Affinage

NLRP14

NACHT, LRR and PYD domains-containing protein 14 · UniProt Q86W24

Length
1093 aa
Mass
124.7 kDa
Annotated
2026-06-10
33 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NLRP14 is a gonad-specific NLR protein that operates as a multifunctional regulator of germ cell development and the oocyte-to-embryo transition, acting primarily by controlling protein ubiquitination and stability of key partners (PMID:32839316, PMID:41951593). In germ cells it dampens innate nucleic acid sensing by physically engaging the cytosolic DNA/RNA sensing machinery and directing TBK1 for ubiquitination and degradation (PMID:28423339). During spermatogenesis NLRP14 recruits the cochaperone BAG2 into a NLRP14-HSPA2-BAG2 complex that shields HSPA2 from CHIP-mediated polyubiquitination and promotes its nuclear translocation, and its loss in mice impairs spermatogonial stem cell differentiation and meiosis (PMID:32839316). In oocytes and early embryos NLRP14 maintains proteostasis through several stabilizing and inhibitory activities: it preserves the mitochondrial Na+/Ca2+ exchanger NCLX by regulating K27-linked ubiquitination to sustain calcium oscillations and mitochondrial integrity (PMID:37493331), and it restrains excessive ubiquitination by acting as a dual E3 ligase inhibitor — competitively blocking KDM2A-dependent SCF assembly and allosterically inhibiting UHRF1 by occupying the UBE2D-binding site of its UBL domain (PMID:41951593). A central function is the cytoplasmic anchoring and stabilization of UHRF1: NLRP14 protects UHRF1 from proteasomal degradation and retains it in the oocyte cytoplasm, and this nuclear exclusion of UHRF1 (and DNMT1) in zygotes is required for DNA-replication-coupled passive demethylation, chromatin accessibility, and zygotic genome activation, as demonstrated by genetic epistasis in which loss of Uhrf1 rescues the Nlrp14-deficient phenotype (PMID:38060382, PMID:36539615, PMID:42191687). Structurally, NLRP14 contributes to the cytoplasmic lattice filament of oocytes as part of a UBE2D3-UHRF1-NLRP14 assembly (PMID:41845018), and its pyrin domain adopts a charge-relay-controlled conformational switch that governs dimerization and stability (PMID:25004977). Human loss-of-function and compound heterozygous NLRP14 variants are associated with male sterility and female infertility through disruption of these interactions (PMID:28423339, PMID:32839316, PMID:38060382).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2014 High

    Established the structural basis of NLRP14's pyrin domain, showing a conformational switch that governs dimerization and stability rather than a static fold.

    Evidence X-ray crystallography of wild-type and D86V pyrin domain with mutagenesis and stability assays

    PMID:25004977

    Open questions at the time
    • Does not connect the pyrin-domain switch to a specific physiological partner or pathway
    • Effector recruitment consequences inferred structurally, not validated in cells
  2. 2017 High

    Defined NLRP14's first signaling role, answering whether a gonad-specific NLR regulates innate immunity, by placing it as a negative regulator of cytosolic nucleic acid sensing.

    Evidence Co-IP, domain mapping, ubiquitination assays, and a human male-sterility variant showing hyper-responsiveness to nucleic acids

    PMID:28423339

    Open questions at the time
    • The E3 ligase mediating TBK1 ubiquitination is not identified
    • Physiological relevance of immune dampening in germ cells beyond sterility not detailed
  3. 2020 High

    Showed how NLRP14 supports spermatogenesis by acting as a chaperone-stabilizing scaffold that protects HSPA2 from degradation.

    Evidence Nlrp14 knockout mouse, Co-IP reconstituting the NLRP14-HSPA2-BAG2 complex, ubiquitination assay, and a human nonsense variant

    PMID:32839316

    Open questions at the time
    • Mechanism by which HSPA2 nuclear translocation drives meiosis not resolved
    • Whether this complex operates in oocytes not addressed
  4. 2022 High

    Identified NLRP14 as a maternal regulator of epigenetic reprogramming by controlling subcellular localization of the DNA-methylation machinery.

    Evidence Maternal KO mouse with imaging of Dnmt1/Uhrf1 localization, bisulfite and genome-wide methylation profiling

    PMID:36539615

    Open questions at the time
    • Molecular basis of how NLRP14 controls Uhrf1/Dnmt1 nuclear localization not defined here
    • Downstream transcriptional consequences not yet mapped
  5. 2023 High

    Linked NLRP14 to oocyte calcium homeostasis by showing it stabilizes the mitochondrial exchanger NCLX through K27-linked ubiquitination control.

    Evidence Maternal KO mouse, proteomics, Co-IP to NCLX IDR, ubiquitination assay, and spindle/cytoplasm transfer rescue

    PMID:37493331

    Open questions at the time
    • The ubiquitin ligase/deubiquitinase acting on NCLX not identified
    • Causal hierarchy between calcium defects and UHRF1 loss not separated
  6. 2023 High

    Demonstrated direct physical anchoring of UHRF1 by NLRP14 in oocyte cytoplasm, protecting it from proteasomal degradation and explaining maternal infertility variants.

    Evidence Maternal KO mouse, Co-IP, proteasome inhibitor rescue, nuclear/cytoplasmic fractionation, and human compound heterozygous variants

    PMID:38060382

    Open questions at the time
    • Structural mechanism of the NLRP14-UHRF1 interaction not yet resolved at this stage
    • Whether anchoring and stabilization are separable functions unclear
  7. 2026 High

    Resolved the molecular mechanism of NLRP14 as a dual E3 ligase inhibitor, distinguishing competitive (KDM2A/SCF) from allosteric (UHRF1 UBL) inhibition.

    Evidence Cryo-EM/X-ray structures of NLRP14-KDM2A-SKP1 and NLRP14-UHRF1 complexes, KO mouse showing increased oocyte ubiquitination, in vitro ubiquitination assays

    PMID:41951593

    Open questions at the time
    • Full set of E3 ligases regulated by NLRP14 in vivo not enumerated
    • Quantitative contribution of each inhibitory mode to proteostasis not partitioned
  8. 2026 High

    Placed NLRP14 as a structural subunit of the oocyte cytoplasmic lattice, integrating its UHRF1-anchoring role into a defined macromolecular architecture.

    Evidence Cryo-EM of native cytoplasmic lattice from mouse oocytes with mass-spectrometry subunit identification (UBE2D3-UHRF1-NLRP14 assembly)

    PMID:41845018

    Open questions at the time
    • Functional requirement of NLRP14 for CPL assembly versus being a passenger not tested
    • Relationship between CPL incorporation and UHRF1 sequestration not mechanistically linked
  9. 2026 High

    Established UHRF1 nuclear exclusion as the causal downstream effector of NLRP14 in zygotic genome activation through genetic epistasis.

    Evidence Nlrp14 KO, Uhrf1/Nlrp14 and Dnmt1/Nlrp14 double KO with ATAC-seq, ChIP-seq, and bisulfite sequencing

    PMID:42191687

    Open questions at the time
    • How LINE1 demethylation drives chromatin opening mechanistically not fully resolved
    • Contribution of NLRP14's other targets (NCLX, KDM2A) to ZGA not dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how NLRP14's diverse activities — immune dampening, chaperone scaffolding, calcium homeostasis, dual ligase inhibition, and cytoplasmic lattice structure — are integrated and temporally coordinated across germ cell and embryonic stages.
  • No unifying model connecting the immune and reproductive functions
  • Stage-specific partner switching not characterized
  • Upstream signals controlling NLRP14 activity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0005198 structural molecule activity 1
Localization
GO:0005829 cytosol 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-1474165 Reproduction 2 R-HSA-4839726 Chromatin organization 2 R-HSA-168256 Immune System 1
Partners
BAG2DNMT1HSPA2KDM2ANCLXTBK1UBE2D3UHRF1
Complex memberships
NLRP14-HSPA2-BAG2 complexcytoplasmic lattice (UBE2D3-UHRF1-NLRP14 assembly)

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 NLRP14 physically interacts with components of the nucleic acid sensing pathway and targets TBK1 (TANK binding kinase 1) for ubiquitination and degradation, thereby negatively regulating cytosolic DNA and RNA sensing in germ cells. Specific domains in NLRP14 and TBK1 mediate this inhibitory function. Co-immunoprecipitation, functional genomics, domain mapping, ubiquitination assays; human loss-of-function germline variant associated with male sterility showed hyper-responsiveness to nucleic acids Immunity High 28423339
2020 NLRP14 promotes spermatogenesis by recruiting the chaperone cofactor BAG2 to bind HSPA2, forming a NLRP14-HSPA2-BAG2 complex that inhibits CHIP E3 ligase-mediated HSPA2 polyubiquitination and promotes HSPA2 nuclear translocation. Knockout of Nlrp14 in mice inhibits spermatogonial stem cell differentiation and meiosis, causing oligozoospermia and sperm abnormality. A human nonsense germline variant confirmed loss of BAG2 recruitment. Mouse knockout, co-immunoprecipitation, ubiquitination assay, in vitro PGCLC differentiation, human variant functional characterization Proceedings of the National Academy of Sciences of the United States of America High 32839316
2023 NLRP14 interacts with the intrinsically disordered region (IDR) domain of the mitochondrial Na+/Ca2+ exchanger NCLX (encoded by Slc8b1) and maintains NCLX protein stability by regulating K27-linked ubiquitination. Loss of maternal NLRP14 leads to decreased NCLX levels, disrupted calcium oscillations, altered mitochondrial distribution/morphology, impaired cytoplasmic UHRF1 abundance, and early embryonic arrest at the 2-cell stage. Maternal knockout mouse model, proteomics, co-immunoprecipitation, ubiquitination assay, spindle transfer rescue experiment Advanced science (Weinheim, Baden-Wurttemberg, Germany) High 37493331
2023 NLRP14 maintains cytoplasmic UHRF1 abundance by protecting it from proteasome-dependent degradation and anchoring it from nuclear translocation in oocytes. Maternal loss of Nlrp14 causes oocyte maturation defects and early embryonic arrest. Human compound heterozygous NLRP14 variants found in infertile women interrupted the NLRP14-UHRF1 interaction and decreased UHRF1 levels. Maternal knockout mouse, co-immunoprecipitation, proteasome inhibitor rescue, nuclear/cytoplasmic fractionation, human variant functional analysis Cell reports High 38060382
2014 Crystal structures of human NLRP14 pyrin domain (wild-type and clinical D86V mutant) revealed an unexpected rearrangement of the C-terminal helix α6, resulting in an extended α5/6 stem-helix that mediates a novel symmetric pyrin-domain dimerization mode. This conformational switching is controlled by a charge-relay system that dramatically impacts protein stability and influences downstream effector recruitment. X-ray crystallography, mutagenesis, protein stability assays Acta crystallographica. Section D, Biological crystallography High 25004977
2022 Maternal deficiency of Nlrp14 causes aberrant nuclear localization of Dnmt1/Uhrf1 in mouse zygotes, leading to defects in DNA-replication-coupled passive demethylation and impaired 5hmC deposition, revealing NLRP14 as a regulator of epigenetic reprogramming in early embryos. Maternal knockout mouse, immunofluorescence/subcellular localization, bisulfite sequencing, genome-wide methylation profiling Nature genetics High 36539615
2026 NLRP14 acts as a dual regulator of E3 ubiquitin ligases during the oocyte-to-embryo transition. Structural studies (cryo-EM/X-ray) identified KDM2A and UHRF1 as two distinct binding partners. NLRP14 competitively inhibits KDM2A-mediated SCF (SKP1-CUL1-F-box) complex assembly, and allosterically inhibits UHRF1 activity by occupying the UBE2D (E2 ubiquitin-conjugating enzyme) binding site of its UBL domain. NLRP14 deletion in mice increases ubiquitination levels in oocytes, demonstrating it restrains excessive protein ubiquitination to maintain proteostasis. Cryo-EM/X-ray structure determination of NLRP14-KDM2A-SKP1 and NLRP14-UHRF1 complexes, mouse knockout, in vitro ubiquitination assay Nature communications High 41951593
2026 NLRP14 is a structural component of the cytoplasmic lattice (CPL) in mammalian oocytes. Cryo-EM structure of isolated CPL revealed that NLRP14 is part of central-symmetric assemblies (UBE2D3-UHRF1-NLRP14) forming the underfoot base of the U-shaped basket (UB) structural unit within the repeating CPL filament. Cryo-EM structure determination of CPL isolated from mouse oocytes, mass spectrometry identification of subunits Nature High 41845018
2026 Using an Nlrp14-deficient model (which disrupts zygotic localization of UHRF1 and DNMT1), nuclear exclusion of UHRF1 was shown to be essential for mouse zygotic genome activation (ZGA). Failure to exclude UHRF1 from the nucleus impedes DNA demethylation at LINE1 elements, promotes UHRF1 binding to silence their expression, reduces global chromatin accessibility, and inhibits ZGA. Uhrf1/Nlrp14 double knockout embryos rescued ZGA, confirming UHRF1 as the downstream effector of NLRP14's role in ZGA. Nlrp14 KO, Uhrf1/Nlrp14 double KO, Dnmt1/Nlrp14 double KO, ATAC-seq, ChIP-seq, bisulfite sequencing, genetic epistasis Cell discovery High 42191687

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 Dynamics of DNA hydroxymethylation and methylation during mouse embryonic and germline development. Nature genetics 93 36539615
2011 Pathogen recognition receptors in channel catfish: I. Identification, phylogeny and expression of NOD-like receptors. Developmental and comparative immunology 84 22200599
2016 Comparative analysis of testis transcriptomes associated with male infertility in cattleyak. Theriogenology 68 27865410
2019 Leucine Rich Repeat Proteins: Sequences, Mutations, Structures and Diseases. Protein and peptide letters 57 30526451
2017 Germ-Cell-Specific Inflammasome Component NLRP14 Negatively Regulates Cytosolic Nucleic Acid Sensing to Promote Fertilization. Immunity 49 28423339
2023 NLRP14 Safeguards Calcium Homeostasis via Regulating the K27 Ubiquitination of Nclx in Oocyte-to-Embryo Transition. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 40 37493331
2017 A genome-wide association analysis identifies NMNAT2 and HCP5 as susceptibility loci for Kawasaki disease. Journal of human genetics 40 28855716
2020 A noncanonical role of NOD-like receptor NLRP14 in PGCLC differentiation and spermatogenesis. Proceedings of the National Academy of Sciences of the United States of America 38 32839316
2020 Integrated characterisation of cancer genes identifies key molecular biomarkers in stomach adenocarcinoma. Journal of clinical pathology 34 32034058
2014 Pre- and postovulatory aging of murine oocytes affect the transcript level and poly(A) tail length of maternal effect genes. PloS one 33 25271735
2012 The evolutionary landscape of cytosolic microbial sensors in humans. American journal of human genetics 32 22748209
2021 Analysis of Genomic DNA from Medieval Plague Victims Suggests Long-Term Effect of Yersinia pestis on Human Immunity Genes. Molecular biology and evolution 31 34002224
2023 NLRP14 deficiency causes female infertility with oocyte maturation defects and early embryonic arrest by impairing cytoplasmic UHRF1 abundance. Cell reports 25 38060382
2018 Isolation and characterization of endophytes from nodules of Mimosa pudica with biotechnological potential. Microbiological research 23 30454661
2018 Negative Regulation of Cytosolic Sensing of DNA. International review of cell and molecular biology 21 30798991
2014 Structures of the NLRP14 pyrin domain reveal a conformational switch mechanism regulating its molecular interactions. Acta crystallographica. Section D, Biological crystallography 19 25004977
2022 Involvement and characterization of NLRCs and pyroptosis-related genes in Nile tilapia (Oreochromis niloticus) immune response. Fish & shellfish immunology 18 36150410
1992 Development of a transformation system for the thermophilic fungus Talaromyces sp. CL240 based on the use of phleomycin resistance as a dominant selectable marker. Molecular & general genetics : MGG 17 1406595
1992 Transformation frequencies are enhanced and vector DNA is targeted during retransformation of Leptosphaeria maculans, a fungal plant pathogen. Molecular & general genetics : MGG 17 1736094
2012 Gene disruption in Coccidioides using hygromycin or phleomycin resistance markers. Methods in molecular biology (Clifton, N.J.) 9 22328372
2003 [Creation and genetic study of a collection of symbiotic mutants of the pea (Pisum sativum L.)]. Genetika 8 12760250
1996 Biological characteristics of an immunoregulatory activity secreted by an autoreactive CD4+ T cell clone that suppresses autoimmune diabetes in non-obese diabetic mice. International immunology 8 8671656
2024 Genetic Abnormalities of Oocyte Maturation: Mechanisms and Clinical Implications. International journal of molecular sciences 5 39684710
2017 Pattern recognition receptor genes expression profiling in indigenous chickens of India and White Leghorn. Poultry science 5 28854748
2024 Genetic Diversity and Selection Signatures of Lvliang Black Goat Using Genome-Wide SNP Data. Animals : an open access journal from MDPI 3 39518877
2025 Quantitative proteomic analysis of pathological and physiological ovarian aging: model evaluation, molecular mechanisms, and identification of early biomarkers and therapeutic targets. Journal of ovarian research 2 41316481
2017 The Birds, the Bees, and Innate Immunity. Immunity 2 28423330
2026 Molecular basis of oocyte cytoplasmic lattice assembly. Nature 1 41845018
2026 NLRP14 modulates the activity of E3 ubiquitin ligases during the oocyte-to-embryo transition. Nature communications 1 41951593
2026 Genome-Wide Characterization of Sex-Linked Regions in the Sangzhi Horned Toad (Boulenophrys sangzhiensis) Reveals Complex Sex Determination Mechanisms. Molecular ecology resources 0 41948963
2026 Selective cellular localization of UHRF1 safeguards mammalian zygotic genome activation and early embryonic development. Cell discovery 0 42191687
2026 Identification and Functional Characterization of a Novel Long Non-Coding RNA NLRP14-OT in Turbot (Scophthalmus maximus) Immune Response Against Vibrio anguillarum Infection. Animals : an open access journal from MDPI 0 42193734
2017 Shutting down innate immune responses during fertilization. Science signaling 0 28465417

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