates inter-molecular oligomerization, and disease-causing mutations impair oligomerization; in reproductive contexts NLRP7 sequesters the DNMT3A inhibitor TCL1A in the cytoplasm to permit oocyte de novo DNA methylation (cryo-EM structure of the complex determined), interacts with YY1 and ZBTB16 to influence chromatin state, translocates to the nucleus during decidualization to potentiate progesterone receptor activity, localizes to the cytoskeleton/MTOC/Golgi in hematopoietic cells and to the oocyte cortex, and modulates BMP4 signaling and alternative splicing of HR genes (BRCA1, RAD51) to maintain genomic stability in early embryos; in trophoblasts NLRP7 promotes HLA-C expression via suppression of IκBα degradation under ELF3 transcriptional control and can act in an inflammasome-independent mode to support cell survival and immune evasion."},"narrative":{"mechanistic_narrative":"NLRP7 is a cytoplasmic NLR protein that operates in two broad arenas: it nucleates an inflammasome in innate immune cells and it governs DNA methylation and genomic integrity in the oocyte and early embryo [PMID:22361007, PMID:41786744]. Its N-terminal PYD adopts a six-helix death-fold whose electrostatic surface differs from NLRP1, providing a structural basis for signaling specificity [PMID:20547486], while its central NACHT-associated domain (NAD) mediates inter-molecular oligomerization in which the NAD and LRR of one molecule engage the NACHT of a second [PMID:25082979], and its nucleotide-binding domain binds and hydrolyzes ATP through an intact Walker A motif required for oligomerization and inflammasome activity [PMID:26143398]. In macrophages NLRP7 assembles an ASC-dependent, caspase-1-activating inflammasome in response to microbial acylated lipopeptides, driving IL-1β/IL-18 maturation, pyroptosis and restriction of intracellular bacteria [PMID:22361007], a response also engaged by mycobacterial infection and by lipopeptide stimulation of amnion epithelial cells where gasdermin D is cleaved [PMID:27043315, PMID:32849565]. NLRP7 protein abundance is set by constitutive ubiquitination and endolysosomal degradation that is reversed by the deubiquitinase STAMBP upon TLR ligation to potentiate inflammasome output, with USP10 performing analogous stabilizing deubiquitination at K379 in cancer cells [PMID:28492230, PMID:33838681]. In reproductive contexts NLRP7 sequesters the DNMT3A inhibitor TCL1A in the cytoplasm — a complex resolved by cryo-EM — to license de novo DNA methylation, and recurrent hydatidiform mole-causing variants disrupt this interaction [PMID:41786744]; it further interacts with the chromatin factors YY1 and the repressor ZBTB16 to influence DNA methylation and lineage differentiation [PMID:24105472, PMID:26121690], translocates to the nucleus during decidualization to potentiate progesterone receptor activity [PMID:28810880], and binds splicing and DNA-damage-response factors to maintain genomic integrity in early embryos [PMID:39865169]. In trophoblast and choriocarcinoma cells NLRP7 acts in an inflammasome-independent mode to control proliferation, survival and immune evasion, including ELF3-driven promotion of HLA-C expression and modulation of NF-κB signaling [PMID:34203890, PMID:36980199, PMID:39052836].","teleology":[{"year":2005,"claim":"Established the first functional placement of NLRP7 in innate immunity by showing it regulates IL-1β secretion, framing it as a feedback modulator rather than an inert NLR.","evidence":"Stable NLRP7 expression in THP-1 cells with LPS/IL-1β stimulation and IL-1β secretion assays","pmids":["15817483"],"confidence":"Medium","gaps":["Whether NLRP7 inhibits or activates IL-1β was context-dependent and not yet reconciled","No complex composition or direct molecular target identified"]},{"year":2010,"claim":"Resolved the NLRP7 PYD fold at atomic resolution, providing a structural rationale for why NLRP7 signals distinctly from other PYD-containing NLRs.","evidence":"NMR 3D structure determination of the NLRP7 PYD with comparison to NLRP1 PYD","pmids":["20547486"],"confidence":"High","gaps":["Did not define which downstream partner the PYD engages","No full-length protein structure"]},{"year":2011,"claim":"Linked NLRP7 to specific subcellular compartments and tied protein-truncating mutations to loss of its cytokine-regulatory function in patient cells.","evidence":"Immunofluorescence co-localization with Golgi/MTOC/microtubules and ELISA on patient PBMCs with truncation mutants","pmids":["22025618"],"confidence":"Medium","gaps":["Functional meaning of Golgi/MTOC localization unresolved","Direction of cytokine regulation appeared inhibitory, conflicting with later inflammasome activation data"]},{"year":2012,"claim":"Defined NLRP7 as a bona fide inflammasome platform, showing it senses acylated lipopeptides to assemble an ASC/caspase-1 complex that matures IL-1β/IL-18, triggers pyroptosis and restricts bacteria.","evidence":"Reciprocal Co-IP of ASC/caspase-1, knockdown, multi-cytokine ELISA and bacterial replication assays in human macrophages","pmids":["22361007"],"confidence":"High","gaps":["Direct ligand-binding event not demonstrated","Reconciliation with earlier inhibitory phenotypes not addressed"]},{"year":2014,"claim":"Identified the NAD as the engine of NLRP7 self-assembly and showed disease mutations impair oligomerization, connecting the activation mechanism to pathology.","evidence":"Yeast two-hybrid inter-domain mapping, in silico modeling and confocal microscopy of disease mutants (L398R, R693W) in HEK293T cells","pmids":["25082979"],"confidence":"Medium","gaps":["No structure of the oligomer","Inter-domain interaction not confirmed in full-length endogenous protein"]},{"year":2014,"claim":"Mapped NLRP7 localization dynamics across human oogenesis and preimplantation development, indicating a polarized, stage-dependent role beyond immunity.","evidence":"High-resolution confocal and electron microscopy on human oocytes and embryos (n=164)","pmids":["25358348"],"confidence":"Medium","gaps":["Molecular function at the oocyte cortex not defined","Mechanism of asymmetric confinement unknown"]},{"year":2015,"claim":"Demonstrated that NLRP7 is an ATP-binding ATPase whose Walker A motif is mechanistically required for oligomerization and inflammasome activation, establishing the nucleotide-dependent activation cycle.","evidence":"In vitro ATP binding/ATPase assays, Walker A mutagenesis, Co-IP and IL-1β/pyroptosis readouts in THP-1 cells","pmids":["26143398"],"confidence":"High","gaps":["Conformational change driven by ATP hydrolysis not visualized","Coupling of ATPase cycle to ligand sensing unresolved"]},{"year":2013,"claim":"Connected NLRP7 to chromatin reprogramming by identifying YY1 as a partner and showing NLRP7 loss alters DNA methylation and trophoblast differentiation.","evidence":"Co-IP of NLRP7–YY1, knockdown in hESCs, methylation analysis and differentiation assays","pmids":["24105472"],"confidence":"Medium","gaps":["Direct effect of NLRP7 on methylation machinery not defined","YY1-dependence of methylation changes not isolated"]},{"year":2015,"claim":"Showed NLRP7 physically sequesters the transcriptional repressor ZBTB16 in the cytoplasm, suggesting a mechanism by which it can regulate nuclear transcription factors from the cytoplasm.","evidence":"Yeast two-hybrid, Co-IP, native PAGE (~480 kDa complex) and confocal microscopy","pmids":["26121690"],"confidence":"Medium","gaps":["Functional/transcriptional consequence of ZBTB16 sequestration not measured","Physiological context of the complex unclear"]},{"year":2016,"claim":"Extended inflammasome activation to a clinically relevant pathogen, showing virulent M. bovis engages the NLRP7 inflammasome.","evidence":"siRNA knockdown in THP-1 macrophages with M. bovis infection, caspase-1, IL-1β and pyroptosis readouts","pmids":["27043315"],"confidence":"Medium","gaps":["Bacterial ligand sensed not identified","Single readout per assay"]},{"year":2017,"claim":"Defined a post-translational rheostat controlling NLRP7 abundance: constitutive ubiquitination/lysosomal degradation countered by STAMBP deubiquitination upon TLR ligation tunes inflammasome output.","evidence":"Ubiquitination assays, STAMBP knockdown, endolysosomal trafficking assays, BC-1471 inhibitor and IL-1β ELISA","pmids":["28492230"],"confidence":"High","gaps":["E3 ligase responsible for constitutive ubiquitination not identified","Ubiquitin acceptor sites not mapped in this study"]},{"year":2017,"claim":"Revealed a nuclear, inflammasome-independent role in decidualization, with NLRP7 potentiating progesterone receptor activity.","evidence":"Subcellular fractionation, confocal microscopy, siRNA/lentiviral OE in T-HESCs, PR reporter and IGFBP-1/prolactin ELISA","pmids":["28810880"],"confidence":"Medium","gaps":["Mechanism of nuclear translocation unknown","Direct interaction with PR not established"]},{"year":2020,"claim":"Linked NLRP7 loss-of-function to dysregulated trophoblast differentiation through BMP4 signaling, using patient-derived genetics.","evidence":"Patient iPSC trophoblast differentiation, whole transcriptome profiling and BMP pathway inhibition rescue","pmids":["32814763"],"confidence":"Medium","gaps":["Molecular link between NLRP7 and BMP4 pathway not defined","Whether effect is cell-autonomous through methylation unresolved"]},{"year":2020,"claim":"Characterized NLRP7's trophoblast functions, showing it controls proliferation, syncytial and invasive differentiation and has an anti-apoptotic role, with selective IL-1β (not IL-18) output.","evidence":"Knockdown/overexpression in primary trophoblasts and cell lines with proliferation, invasion, hCG/syncytin and cytokine readouts under hypoxia","pmids":["30617930"],"confidence":"Medium","gaps":["Mechanism of differential IL-1β vs IL-18 release unknown","Basis of anti-apoptotic effect not defined"]},{"year":2020,"claim":"Showed NLRP7 assembles an inflammasome in amnion epithelial cells in response to a Mycoplasma lipopeptide, extending its sensing role to gestational tissues.","evidence":"Immunofluorescence (NLRP7/ASC co-localization), Western blot for caspase-1 and gasdermin D cleavage in primary AECs","pmids":["32849565"],"confidence":"Medium","gaps":["Physiological trigger in pregnancy not established","Direct lipopeptide binding not shown"]},{"year":2020,"claim":"Resolved how domain-specific patient mutations produce distinct cellular defects, separating effects on pro-IL-1β levels from defects in IL-1β processing/trafficking.","evidence":"Patient PBMC stimulation, intracellular pro/mature IL-1β staining and reconstitution with NLRP7 variant plasmids plus ASC/caspase-1","pmids":["32484253"],"confidence":"Medium","gaps":["Genotype-phenotype mapping incomplete","Mechanistic basis of trafficking defects not defined"]},{"year":2021,"claim":"Demonstrated an inflammasome-independent pro-tumor function in choriocarcinoma, with NLRP7 supporting growth and limiting maternal immune response in vivo.","evidence":"Knockdown in CC cell lines, proliferation/3D assays and orthotopic mouse model with immune phenotyping","pmids":["34203890"],"confidence":"Medium","gaps":["Molecular effectors of inflammasome-independent growth not fully defined","Mechanism of immune suppression unresolved"]},{"year":2021,"claim":"Identified USP10 as the deubiquitinase stabilizing NLRP7 in cancer cells via K379 and connected NLRP7 to NF-κB-driven CCL2 expression and M2 macrophage polarization.","evidence":"Co-IP/MS, ubiquitination/deubiquitination assays, K379 mutagenesis, RNA-seq, NF-κB reporter, CCL2 ELISA and in vivo tumor models","pmids":["33838681"],"confidence":"Medium","gaps":["Whether STAMBP and USP10 act in the same cells unresolved","Direct NLRP7 control of NF-κB mechanism not defined"]},{"year":2023,"claim":"Distinguished NLRP7's tumor-context behavior, showing it differentially regulates NF-κB and promotes survival, dedifferentiation and metastatic colonization in choriocarcinoma versus a canonical inflammasome role in non-tumor trophoblasts.","evidence":"shRNA knockdown in JEG-3, overexpression in HTR8/SVneo, NF-κB assays and in vivo metastatic mouse model","pmids":["36980199"],"confidence":"Medium","gaps":["Switch between inflammasome-dependent and -independent modes not mechanistically defined","Direct NF-κB target not isolated"]},{"year":2024,"claim":"Placed NLRP7 within an ELF3-controlled transcriptional axis governing maternal immune evasion, with NLRP7 promoting HLA-C expression via IκBα modulation opposite to NLRP2.","evidence":"ELF3 knockout in JEG-3, ELF3 enhancer-binding analysis, NLRP7/NLRP2 OE/KD with HLA-C and IκBα readouts","pmids":["39052836"],"confidence":"Medium","gaps":["Direct mechanism by which NLRP7 alters IκBα kinetics not established","Relationship to inflammasome activity unclear"]},{"year":2025,"claim":"Provided the definitive mechanism for oocyte hypomethylation in recurrent hydatidiform mole by resolving the NLRP7–TCL1A cryo-EM structure and showing NLRP7 cytoplasmically sequesters TCL1A to license DNMT3A activity, with disease variants disrupting this interaction.","evidence":"Cryo-EM of the NLRP7–TCL1A complex, Co-IP, subcellular fractionation and variant interaction analysis","pmids":["41786744"],"confidence":"High","gaps":["In vivo demonstration in human oocytes not performed","How NLRP7 activation state controls TCL1A release unresolved"]},{"year":2025,"claim":"Connected NLRP7 to genomic integrity in early embryos, showing it binds splicing/DNA-repair factors and that its loss causes aberrant splicing of HR genes, DNA damage and apoptosis.","evidence":"NLRP7 knockout in hESCs and blastoids, Co-IP identifying DDX39B/PRPF8/THRAP3/PARP1, RNA-seq splicing analysis, γH2AX and apoptosis assays","pmids":["39865169"],"confidence":"Medium","gaps":["Which interaction directly drives the splicing defect not isolated","Direct vs indirect role in DNA damage response unresolved"]},{"year":null,"claim":"How NLRP7 switches between its cytoplasmic inflammasome-sensing role and its nuclear/chromatin and methylation-regulatory roles, and what upstream signal directs each mode, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating immune and reproductive functions","Direct ligand for inflammasome activation undefined","Full-length and oligomeric structures not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[7]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[7]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[8,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator 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inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/32801829","citation_count":5,"is_preprint":false},{"pmid":"38639821","id":"PMC_38639821","title":"C-type lectin 4 of Toxocara canis activates NF-ĸB and MAPK pathways by modulating NOD1/2 and RIP2 in murine macrophages in vitro.","date":"2024","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/38639821","citation_count":4,"is_preprint":false},{"pmid":"37265977","id":"PMC_37265977","title":"High Risk of Gestational Trophoblastic Neoplasia Development in Recurrent Hydatidiform Moles with NLRP7 Pathogenic Variations.","date":"2023","source":"Balkan journal of medical genetics : BJMG","url":"https://pubmed.ncbi.nlm.nih.gov/37265977","citation_count":3,"is_preprint":false},{"pmid":"34087990","id":"PMC_34087990","title":"Reprogramming of human peripheral blood mononuclear cells from a patient suffering from recurrent hydatidiform mole to an iPSC line FAHZUi001-A carrying a homozygous p.Gln421Ter mutation in NLRP7 gene.","date":"2021","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34087990","citation_count":3,"is_preprint":false},{"pmid":"19888692","id":"PMC_19888692","title":"Backbone and sidechain (1)H, (15)N and (13)C assignments of the NLRP7 pyrin domain.","date":"2009","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/19888692","citation_count":3,"is_preprint":false},{"pmid":"40218399","id":"PMC_40218399","title":"Molecular Identification and Expression Analysis of NOD1/2 and TBK1 in Response to Viral or Bacterial Infection in the Spotted Knifejaw (Oplegnathus punctatus).","date":"2025","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/40218399","citation_count":2,"is_preprint":false},{"pmid":"34189227","id":"PMC_34189227","title":"High-Risk Gestational Trophoblastic Neoplasia from a Homozygous NLRP7 Mutation.","date":"2021","source":"Gynecologic oncology 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THP-1 cells abrogated LPS-induced IL-1β production, and NLRP7 mRNA expression was induced by LPS or IL-1β stimulation, placing it as a feedback regulator of IL-1β secretion.\",\n      \"method\": \"Stable transfection in THP-1 monocytic cells, LPS/IL-1β stimulation, IL-1β secretion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD/OE with defined cellular phenotype (IL-1β secretion) in THP-1 cells, single lab, two methods (stable expression + mRNA induction)\",\n      \"pmids\": [\"15817483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The N-terminal pyrin domain (PYD) of NLRP7 adopts a six-alpha-helix bundle death domain fold; helix α3 and loop α2-α3 are stabilized by a strong hydrophobic cluster, and the electrostatic surface differs from NLRP1 PYD, providing a structural basis for differential inflammasome signaling specificity.\",\n      \"method\": \"NMR spectroscopy (3D structure determination of NLRP7 PYD)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional interpretation and comparison to other PYDs, single lab but structure-grade evidence\",\n      \"pmids\": [\"20547486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NLRP7 co-localizes with the Golgi apparatus and the microtubule-organizing center (MTOC) and is associated with microtubules in peripheral blood mononuclear cells; cells from patients with NLRP7 mutations secrete low levels of IL-1β and TNF in response to LPS, and NLRP7 down-regulates pro-IL-1β synthesis; this inhibitory function is abolished by protein-truncating mutations after the Pyrin domain.\",\n      \"method\": \"Immunofluorescence co-localization, transient transfection with truncation mutants, ELISA for IL-1β/TNF from patient PBMCs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence tied to functional consequence (cytokine secretion), mutant constructs, patient cells; single lab\",\n      \"pmids\": [\"22025618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NLRP7 assembles an inflammasome complex in human macrophages in response to microbial acylated lipopeptides; this complex is ASC-dependent, activates caspase-1, drives maturation and release of IL-1β and IL-18, induces pyroptosis, and restricts intracellular bacterial replication; it does not affect caspase-1-independent secretion of IL-6 or TNF-α.\",\n      \"method\": \"Co-immunoprecipitation (ASC/caspase-1 complex), NLRP7 knockdown, IL-1β/IL-18/IL-6/TNF-α ELISA, bacterial replication assays in human macrophages\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP demonstrating complex assembly, KD with multiple cytokine readouts and bacterial restriction phenotype; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22361007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NLRP7 and KHDC3L co-localize to a juxta-perinuclear signal consistent with the MTOC/Golgi in lymphoblastoid cell lines from normal subjects; KHDC3L mutations do not change the subcellular localization of KHDC3L but NLRP7 and KHDC3L proteins co-localize in this compartment.\",\n      \"method\": \"Immunofluorescence in lymphoblastoid cell lines\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (immunofluorescence), single lab, no functional consequence linked to co-localization\",\n      \"pmids\": [\"23232697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NLRP7 interacts with YY1 (a chromatin-binding transcription factor) in human embryonic stem cells; reduced NLRP7 levels alter DNA methylation and accelerate trophoblast lineage differentiation, demonstrating a role in chromatin reprogramming and DNA methylation.\",\n      \"method\": \"Co-immunoprecipitation (NLRP7–YY1 interaction), NLRP7 knockdown in hESCs, DNA methylation analysis, trophoblast differentiation assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing interaction, KD with defined cellular phenotype (methylation + differentiation), single lab\",\n      \"pmids\": [\"24105472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The NACHT-associated domain (NAD) of NLRP7 is central to its oligomeric assembly; upon activation, the NAD and part of the LRR of one NLRP7 molecule interact with the NACHT domain of a second molecule to form an oligomer. Disease-causing missense mutations L398R and R693W decrease oligomerization potential and increase aggresome formation.\",\n      \"method\": \"Yeast two-hybrid inter-domain interaction screen, in silico structural modeling, confocal microscopy of transiently transfected NLRP7 mutants in HEK293T cells\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus confocal microscopy with disease mutants, single lab, two orthogonal methods\",\n      \"pmids\": [\"25082979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The NBD of NLRP7 is an ATP-binding domain with ATPase activity; an intact Walker A motif is required for nucleotide binding, hydrolysis, NLRP7 oligomerization, inflammasome formation, and activity. THP-1 cells expressing a Walker A mutant display defective NLRP7 inflammasome activation, IL-1β release, and pyroptosis in response to acylated lipopeptides and S. aureus infection.\",\n      \"method\": \"In vitro ATP binding and ATPase assays, Walker A motif mutagenesis, co-immunoprecipitation (oligomerization), IL-1β ELISA, pyroptosis assay in THP-1 cells\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay plus mutagenesis, multiple orthogonal methods (binding, hydrolysis, oligomerization, cell-based inflammasome activity), single lab\",\n      \"pmids\": [\"26143398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NLRP7 interacts with the transcriptional repressor ZBTB16; this interaction was verified by yeast two-hybrid, co-immunoprecipitation, and confocal microscopy in mammalian cells; both proteins are found in a ~480 kDa complex and co-localize in cytoplasmic juxtanuclear aggregates; overexpressed NLRP7 sequesters ZBTB16 in the cytoplasm away from the nucleus.\",\n      \"method\": \"Yeast two-hybrid (ovarian library screen), co-immunoprecipitation, native PAGE (480 kDa complex), confocal microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Y2H, Co-IP, native complex, microscopy) establishing interaction, single lab\",\n      \"pmids\": [\"26121690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NLRP7 and KHDC3L localize to the oocyte cytoskeleton and are predominant at the cortical region in growing oocytes; after first cell division they become asymmetrically confined to the outer cortical region and excluded from the cell-to-cell contact region until the blastocyst stage where they redistribute to the cytoplasm and nucleus respectively.\",\n      \"method\": \"High-resolution confocal immunofluorescence and electron microscopy on human oocytes and preimplantation embryos (n=164)\",\n      \"journal\": \"Human reproduction (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by confocal + electron microscopy in primary human material, large sample size, single lab\",\n      \"pmids\": [\"25358348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NLRP7 protein is constitutively ubiquitinated and targeted to the endolysosome for degradation; upon TLR ligation (LPS or Pam3CSK4), the deubiquitinase STAMBP deubiquitinates NLRP7, prevents its lysosomal trafficking, and increases NLRP7 protein abundance, thereby potentiating inflammasome activation and IL-1β release. A small-molecule STAMBP inhibitor (BC-1471) reduces NLRP7 levels and suppresses IL-1β release.\",\n      \"method\": \"Ubiquitination assays, STAMBP knockdown, endolysosomal trafficking assays, small-molecule inhibitor (BC-1471), IL-1β ELISA\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (ubiquitination assay, KD, trafficking, pharmacological inhibition), single lab, clear mechanistic pathway established\",\n      \"pmids\": [\"28492230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NLRP7 translocates to the nucleus of decidualized endometrial stromal cells and promotes progesterone receptor (PR) transcriptional activity and IGFBP-1 expression; knockdown of NLRP7 reduces decidualization markers while overexpression enhances them.\",\n      \"method\": \"Subcellular fractionation, confocal microscopy, siRNA knockdown and lentiviral overexpression in T-HESCs, PR reporter assay, ELISA for IGFBP-1 and prolactin\",\n      \"journal\": \"Reproductive biology and endocrinology : RB&E\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct nuclear translocation shown by fractionation and confocal, KD/OE with defined phenotype (PR activity, IGFBP-1), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28810880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The NLRP7 inflammasome is activated by virulent Mycobacterium bovis Beijing strain in THP-1 macrophages, promoting IL-1β secretion, caspase-1 activation, pyroptosis induction, and upregulation of TNF-α, CCL3, and IL-1β mRNAs.\",\n      \"method\": \"NLRP7 knockdown (siRNA) in THP-1 macrophages, M. bovis infection, caspase-1 activity assay, IL-1β ELISA, pyroptosis assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KD with defined phenotypic readouts (caspase-1, IL-1β, pyroptosis), single lab, single method for each readout\",\n      \"pmids\": [\"27043315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NLRP7 is deubiquitinated by USP10 in colorectal cancer cells; this stabilizes NLRP7 protein (K379 is an important lysine acceptor site for ubiquitination); NLRP7 promotes NF-κB nuclear translocation and CCL2 transcription, which induces polarization of pro-tumor M2-like macrophages.\",\n      \"method\": \"Co-immunoprecipitation/mass spectrometry, ubiquitination/deubiquitination assays, K379 mutagenesis, RNA sequencing, NF-κB reporter, ELISA for CCL2, flow cytometry for macrophage phenotype, in vivo tumor models\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS identifying USP10, mutagenesis of ubiquitination site, multiple downstream readouts; single lab\",\n      \"pmids\": [\"33838681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NLRP7 deficiency in patient-derived trophoblasts (iPSC model) causes precocious downregulation of pluripotency factors and excessive trophoblast differentiation; these phenotypes are dependent on BMP4 signaling, as BMP pathway inhibition corrects the excessive differentiation.\",\n      \"method\": \"Patient-derived iPSC trophoblast differentiation model, whole transcriptome profiling, BMP pathway inhibition rescue experiment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function (patient NLRP7 mutations in iPSCs) with defined cellular phenotype and pharmacological epistasis (BMP inhibition rescue), single lab\",\n      \"pmids\": [\"32814763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NLRP7 inflammasome activation in trophoblast cells increases IL-1β secretion but not IL-18 secretion; NLRP7 controls trophoblast proliferation, differentiation towards syncytium, and invasive extravillous trophoblast differentiation, and has an anti-apoptotic role; NLRP7 expression is upregulated by hypoxia.\",\n      \"method\": \"NLRP7 knockdown/overexpression in primary trophoblasts and trophoblast cell lines, [3H]-thymidine proliferation assay, 2D/3D invasion cultures, xCELLigence, β-hCG/syncytin ELISA, IL-1β/IL-18 ELISA, hypoxia treatment\",\n      \"journal\": \"Journal of molecular medicine (Berlin, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple KD/OE experiments with defined functional readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"30617930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NLRP7 inflammasome assembles around the nucleus in human amnion epithelial cells (AECs) upon stimulation with FSL-1 (a Mycoplasma salivarium-derived lipopeptide), leading to NLRP7–ASC co-localization, pro-caspase-1 and gasdermin D cleavage into mature forms.\",\n      \"method\": \"Immunofluorescence (NLRP7/ASC co-localization), Western blot (pro-caspase-1 and gasdermin D cleavage), RT-qPCR, FSL-1 stimulation of primary AECs\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct inflammasome assembly shown by co-localization and caspase/gasdermin D cleavage in primary cells, single lab\",\n      \"pmids\": [\"32849565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NLRP7 promotes choriocarcinoma (CC) cell proliferation, 3D organization, and tumor growth in an inflammasome-independent manner; CC cells with NLRP7 invalidated generated smaller tumors with higher maternal immune response and less metastases in an orthotopic mouse model.\",\n      \"method\": \"NLRP7 knockdown in CC cell lines, in vitro proliferation/3D culture assays, orthotopic mouse CC model, immune phenotyping\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with defined tumor growth and immune phenotype, KD with multiple readouts; single lab\",\n      \"pmids\": [\"34203890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In choriocarcinoma (JEG-3) cells, NLRP7 functions in an inflammasome-independent manner and differentially regulates NF-κB activity (compared to non-tumor HTR8/SVneo cells where it acts inflammasome-dependently); NLRP7 increases malignant cell survival, dedifferentiation, and immune camouflage, and facilitates tumor cell colonization of the lungs in a preclinical GC model.\",\n      \"method\": \"NLRP7 knockdown (shRNA) in JEG-3, NLRP7 overexpression in HTR8/SVneo, NF-κB activity assay, in vivo metastatic mouse model\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — parallel cell systems with KD/OE, in vivo validation, NF-κB pathway placement; single lab\",\n      \"pmids\": [\"36980199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ELF3 transactivates NLRP7 while suppressing NLRP2 in extravillous trophoblast (EVT) JEG-3 cells by binding to their shared enhancer; NLRP7 and NLRP2 have opposing effects on HLA-C expression, with NLRP7 promoting HLA-C levels (likely through modulating IκBα degradation kinetics) and NLRP2 suppressing them, implicating this axis in maternal immune evasion.\",\n      \"method\": \"ELF3 knockout in JEG-3, ChIP-like analysis of ELF3 binding to NLRP2/NLRP7 enhancer, NLRP7/NLRP2 overexpression/knockdown with HLA-C expression readout, IκBα protein level measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus OE/KD with defined molecular readout (HLA-C, IκBα), single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"39052836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NLRP7 interacts with TCL1A (a DNMT3A inhibitor) and the cryo-EM structure of the NLRP7-TCL1A complex was determined; NLRP7 sequesters TCL1A in the cytoplasm, preventing its nuclear entry and consequent suppression of DNMT3A-mediated de novo methylation; most recurrent hydatidiform mole-causing NLRP7 variants impair the NLRP7-TCL1A interaction, providing a mechanistic explanation for oocyte hypomethylation.\",\n      \"method\": \"Cryo-EM structure determination of NLRP7-TCL1A complex, co-immunoprecipitation, subcellular fractionation (TCL1A cytoplasmic retention), interaction analysis of NLRP7 pathogenic variants, in silico pathogenicity predictions\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus multiple orthogonal methods (Co-IP, fractionation, variant interaction analysis), single lab but Tier 1 structural evidence with mechanistic validation\",\n      \"pmids\": [\"41786744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NLRP7 knockout in human embryonic stem cells and blastoids increases DNA damage and apoptosis; mechanistically, NLRP7 interacts with alternative splicing factors and DNA damage response proteins (DDX39B, PRPF8, THRAP3, PARP1), and its loss causes abnormal alternative splicing of homologous recombination genes (BRCA1, RAD51), compromising genomic integrity during early embryogenesis.\",\n      \"method\": \"NLRP7 knockout in hESCs and blastoids, co-immunoprecipitation identifying DDX39B/PRPF8/THRAP3/PARP1 as binding partners, RNA-seq for alternative splicing analysis, DNA damage assays (γH2AX), apoptosis assay\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO phenotype plus Co-IP establishing binding partners plus RNA-seq mechanism, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39865169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In NLRP7-mutated patient monocytes, homozygous or compound heterozygous mutations in different NLRP7 domains cause distinct defects: abnormal intracellular pro-IL-1β levels or impaired mature IL-1β processing; plasmids encoding NLRP7 non-synonymous variants affect pro-IL-1β processing and/or trafficking together with caspase-1 and ASC.\",\n      \"method\": \"Patient PBMC LPS stimulation, ELISA for secreted IL-1β, intracellular staining for pro-IL-1β and mature IL-1β, overexpression of NLRP7 variant plasmids in cell lines, ASC/caspase-1 co-expression\",\n      \"journal\": \"Clinical and experimental immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient cells plus reconstitution with mutant constructs, multiple readouts; single lab\",\n      \"pmids\": [\"32484253\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NLRP7 is a cytoplasmic NLR protein whose PYD domain adopts a six-helix death-fold (NMR structure) and whose NACHT domain binds and hydrolyzes ATP (Walker A motif essential) to drive oligomerization and assembly of an ASC/caspase-1 inflammasome in response to microbial acylated lipopeptides, resulting in IL-1β/IL-18 maturation, pyroptosis, and bacterial restriction; NLRP7 protein stability is controlled by constitutive ubiquitination and lysosomal degradation, countered by the deubiquitinase STAMBP upon TLR ligation, while in cancer cells USP10 performs the same stabilizing deubiquitination at K379; the NAD mediates inter-molecular oligomerization, and disease-causing mutations impair oligomerization; in reproductive contexts NLRP7 sequesters the DNMT3A inhibitor TCL1A in the cytoplasm to permit oocyte de novo DNA methylation (cryo-EM structure of the complex determined), interacts with YY1 and ZBTB16 to influence chromatin state, translocates to the nucleus during decidualization to potentiate progesterone receptor activity, localizes to the cytoskeleton/MTOC/Golgi in hematopoietic cells and to the oocyte cortex, and modulates BMP4 signaling and alternative splicing of HR genes (BRCA1, RAD51) to maintain genomic stability in early embryos; in trophoblasts NLRP7 promotes HLA-C expression via suppression of IκBα degradation under ELF3 transcriptional control and can act in an inflammasome-independent mode to support cell survival and immune evasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NLRP7 is a cytoplasmic NLR protein that operates in two broad arenas: it nucleates an inflammasome in innate immune cells and it governs DNA methylation and genomic integrity in the oocyte and early embryo [#3, #20]. Its N-terminal PYD adopts a six-helix death-fold whose electrostatic surface differs from NLRP1, providing a structural basis for signaling specificity [#1], while its central NACHT-associated domain (NAD) mediates inter-molecular oligomerization in which the NAD and LRR of one molecule engage the NACHT of a second [#6], and its nucleotide-binding domain binds and hydrolyzes ATP through an intact Walker A motif required for oligomerization and inflammasome activity [#7]. In macrophages NLRP7 assembles an ASC-dependent, caspase-1-activating inflammasome in response to microbial acylated lipopeptides, driving IL-1\\u03b2/IL-18 maturation, pyroptosis and restriction of intracellular bacteria [#3], a response also engaged by mycobacterial infection and by lipopeptide stimulation of amnion epithelial cells where gasdermin D is cleaved [#12, #16]. NLRP7 protein abundance is set by constitutive ubiquitination and endolysosomal degradation that is reversed by the deubiquitinase STAMBP upon TLR ligation to potentiate inflammasome output, with USP10 performing analogous stabilizing deubiquitination at K379 in cancer cells [#10, #13]. In reproductive contexts NLRP7 sequesters the DNMT3A inhibitor TCL1A in the cytoplasm \\u2014 a complex resolved by cryo-EM \\u2014 to license de novo DNA methylation, and recurrent hydatidiform mole-causing variants disrupt this interaction [#20]; it further interacts with the chromatin factors YY1 and the repressor ZBTB16 to influence DNA methylation and lineage differentiation [#5, #8], translocates to the nucleus during decidualization to potentiate progesterone receptor activity [#11], and binds splicing and DNA-damage-response factors to maintain genomic integrity in early embryos [#21]. In trophoblast and choriocarcinoma cells NLRP7 acts in an inflammasome-independent mode to control proliferation, survival and immune evasion, including ELF3-driven promotion of HLA-C expression and modulation of NF-\\u03baB signaling [#17, #18, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the first functional placement of NLRP7 in innate immunity by showing it regulates IL-1\\u03b2 secretion, framing it as a feedback modulator rather than an inert NLR.\",\n      \"evidence\": \"Stable NLRP7 expression in THP-1 cells with LPS/IL-1\\u03b2 stimulation and IL-1\\u03b2 secretion assays\",\n      \"pmids\": [\"15817483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NLRP7 inhibits or activates IL-1\\u03b2 was context-dependent and not yet reconciled\", \"No complex composition or direct molecular target identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved the NLRP7 PYD fold at atomic resolution, providing a structural rationale for why NLRP7 signals distinctly from other PYD-containing NLRs.\",\n      \"evidence\": \"NMR 3D structure determination of the NLRP7 PYD with comparison to NLRP1 PYD\",\n      \"pmids\": [\"20547486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which downstream partner the PYD engages\", \"No full-length protein structure\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked NLRP7 to specific subcellular compartments and tied protein-truncating mutations to loss of its cytokine-regulatory function in patient cells.\",\n      \"evidence\": \"Immunofluorescence co-localization with Golgi/MTOC/microtubules and ELISA on patient PBMCs with truncation mutants\",\n      \"pmids\": [\"22025618\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional meaning of Golgi/MTOC localization unresolved\", \"Direction of cytokine regulation appeared inhibitory, conflicting with later inflammasome activation data\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined NLRP7 as a bona fide inflammasome platform, showing it senses acylated lipopeptides to assemble an ASC/caspase-1 complex that matures IL-1\\u03b2/IL-18, triggers pyroptosis and restricts bacteria.\",\n      \"evidence\": \"Reciprocal Co-IP of ASC/caspase-1, knockdown, multi-cytokine ELISA and bacterial replication assays in human macrophages\",\n      \"pmids\": [\"22361007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ligand-binding event not demonstrated\", \"Reconciliation with earlier inhibitory phenotypes not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified the NAD as the engine of NLRP7 self-assembly and showed disease mutations impair oligomerization, connecting the activation mechanism to pathology.\",\n      \"evidence\": \"Yeast two-hybrid inter-domain mapping, in silico modeling and confocal microscopy of disease mutants (L398R, R693W) in HEK293T cells\",\n      \"pmids\": [\"25082979\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the oligomer\", \"Inter-domain interaction not confirmed in full-length endogenous protein\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped NLRP7 localization dynamics across human oogenesis and preimplantation development, indicating a polarized, stage-dependent role beyond immunity.\",\n      \"evidence\": \"High-resolution confocal and electron microscopy on human oocytes and embryos (n=164)\",\n      \"pmids\": [\"25358348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular function at the oocyte cortex not defined\", \"Mechanism of asymmetric confinement unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that NLRP7 is an ATP-binding ATPase whose Walker A motif is mechanistically required for oligomerization and inflammasome activation, establishing the nucleotide-dependent activation cycle.\",\n      \"evidence\": \"In vitro ATP binding/ATPase assays, Walker A mutagenesis, Co-IP and IL-1\\u03b2/pyroptosis readouts in THP-1 cells\",\n      \"pmids\": [\"26143398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational change driven by ATP hydrolysis not visualized\", \"Coupling of ATPase cycle to ligand sensing unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected NLRP7 to chromatin reprogramming by identifying YY1 as a partner and showing NLRP7 loss alters DNA methylation and trophoblast differentiation.\",\n      \"evidence\": \"Co-IP of NLRP7\\u2013YY1, knockdown in hESCs, methylation analysis and differentiation assays\",\n      \"pmids\": [\"24105472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effect of NLRP7 on methylation machinery not defined\", \"YY1-dependence of methylation changes not isolated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed NLRP7 physically sequesters the transcriptional repressor ZBTB16 in the cytoplasm, suggesting a mechanism by which it can regulate nuclear transcription factors from the cytoplasm.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, native PAGE (~480 kDa complex) and confocal microscopy\",\n      \"pmids\": [\"26121690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional/transcriptional consequence of ZBTB16 sequestration not measured\", \"Physiological context of the complex unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended inflammasome activation to a clinically relevant pathogen, showing virulent M. bovis engages the NLRP7 inflammasome.\",\n      \"evidence\": \"siRNA knockdown in THP-1 macrophages with M. bovis infection, caspase-1, IL-1\\u03b2 and pyroptosis readouts\",\n      \"pmids\": [\"27043315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Bacterial ligand sensed not identified\", \"Single readout per assay\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a post-translational rheostat controlling NLRP7 abundance: constitutive ubiquitination/lysosomal degradation countered by STAMBP deubiquitination upon TLR ligation tunes inflammasome output.\",\n      \"evidence\": \"Ubiquitination assays, STAMBP knockdown, endolysosomal trafficking assays, BC-1471 inhibitor and IL-1\\u03b2 ELISA\",\n      \"pmids\": [\"28492230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase responsible for constitutive ubiquitination not identified\", \"Ubiquitin acceptor sites not mapped in this study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a nuclear, inflammasome-independent role in decidualization, with NLRP7 potentiating progesterone receptor activity.\",\n      \"evidence\": \"Subcellular fractionation, confocal microscopy, siRNA/lentiviral OE in T-HESCs, PR reporter and IGFBP-1/prolactin ELISA\",\n      \"pmids\": [\"28810880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of nuclear translocation unknown\", \"Direct interaction with PR not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked NLRP7 loss-of-function to dysregulated trophoblast differentiation through BMP4 signaling, using patient-derived genetics.\",\n      \"evidence\": \"Patient iPSC trophoblast differentiation, whole transcriptome profiling and BMP pathway inhibition rescue\",\n      \"pmids\": [\"32814763\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between NLRP7 and BMP4 pathway not defined\", \"Whether effect is cell-autonomous through methylation unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Characterized NLRP7's trophoblast functions, showing it controls proliferation, syncytial and invasive differentiation and has an anti-apoptotic role, with selective IL-1\\u03b2 (not IL-18) output.\",\n      \"evidence\": \"Knockdown/overexpression in primary trophoblasts and cell lines with proliferation, invasion, hCG/syncytin and cytokine readouts under hypoxia\",\n      \"pmids\": [\"30617930\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of differential IL-1\\u03b2 vs IL-18 release unknown\", \"Basis of anti-apoptotic effect not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed NLRP7 assembles an inflammasome in amnion epithelial cells in response to a Mycoplasma lipopeptide, extending its sensing role to gestational tissues.\",\n      \"evidence\": \"Immunofluorescence (NLRP7/ASC co-localization), Western blot for caspase-1 and gasdermin D cleavage in primary AECs\",\n      \"pmids\": [\"32849565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological trigger in pregnancy not established\", \"Direct lipopeptide binding not shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved how domain-specific patient mutations produce distinct cellular defects, separating effects on pro-IL-1\\u03b2 levels from defects in IL-1\\u03b2 processing/trafficking.\",\n      \"evidence\": \"Patient PBMC stimulation, intracellular pro/mature IL-1\\u03b2 staining and reconstitution with NLRP7 variant plasmids plus ASC/caspase-1\",\n      \"pmids\": [\"32484253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genotype-phenotype mapping incomplete\", \"Mechanistic basis of trafficking defects not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated an inflammasome-independent pro-tumor function in choriocarcinoma, with NLRP7 supporting growth and limiting maternal immune response in vivo.\",\n      \"evidence\": \"Knockdown in CC cell lines, proliferation/3D assays and orthotopic mouse model with immune phenotyping\",\n      \"pmids\": [\"34203890\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular effectors of inflammasome-independent growth not fully defined\", \"Mechanism of immune suppression unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified USP10 as the deubiquitinase stabilizing NLRP7 in cancer cells via K379 and connected NLRP7 to NF-\\u03baB-driven CCL2 expression and M2 macrophage polarization.\",\n      \"evidence\": \"Co-IP/MS, ubiquitination/deubiquitination assays, K379 mutagenesis, RNA-seq, NF-\\u03baB reporter, CCL2 ELISA and in vivo tumor models\",\n      \"pmids\": [\"33838681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STAMBP and USP10 act in the same cells unresolved\", \"Direct NLRP7 control of NF-\\u03baB mechanism not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Distinguished NLRP7's tumor-context behavior, showing it differentially regulates NF-\\u03baB and promotes survival, dedifferentiation and metastatic colonization in choriocarcinoma versus a canonical inflammasome role in non-tumor trophoblasts.\",\n      \"evidence\": \"shRNA knockdown in JEG-3, overexpression in HTR8/SVneo, NF-\\u03baB assays and in vivo metastatic mouse model\",\n      \"pmids\": [\"36980199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Switch between inflammasome-dependent and -independent modes not mechanistically defined\", \"Direct NF-\\u03baB target not isolated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed NLRP7 within an ELF3-controlled transcriptional axis governing maternal immune evasion, with NLRP7 promoting HLA-C expression via I\\u03baB\\u03b1 modulation opposite to NLRP2.\",\n      \"evidence\": \"ELF3 knockout in JEG-3, ELF3 enhancer-binding analysis, NLRP7/NLRP2 OE/KD with HLA-C and I\\u03baB\\u03b1 readouts\",\n      \"pmids\": [\"39052836\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism by which NLRP7 alters I\\u03baB\\u03b1 kinetics not established\", \"Relationship to inflammasome activity unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the definitive mechanism for oocyte hypomethylation in recurrent hydatidiform mole by resolving the NLRP7\\u2013TCL1A cryo-EM structure and showing NLRP7 cytoplasmically sequesters TCL1A to license DNMT3A activity, with disease variants disrupting this interaction.\",\n      \"evidence\": \"Cryo-EM of the NLRP7\\u2013TCL1A complex, Co-IP, subcellular fractionation and variant interaction analysis\",\n      \"pmids\": [\"41786744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo demonstration in human oocytes not performed\", \"How NLRP7 activation state controls TCL1A release unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected NLRP7 to genomic integrity in early embryos, showing it binds splicing/DNA-repair factors and that its loss causes aberrant splicing of HR genes, DNA damage and apoptosis.\",\n      \"evidence\": \"NLRP7 knockout in hESCs and blastoids, Co-IP identifying DDX39B/PRPF8/THRAP3/PARP1, RNA-seq splicing analysis, \\u03b3H2AX and apoptosis assays\",\n      \"pmids\": [\"39865169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which interaction directly drives the splicing defect not isolated\", \"Direct vs indirect role in DNA damage response unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NLRP7 switches between its cytoplasmic inflammasome-sensing role and its nuclear/chromatin and methylation-regulatory roles, and what upstream signal directs each mode, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating immune and reproductive functions\", \"Direct ligand for inflammasome activation undefined\", \"Full-length and oligomeric structures not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [8, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8, 20]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 16]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [5, 20]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [11, 20]}\n    ],\n    \"complexes\": [\"NLRP7 inflammasome (NLRP7\\u2013ASC\\u2013caspase-1)\"],\n    \"partners\": [\"ASC\", \"CASP1\", \"YY1\", \"ZBTB16\", \"TCL1A\", \"STAMBP\", \"USP10\", \"KHDC3L\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}