{"gene":"POP1","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":1994,"finding":"POP1 (yeast) encodes a 100.5 kD protein that is a shared protein component of both RNase MRP and RNase P ribonucleoproteins; immunoprecipitation demonstrated its association with both complexes, and pop1-1 mutation inhibits cleavage at pre-rRNA site A3 (requiring RNase MRP) and blocks pre-tRNA processing (requiring RNase P), with both RNA components underaccumulated in pop1-1 strains.","method":"Temperature-sensitive mutant screening, immunoprecipitation, RNA processing assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal co-IP with functional validation, multiple orthogonal methods in foundational paper with 202 citations","pmids":["7926742"],"is_preprint":false},{"year":1995,"finding":"C. elegans POP-1 encodes an HMG box protein required for MS blastomere fate specification; loss of pop-1 causes MS to adopt E (endoderm) fate, and POP-1 functions together with SKN-1 transcription factor for MS-specific differentiation.","method":"Genetic loss-of-function, lineage analysis, sequence analysis revealing HMG box domain","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — clean loss-of-function with defined cellular phenotype, foundational paper with 265 citations","pmids":["7585963"],"is_preprint":false},{"year":1997,"finding":"Fission yeast Pop1, a WD-repeat F-box protein, functions as a recognition/substrate-specificity factor in the ubiquitin-proteasome pathway for degradation of CDK inhibitor Rum1 and S-phase initiator Cdc18; Pop1 binds Cdc18 in vivo, and ubiquitinated forms of Rum1 and Cdc18 are absent in pop1 mutants.","method":"Genetic epistasis, in vivo co-immunoprecipitation, Western blot for ubiquitinated forms, 26S proteasome mutant analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, epistasis, multiple orthogonal methods, 147 citations","pmids":["9203581"],"is_preprint":false},{"year":1998,"finding":"C. elegans POP-1 nuclear levels are asymmetric between sister cells born from anterior-posterior divisions (anterior cells have higher nuclear POP-1), and this asymmetry requires Wnt pathway genes; loss of pop-1 activity causes anterior cells to adopt posterior sister fates.","method":"Immunofluorescence quantification of nuclear POP-1, genetic epistasis with Wnt pathway mutants, loss-of-function analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — direct localization with functional consequence, epistasis, 235 citations","pmids":["9458047"],"is_preprint":false},{"year":1998,"finding":"Fission yeast Pop1 and Pop2 form hetero- and homo-dimeric complexes together with cullin-1 to constitute the SCF ubiquitin ligase (SCFPop1/Pop1, SCFPop1/Pop2, SCFPop2/Pop2) that controls degradation of Rum1 and Cdc18.","method":"Co-immunoprecipitation, genetic analysis, biochemical fractionation","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP demonstrating complex composition, functionally validated","pmids":["9990507"],"is_preprint":false},{"year":2001,"finding":"C. elegans POP-1 acts as a transcriptional repressor of end-1 (endoderm gene) in the MS lineage by recruiting histone deacetylase HDA-1 and co-repressor UNC-37 (Groucho homolog).","method":"Genetic epistasis, reporter gene assays, co-immunoprecipitation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — co-IP identifying binding partners, functional reporter assays, epistasis, 75 citations","pmids":["11742996"],"is_preprint":false},{"year":2002,"finding":"C. elegans POP-1 undergoes Wnt-dependent nucleocytoplasmic redistribution immediately following cytokinesis; POP-1 coalescences into subnuclear domains during interphase in unsignaled (anterior) cells coincident with repressor activity; its asymmetric distribution requires a 124-amino-acid internal domain but not the HMG box or beta-catenin interaction domains; POP-1 binds end-1 and end-3 target gene promoters in vivo and blocks their activation in anterior sisters.","method":"Live imaging in embryos, domain deletion analysis, in vivo chromatin binding assays","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — live imaging with functional consequence, domain mapping, in vivo binding assays, 85 citations","pmids":["12142026"],"is_preprint":false},{"year":2002,"finding":"Mouse Pop1 (Popeye/BVES), a putative transmembrane protein expressed in striated and smooth muscle, is required for skeletal muscle regeneration; Pop1 knockout mice show retarded regeneration after cardiotoxin injury, and satellite cells show persistent elevated Pop1 expression during regeneration.","method":"Knockout mouse model, cardiotoxin injury assay, lacZ reporter lineage tracing, immunofluorescence","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with defined regeneration phenotype, single lab","pmids":["11839816"],"is_preprint":false},{"year":2002,"finding":"C. elegans POP-1 controls the asymmetric division of gonadal precursor cells Z1 and Z4 to establish the proximal-distal axis of the gonad; this requires the beta-catenin binding domain of POP-1, and Wnt pathway components wrm-1 and lit-1 are required for POP-1 function in this context.","method":"RNAi, genetic epistasis, domain-specific allele analysis","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 — multiple alleles, RNAi, genetic epistasis, 113 citations","pmids":["11807036"],"is_preprint":false},{"year":2003,"finding":"Human POP1/ASC2 (PYRIN domain-only protein) associates with ASC via PAAD-PAAD (pyrin-pyrin) domain interactions and suppresses ASC-mediated NF-κB activation and pro-caspase-1 regulation.","method":"Gene transfer/overexpression, co-immunoprecipitation, NF-κB reporter assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 — single co-IP with functional assay, foundational characterization paper, 150 citations","pmids":["12656673"],"is_preprint":false},{"year":2003,"finding":"Acetylation of three specific lysine residues in C. elegans POP-1 enhances nuclear retention by increasing nuclear import and blocking nuclear export; these lysines are essential for proper nuclear localization and biological activity during embryogenesis.","method":"In vivo mutagenesis of acetylation sites, nuclear localization assays, functional rescue experiments","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 — site-directed mutagenesis with functional validation and localization assays, 40 citations","pmids":["12651889"],"is_preprint":false},{"year":2003,"finding":"POP-1 asymmetry in C. elegans early embryos is established by Wnt-like signaling from multiple distinct signaling cells; some cells use P2-like Wnt signaling while others use apparently distinct pathways.","method":"Cell ablation, blastomere isolation, genetic epistasis","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 — cell ablation experiments with defined signaling epistasis, single lab","pmids":["12810601"],"is_preprint":false},{"year":2005,"finding":"C. elegans POP-1 functions as a direct transcriptional activator (not only repressor) of Wnt target genes in the endoderm precursor; Wnt signaling converts POP-1 from repressor to activator by lowering its nuclear levels, and a Lef-1-like binding site in the end-1 promoter is essential for this activation.","method":"Reporter gene assays, promoter mutagenesis, genetic epistasis with Wnt pathway","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — promoter mutagenesis, functional reporter assays, epistasis, 91 citations","pmids":["16112103","16084508"],"is_preprint":false},{"year":2007,"finding":"The beta-catenin SYS-1 acts as a coactivator for C. elegans POP-1; SYS-1 and POP-1 exhibit reciprocal asymmetry in posterior vs. anterior cells, and the SYS-1-to-POP-1 ratio determines anterior vs. posterior cell fate (high ratio drives posterior fate, low ratio drives anterior fate); SYS-1 and POP-1 asymmetries are regulated by distinct subsets of Wnt/MAP kinase pathway genes.","method":"Fluorescent protein reporters, genetic epistasis, RNAi, quantitative imaging","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 — quantitative imaging, epistasis, multiple orthogonal approaches, 82 citations","pmids":["17567664"],"is_preprint":false},{"year":2008,"finding":"Human POP1 (PYD-only protein) specifically interacts with the ASC pyrin domain (Kd = 4.08 μM) but not with Cryopyrin; the interaction involves a negative electrostatic surface patch on ASC_PYD (helices H1 and H4) and a positive electrostatic surface patch on POP1 (helices H2 and H3); conformational changes in the ASC_PYD H2-H3 loop affect POP1 binding.","method":"In vitro binding assays with purified proteins, NMR chemical shift mapping, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with purified proteins, NMR structural mapping, mutagenesis validation","pmids":["18362139"],"is_preprint":false},{"year":2011,"finding":"Compound heterozygous loss-of-function mutations in human POP1 impair the integrity and activity of the RNase MRP complex and impair cell proliferation, causing a skeletal dysplasia phenotype resembling anauxetic dysplasia.","method":"Whole-exome sequencing, RNase MRP activity assays, cell proliferation assays","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 — functional validation of complex integrity and activity, single lab, 62 citations","pmids":["21455487"],"is_preprint":false},{"year":2015,"finding":"Human POP1 (PYD-only protein) inhibits ASC-dependent inflammasome assembly by preventing inflammasome nucleation, thereby blocking caspase-1 activation, IL-1β and IL-18 release, pyroptosis, and ASC particle release; POP1 expression is regulated by TLR and IL-1R signaling as a regulatory feedback loop.","method":"Transgenic mouse model (human POP1 in monocytes/macrophages/DCs), inflammasome assembly assays, caspase-1 activation assays, cytokine measurement","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — transgenic model with multiple functional readouts, 112 citations","pmids":["26275995"],"is_preprint":false},{"year":2015,"finding":"Yeast Pop1 protein directly interacts with the RNA moieties of both RNase P and RNase MRP and plays a structural scaffolding role stabilizing the global architecture of eukaryotic RNase P RNA, substituting for RNA-RNA tertiary interactions present in bacterial RNase P.","method":"Footprinting analysis, RNA-protein interaction mapping","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical interaction mapping with structural implications, single lab","pmids":["26135751"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of human POP1 (PYD-only protein) reveals a six-helix bundle PYD domain; POP1 directly binds ASC via PYD:PYD interaction, preventing ASC recruitment to Nod-like receptors and thereby inhibiting inflammasome assembly.","method":"X-ray crystallography, structural analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 — crystal structure determined, but limited functional mutagenesis validation in same paper","pmids":["25839653"],"is_preprint":false},{"year":2019,"finding":"In C. elegans seam cells, high nuclear POP-1 levels induce differentiation while low nuclear POP-1 promotes self-renewal; before symmetric division, RNT-1 (Runx) and BRO-1 (CBFβ) downregulate pop-1 expression to reduce POP-1 below the threshold needed for its repressor function, converting asymmetric (differentiative) to symmetric (proliferative) division.","method":"Time-lapse fluorescence microscopy, lineage-specific knockout, GFP-tagging of endogenous pop-1, RNAi","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 — endogenous tagging, KO with defined phenotype, epistasis","pmids":["31740621"],"is_preprint":false},{"year":2022,"finding":"Human POP1 (PYD-only protein) inhibits NLRP3 inflammasome activation by interfering with the NLRP3-ASC PYD-PYD interaction within the inflammasome complex; reduced POP1 expression in human macrophages enhances IL-1β secretion; a cell-permeable version of POP1 ameliorates MSU crystal-induced inflammation in vivo.","method":"Macrophage overexpression/knockdown, NLRP3 inflammasome assembly assays, in vivo gout models (airpouch, ankle joint), cytokine measurement","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — gain and loss of function with defined mechanism, in vivo validation, multiple readouts","pmids":["36225929"],"is_preprint":false},{"year":2023,"finding":"Human POP1 (RNase MRP component) promotes breast cancer cell proliferation by interacting with and stabilizing the telomerase RNA component TERC, thereby protecting telomeres from shortening.","method":"Co-immunoprecipitation, knockdown/overexpression, xenograft model, telomere length assays","journal":"Carcinogenesis","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single co-IP, limited mechanistic validation","pmids":["37010429"],"is_preprint":false},{"year":2024,"finding":"Human POP1 (RNase MRP component) directly binds the coding sequence (CDS) region of CDKN1A mRNA and promotes its degradation in a manner dependent on N6-methyladenosine (m6A) modification at position 497 of CDKN1A and recognition of this mark by YTHDF2.","method":"RNA immunoprecipitation, m6A site mutagenesis, YTHDF2 knockdown, in vitro and in vivo proliferation assays, m6A inhibitor treatment","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 — RNA-IP with mutagenesis of m6A site, multiple orthogonal approaches in single lab","pmids":["39268503"],"is_preprint":false},{"year":2024,"finding":"PGC-1α transcriptionally activates POP1 (PYD-only protein) by binding to the POP1 promoter region; this PGC-1α→POP1 axis inactivates NLRP3 signaling to reduce inflammation in LPS-treated periodontal stem cells.","method":"Promoter binding assay (ChIP or luciferase), overexpression/knockdown, NLRP3 pathway assays","journal":"Prostaglandins & other lipid mediators","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single study with limited mechanistic detail on promoter binding","pmids":["38763227"],"is_preprint":false}],"current_model":"POP1 refers to multiple distinct proteins: (1) the human/yeast RNase MRP/RNase P core protein component that scaffolds RNA architecture and is required for pre-rRNA and pre-tRNA processing, with mutations causing skeletal dysplasia; (2) the human PYD-only protein (inflammasome regulator) that inhibits NLRP3 inflammasome assembly by competitively binding the ASC pyrin domain via defined electrostatic surface patches, thereby blocking caspase-1 activation and IL-1β/IL-18 release; and (3) the C. elegans TCF/LEF homolog that acts as a Wnt-regulated nuclear effector, switching between repressor (via HDA-1/UNC-37 recruitment) and activator states depending on its nuclear concentration and interaction with beta-catenin SYS-1, to specify anterior-posterior cell fate asymmetry throughout development."},"narrative":{"teleology":[{"year":1994,"claim":"Identification of yeast POP1 as a shared subunit of RNase MRP and RNase P established that a single protein bridges both RNA-processing ribonucleoproteins and is essential for pre-rRNA and pre-tRNA maturation.","evidence":"Temperature-sensitive mutant screening, immunoprecipitation of both complexes, and RNA processing assays in S. cerevisiae","pmids":["7926742"],"confidence":"High","gaps":["Structural basis of POP1 interaction with the RNA subunits was unknown","Whether POP1 contributed catalytic or purely structural roles was unresolved"]},{"year":2003,"claim":"Discovery that human POP1 (PYD-only protein) binds ASC via pyrin-pyrin domain interactions and suppresses NF-κB activation and caspase-1 regulation revealed a new class of endogenous inflammasome inhibitors.","evidence":"Co-immunoprecipitation and NF-κB reporter assays in transfected cells","pmids":["12656673"],"confidence":"Medium","gaps":["Only overexpression data; endogenous POP1 function unconfirmed","Specificity for ASC versus other PYD-containing proteins untested","No structural detail on the PYD-PYD interface"]},{"year":2008,"claim":"NMR mapping and mutagenesis defined the molecular interface between POP1 and ASC, showing that complementary electrostatic patches (negative on ASC helices H1/H4, positive on POP1 helices H2/H3) mediate binding with micromolar affinity, explaining POP1's selectivity for ASC over Cryopyrin.","evidence":"In vitro binding with purified proteins, NMR chemical shift perturbation, site-directed mutagenesis","pmids":["18362139"],"confidence":"High","gaps":["No full atomic-resolution structure of the POP1-ASC complex","In vivo relevance of specific interface residues not tested"]},{"year":2011,"claim":"Linking compound heterozygous POP1 mutations to anauxetic dysplasia demonstrated that RNase MRP integrity in humans depends on POP1 and that its loss causes a Mendelian skeletal dysplasia.","evidence":"Whole-exome sequencing of patients, RNase MRP activity and integrity assays, cell proliferation assays","pmids":["21455487"],"confidence":"Medium","gaps":["Limited number of families studied","Relative contributions of RNase MRP versus RNase P dysfunction to skeletal phenotype unclear"]},{"year":2015,"claim":"Three converging studies established POP1's structural basis and in vivo inflammasome-regulatory function: crystal structure revealed a canonical six-helix PYD fold, footprinting showed yeast Pop1 scaffolds RNase P RNA architecture, and a transgenic mouse model demonstrated that POP1 blocks inflammasome nucleation, caspase-1 activation, IL-1β/IL-18 release, and pyroptosis in a feedback loop regulated by TLR/IL-1R signaling.","evidence":"X-ray crystallography of human POP1 PYD; RNA footprinting of yeast Pop1-RNA interactions; transgenic mice expressing human POP1 in myeloid cells with inflammasome functional assays","pmids":["25839653","26135751","26275995"],"confidence":"High","gaps":["Whether POP1 inhibits all ASC-dependent inflammasomes or preferentially NLRP3 was unresolved","Stoichiometry of POP1 relative to ASC in endogenous settings unknown"]},{"year":2022,"claim":"Gain- and loss-of-function experiments in human macrophages plus in vivo gout models showed POP1 specifically interferes with the NLRP3-ASC PYD-PYD interaction, and a cell-permeable POP1 peptide ameliorates MSU crystal-induced inflammation, validating POP1 as a therapeutic concept.","evidence":"Macrophage knockdown/overexpression, NLRP3 assembly assays, in vivo airpouch and ankle joint gout models","pmids":["36225929"],"confidence":"High","gaps":["Long-term safety and specificity of cell-permeable POP1 not assessed","Effect on non-NLRP3 inflammasomes (AIM2, NLRC4) in vivo not tested"]},{"year":2024,"claim":"POP1 (RNase MRP component) was shown to bind CDKN1A mRNA and promote its degradation via m6A modification at position 497 recognized by YTHDF2, revealing an RNA-regulatory function beyond canonical rRNA/tRNA processing.","evidence":"RNA immunoprecipitation, m6A site mutagenesis, YTHDF2 knockdown, proliferation assays","pmids":["39268503"],"confidence":"Medium","gaps":["Whether POP1 directly reads or merely facilitates YTHDF2 access to m6A is unclear","Broader mRNA target repertoire of POP1 uncharacterized","Single-lab finding awaiting independent replication"]},{"year":null,"claim":"Key unresolved questions include the full scope of POP1's mRNA targets beyond CDKN1A and TERC, whether the RNase MRP scaffolding and mRNA-decay functions are mechanistically coupled, the stoichiometry and dynamics of POP1 inhibition within native inflammasome assemblies, and whether POP1 therapeutics can selectively modulate specific inflammasome subtypes in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genome-wide mapping of POP1-bound mRNAs","No cryo-EM structure of POP1 within a fully assembled human RNase MRP complex","Therapeutic window for POP1-based inflammasome inhibition undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,17,22]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,14,16,20]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[16,20]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,15]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16,20]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,14,16,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15]}],"complexes":["RNase MRP","RNase P"],"partners":["ASC","NLRP3","TERC","YTHDF2"],"other_free_text":[]},"mechanistic_narrative":"Human POP1 designates two distinct gene products: (1) a core protein subunit of the RNase MRP and RNase P ribonucleoprotein complexes, and (2) a PYD-only protein that regulates inflammasome signaling. As an RNase MRP/P component, POP1 scaffolds the RNA architecture of both complexes and is required for pre-rRNA cleavage and pre-tRNA processing; compound heterozygous loss-of-function mutations in this gene cause anauxetic dysplasia, a skeletal dysplasia, by impairing RNase MRP integrity and cell proliferation [PMID:7926742, PMID:21455487, PMID:26135751]. POP1 also binds CDKN1A mRNA and promotes its m6A/YTHDF2-dependent degradation, and interacts with TERC to stabilize telomerase RNA [PMID:39268503, PMID:37010429]. As the PYD-only inflammasome regulator, POP1 adopts a six-helix bundle pyrin domain fold and competitively binds the ASC pyrin domain via complementary electrostatic surfaces, thereby blocking ASC recruitment to NLRP3, preventing inflammasome nucleation, caspase-1 activation, and IL-1β/IL-18 release [PMID:18362139, PMID:25839653, PMID:26275995, PMID:36225929]."},"prefetch_data":{"uniprot":{"accession":"Q99575","full_name":"Ribonucleases P/MRP protein subunit POP1","aliases":[],"length_aa":1024,"mass_kda":114.7,"function":"Component of ribonuclease P, a ribonucleoprotein complex that generates mature tRNA molecules by cleaving their 5'-ends (PubMed:30454648, PubMed:8918471). Also a component of the MRP ribonuclease complex, which cleaves pre-rRNA sequences (PubMed:28115465)","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q99575/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/POP1","classification":"Common Essential","n_dependent_lines":1167,"n_total_lines":1208,"dependency_fraction":0.9660596026490066},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RPP30","stoichiometry":10.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"ILF3","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"NPM3","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/POP1","total_profiled":1310},"omim":[{"mim_id":"619235","title":"RIBONUCLEASE P/MRP SUBUNIT p25; RPP25","url":"https://www.omim.org/entry/619235"},{"mim_id":"618853","title":"ANAUXETIC DYSPLASIA 3; ANXD3","url":"https://www.omim.org/entry/618853"},{"mim_id":"617396","title":"ANAUXETIC DYSPLASIA 2; ANXD2","url":"https://www.omim.org/entry/617396"},{"mim_id":"615700","title":"PYRIN DOMAIN-CONTAINING PROTEIN 1; PYDC1","url":"https://www.omim.org/entry/615700"},{"mim_id":"611666","title":"PHOSPHOLIPID PHOSPHATASE 6; PLPP6","url":"https://www.omim.org/entry/611666"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/POP1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q8NE79","domains":[{"cath_id":"-","chopping":"37-116","consensus_level":"high","plddt":91.3216,"start":37,"end":116},{"cath_id":"2.60.120.10","chopping":"126-267","consensus_level":"high","plddt":91.6265,"start":126,"end":267}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NE79","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NE79-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NE79-F1-predicted_aligned_error_v6.png","plddt_mean":75.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=POP1","jax_strain_url":"https://www.jax.org/strain/search?query=POP1"},"sequence":{"accession":"Q8NE79","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NE79.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NE79/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NE79"}},"corpus_meta":[{"pmid":"7585963","id":"PMC_7585963","title":"pop-1 encodes an HMG box protein required for the specification of a mesoderm precursor in early C. elegans embryos.","date":"1995","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/7585963","citation_count":265,"is_preprint":false},{"pmid":"9458047","id":"PMC_9458047","title":"POP-1 and anterior-posterior fate decisions in C. elegans embryos.","date":"1998","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9458047","citation_count":235,"is_preprint":false},{"pmid":"7926742","id":"PMC_7926742","title":"The POP1 gene encodes a protein component common to the RNase MRP and RNase P ribonucleoproteins.","date":"1994","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/7926742","citation_count":202,"is_preprint":false},{"pmid":"12656673","id":"PMC_12656673","title":"The PAAD/PYRIN-only protein POP1/ASC2 is a modulator of ASC-mediated nuclear-factor-kappa B and pro-caspase-1 regulation.","date":"2003","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12656673","citation_count":150,"is_preprint":false},{"pmid":"9203581","id":"PMC_9203581","title":"Fission yeast WD-repeat protein pop1 regulates genome ploidy through ubiquitin-proteasome-mediated degradation of the CDK inhibitor Rum1 and the S-phase initiator Cdc18.","date":"1997","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/9203581","citation_count":147,"is_preprint":false},{"pmid":"11807036","id":"PMC_11807036","title":"POP-1 controls axis formation during early gonadogenesis in C. elegans.","date":"2002","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/11807036","citation_count":113,"is_preprint":false},{"pmid":"26275995","id":"PMC_26275995","title":"The PYRIN Domain-only Protein POP1 Inhibits Inflammasome Assembly and Ameliorates Inflammatory Disease.","date":"2015","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/26275995","citation_count":112,"is_preprint":false},{"pmid":"9990507","id":"PMC_9990507","title":"Two F-box/WD-repeat proteins Pop1 and Pop2 form hetero- and homo-complexes together with cullin-1 in the fission yeast SCF (Skp1-Cullin-1-F-box) ubiquitin ligase.","date":"1998","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/9990507","citation_count":93,"is_preprint":false},{"pmid":"16112103","id":"PMC_16112103","title":"C. elegans TCF protein, POP-1, converts from repressor to activator as a result of Wnt-induced lowering of nuclear levels.","date":"2005","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16112103","citation_count":91,"is_preprint":false},{"pmid":"12142026","id":"PMC_12142026","title":"Dynamics of a developmental switch: recursive intracellular and intranuclear redistribution of Caenorhabditis elegans POP-1 parallels Wnt-inhibited transcriptional repression.","date":"2002","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/12142026","citation_count":85,"is_preprint":false},{"pmid":"17567664","id":"PMC_17567664","title":"Binary cell fate specification during C. elegans embryogenesis driven by reiterated reciprocal asymmetry of TCF POP-1 and its coactivator beta-catenin SYS-1.","date":"2007","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/17567664","citation_count":82,"is_preprint":false},{"pmid":"16084508","id":"PMC_16084508","title":"The Wnt effector POP-1 and the PAL-1/Caudal homeoprotein collaborate with SKN-1 to activate C. elegans endoderm development.","date":"2005","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16084508","citation_count":80,"is_preprint":false},{"pmid":"11742996","id":"PMC_11742996","title":"A POP-1 repressor complex restricts inappropriate cell type-specific gene transcription during Caenorhabditis elegans embryogenesis.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11742996","citation_count":75,"is_preprint":false},{"pmid":"39268503","id":"PMC_39268503","title":"POP1 Facilitates Proliferation in Triple-Negative Breast Cancer via m6A-Dependent Degradation of CDKN1A mRNA.","date":"2024","source":"Research (Washington, D.C.)","url":"https://pubmed.ncbi.nlm.nih.gov/39268503","citation_count":67,"is_preprint":false},{"pmid":"11839816","id":"PMC_11839816","title":"Mouse Pop1 is required for muscle regeneration in adult skeletal muscle.","date":"2002","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11839816","citation_count":66,"is_preprint":false},{"pmid":"21455487","id":"PMC_21455487","title":"Whole-exome re-sequencing in a family quartet identifies POP1 mutations as the cause of a novel skeletal dysplasia.","date":"2011","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21455487","citation_count":62,"is_preprint":false},{"pmid":"12810601","id":"PMC_12810601","title":"Establishment of POP-1 asymmetry in early C. elegans embryos.","date":"2003","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/12810601","citation_count":56,"is_preprint":false},{"pmid":"34111560","id":"PMC_34111560","title":"lncRNA lnc-POP1-1 upregulated by VN1R5 promotes cisplatin resistance in head and neck squamous cell carcinoma through interaction with MCM5.","date":"2021","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34111560","citation_count":47,"is_preprint":false},{"pmid":"18362139","id":"PMC_18362139","title":"Mapping of POP1-binding site on pyrin domain of ASC.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18362139","citation_count":42,"is_preprint":false},{"pmid":"12651889","id":"PMC_12651889","title":"Acetylation regulates subcellular localization of the Wnt signaling nuclear effector POP-1.","date":"2003","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/12651889","citation_count":40,"is_preprint":false},{"pmid":"14966204","id":"PMC_14966204","title":"Developmental expression of Pop1/Bves.","date":"2004","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/14966204","citation_count":39,"is_preprint":false},{"pmid":"28067412","id":"PMC_28067412","title":"Broadening the phenotypic spectrum of POP1-skeletal dysplasias: identification of POP1 mutations in a mild and severe skeletal dysplasia.","date":"2017","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28067412","citation_count":20,"is_preprint":false},{"pmid":"11839256","id":"PMC_11839256","title":"Production of monoclonal antibodies against chicken Pop1 (BVES).","date":"2001","source":"Hybridoma and hybridomics","url":"https://pubmed.ncbi.nlm.nih.gov/11839256","citation_count":19,"is_preprint":false},{"pmid":"27380734","id":"PMC_27380734","title":"Further evidence of POP1 mutations as the cause of anauxetic dysplasia.","date":"2016","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/27380734","citation_count":18,"is_preprint":false},{"pmid":"26135751","id":"PMC_26135751","title":"Footprinting analysis of interactions between the largest eukaryotic RNase P/MRP protein Pop1 and RNase P/MRP RNA components.","date":"2015","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/26135751","citation_count":18,"is_preprint":false},{"pmid":"36225929","id":"PMC_36225929","title":"POP1 inhibits MSU-induced inflammasome activation and ameliorates gout.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36225929","citation_count":17,"is_preprint":false},{"pmid":"28370480","id":"PMC_28370480","title":"POP1 might be recruiting its type-Ia interface for NLRP3-mediated PYD-PYD interaction: Insights from MD simulation.","date":"2017","source":"Journal of molecular recognition : JMR","url":"https://pubmed.ncbi.nlm.nih.gov/28370480","citation_count":13,"is_preprint":false},{"pmid":"31740621","id":"PMC_31740621","title":"C. elegans Runx/CBFβ suppresses POP-1 TCF to convert asymmetric to proliferative division of stem cell-like seam cells.","date":"2019","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/31740621","citation_count":12,"is_preprint":false},{"pmid":"25839653","id":"PMC_25839653","title":"Crystal structure of human POP1 and its distinct structural feature for PYD domain.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25839653","citation_count":7,"is_preprint":false},{"pmid":"37010429","id":"PMC_37010429","title":"POP1 promotes the progression of breast cancer through maintaining telomere integrity.","date":"2023","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/37010429","citation_count":5,"is_preprint":false},{"pmid":"32134183","id":"PMC_32134183","title":"The novel R211Q POP1 homozygous mutation causes different pathogenesis and skeletal changes from those of previously reported POP1-associated anauxetic dysplasia.","date":"2020","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/32134183","citation_count":5,"is_preprint":false},{"pmid":"15935751","id":"PMC_15935751","title":"Advocating asymmetry and the POP-1 paradox: noncanonical Wnt signaling in C. elegans.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/15935751","citation_count":2,"is_preprint":false},{"pmid":"38763227","id":"PMC_38763227","title":"PGC-1α inhibits NLRP3 signaling through transcriptional activation of POP1 to alleviate inflammation and strengthen osteogenic differentiation of lipopolysaccharide-induced human periodontal stem cells.","date":"2024","source":"Prostaglandins & other lipid mediators","url":"https://pubmed.ncbi.nlm.nih.gov/38763227","citation_count":1,"is_preprint":false},{"pmid":"38351533","id":"PMC_38351533","title":"Novel phenotype associated with homozygous likely pathogenic variant in the POP1 gene.","date":"2024","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38351533","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.30.621158","title":"In a model of parasite-mediated exhaustion, stem-like CD8 T cells differentiate into an unconventional intermediate effector memory subset","date":"2024-11-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.30.621158","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16734,"output_tokens":5186,"usd":0.063996},"stage2":{"model":"claude-opus-4-6","input_tokens":8784,"output_tokens":2395,"usd":0.155693},"total_usd":0.219689,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"POP1 (yeast) encodes a 100.5 kD protein that is a shared protein component of both RNase MRP and RNase P ribonucleoproteins; immunoprecipitation demonstrated its association with both complexes, and pop1-1 mutation inhibits cleavage at pre-rRNA site A3 (requiring RNase MRP) and blocks pre-tRNA processing (requiring RNase P), with both RNA components underaccumulated in pop1-1 strains.\",\n      \"method\": \"Temperature-sensitive mutant screening, immunoprecipitation, RNA processing assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal co-IP with functional validation, multiple orthogonal methods in foundational paper with 202 citations\",\n      \"pmids\": [\"7926742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"C. elegans POP-1 encodes an HMG box protein required for MS blastomere fate specification; loss of pop-1 causes MS to adopt E (endoderm) fate, and POP-1 functions together with SKN-1 transcription factor for MS-specific differentiation.\",\n      \"method\": \"Genetic loss-of-function, lineage analysis, sequence analysis revealing HMG box domain\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with defined cellular phenotype, foundational paper with 265 citations\",\n      \"pmids\": [\"7585963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Fission yeast Pop1, a WD-repeat F-box protein, functions as a recognition/substrate-specificity factor in the ubiquitin-proteasome pathway for degradation of CDK inhibitor Rum1 and S-phase initiator Cdc18; Pop1 binds Cdc18 in vivo, and ubiquitinated forms of Rum1 and Cdc18 are absent in pop1 mutants.\",\n      \"method\": \"Genetic epistasis, in vivo co-immunoprecipitation, Western blot for ubiquitinated forms, 26S proteasome mutant analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, epistasis, multiple orthogonal methods, 147 citations\",\n      \"pmids\": [\"9203581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"C. elegans POP-1 nuclear levels are asymmetric between sister cells born from anterior-posterior divisions (anterior cells have higher nuclear POP-1), and this asymmetry requires Wnt pathway genes; loss of pop-1 activity causes anterior cells to adopt posterior sister fates.\",\n      \"method\": \"Immunofluorescence quantification of nuclear POP-1, genetic epistasis with Wnt pathway mutants, loss-of-function analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional consequence, epistasis, 235 citations\",\n      \"pmids\": [\"9458047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Fission yeast Pop1 and Pop2 form hetero- and homo-dimeric complexes together with cullin-1 to constitute the SCF ubiquitin ligase (SCFPop1/Pop1, SCFPop1/Pop2, SCFPop2/Pop2) that controls degradation of Rum1 and Cdc18.\",\n      \"method\": \"Co-immunoprecipitation, genetic analysis, biochemical fractionation\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP demonstrating complex composition, functionally validated\",\n      \"pmids\": [\"9990507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"C. elegans POP-1 acts as a transcriptional repressor of end-1 (endoderm gene) in the MS lineage by recruiting histone deacetylase HDA-1 and co-repressor UNC-37 (Groucho homolog).\",\n      \"method\": \"Genetic epistasis, reporter gene assays, co-immunoprecipitation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP identifying binding partners, functional reporter assays, epistasis, 75 citations\",\n      \"pmids\": [\"11742996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"C. elegans POP-1 undergoes Wnt-dependent nucleocytoplasmic redistribution immediately following cytokinesis; POP-1 coalescences into subnuclear domains during interphase in unsignaled (anterior) cells coincident with repressor activity; its asymmetric distribution requires a 124-amino-acid internal domain but not the HMG box or beta-catenin interaction domains; POP-1 binds end-1 and end-3 target gene promoters in vivo and blocks their activation in anterior sisters.\",\n      \"method\": \"Live imaging in embryos, domain deletion analysis, in vivo chromatin binding assays\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — live imaging with functional consequence, domain mapping, in vivo binding assays, 85 citations\",\n      \"pmids\": [\"12142026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mouse Pop1 (Popeye/BVES), a putative transmembrane protein expressed in striated and smooth muscle, is required for skeletal muscle regeneration; Pop1 knockout mice show retarded regeneration after cardiotoxin injury, and satellite cells show persistent elevated Pop1 expression during regeneration.\",\n      \"method\": \"Knockout mouse model, cardiotoxin injury assay, lacZ reporter lineage tracing, immunofluorescence\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined regeneration phenotype, single lab\",\n      \"pmids\": [\"11839816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"C. elegans POP-1 controls the asymmetric division of gonadal precursor cells Z1 and Z4 to establish the proximal-distal axis of the gonad; this requires the beta-catenin binding domain of POP-1, and Wnt pathway components wrm-1 and lit-1 are required for POP-1 function in this context.\",\n      \"method\": \"RNAi, genetic epistasis, domain-specific allele analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple alleles, RNAi, genetic epistasis, 113 citations\",\n      \"pmids\": [\"11807036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human POP1/ASC2 (PYRIN domain-only protein) associates with ASC via PAAD-PAAD (pyrin-pyrin) domain interactions and suppresses ASC-mediated NF-κB activation and pro-caspase-1 regulation.\",\n      \"method\": \"Gene transfer/overexpression, co-immunoprecipitation, NF-κB reporter assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP with functional assay, foundational characterization paper, 150 citations\",\n      \"pmids\": [\"12656673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Acetylation of three specific lysine residues in C. elegans POP-1 enhances nuclear retention by increasing nuclear import and blocking nuclear export; these lysines are essential for proper nuclear localization and biological activity during embryogenesis.\",\n      \"method\": \"In vivo mutagenesis of acetylation sites, nuclear localization assays, functional rescue experiments\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — site-directed mutagenesis with functional validation and localization assays, 40 citations\",\n      \"pmids\": [\"12651889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"POP-1 asymmetry in C. elegans early embryos is established by Wnt-like signaling from multiple distinct signaling cells; some cells use P2-like Wnt signaling while others use apparently distinct pathways.\",\n      \"method\": \"Cell ablation, blastomere isolation, genetic epistasis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell ablation experiments with defined signaling epistasis, single lab\",\n      \"pmids\": [\"12810601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"C. elegans POP-1 functions as a direct transcriptional activator (not only repressor) of Wnt target genes in the endoderm precursor; Wnt signaling converts POP-1 from repressor to activator by lowering its nuclear levels, and a Lef-1-like binding site in the end-1 promoter is essential for this activation.\",\n      \"method\": \"Reporter gene assays, promoter mutagenesis, genetic epistasis with Wnt pathway\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — promoter mutagenesis, functional reporter assays, epistasis, 91 citations\",\n      \"pmids\": [\"16112103\", \"16084508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The beta-catenin SYS-1 acts as a coactivator for C. elegans POP-1; SYS-1 and POP-1 exhibit reciprocal asymmetry in posterior vs. anterior cells, and the SYS-1-to-POP-1 ratio determines anterior vs. posterior cell fate (high ratio drives posterior fate, low ratio drives anterior fate); SYS-1 and POP-1 asymmetries are regulated by distinct subsets of Wnt/MAP kinase pathway genes.\",\n      \"method\": \"Fluorescent protein reporters, genetic epistasis, RNAi, quantitative imaging\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — quantitative imaging, epistasis, multiple orthogonal approaches, 82 citations\",\n      \"pmids\": [\"17567664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human POP1 (PYD-only protein) specifically interacts with the ASC pyrin domain (Kd = 4.08 μM) but not with Cryopyrin; the interaction involves a negative electrostatic surface patch on ASC_PYD (helices H1 and H4) and a positive electrostatic surface patch on POP1 (helices H2 and H3); conformational changes in the ASC_PYD H2-H3 loop affect POP1 binding.\",\n      \"method\": \"In vitro binding assays with purified proteins, NMR chemical shift mapping, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with purified proteins, NMR structural mapping, mutagenesis validation\",\n      \"pmids\": [\"18362139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Compound heterozygous loss-of-function mutations in human POP1 impair the integrity and activity of the RNase MRP complex and impair cell proliferation, causing a skeletal dysplasia phenotype resembling anauxetic dysplasia.\",\n      \"method\": \"Whole-exome sequencing, RNase MRP activity assays, cell proliferation assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional validation of complex integrity and activity, single lab, 62 citations\",\n      \"pmids\": [\"21455487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Human POP1 (PYD-only protein) inhibits ASC-dependent inflammasome assembly by preventing inflammasome nucleation, thereby blocking caspase-1 activation, IL-1β and IL-18 release, pyroptosis, and ASC particle release; POP1 expression is regulated by TLR and IL-1R signaling as a regulatory feedback loop.\",\n      \"method\": \"Transgenic mouse model (human POP1 in monocytes/macrophages/DCs), inflammasome assembly assays, caspase-1 activation assays, cytokine measurement\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — transgenic model with multiple functional readouts, 112 citations\",\n      \"pmids\": [\"26275995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Yeast Pop1 protein directly interacts with the RNA moieties of both RNase P and RNase MRP and plays a structural scaffolding role stabilizing the global architecture of eukaryotic RNase P RNA, substituting for RNA-RNA tertiary interactions present in bacterial RNase P.\",\n      \"method\": \"Footprinting analysis, RNA-protein interaction mapping\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical interaction mapping with structural implications, single lab\",\n      \"pmids\": [\"26135751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of human POP1 (PYD-only protein) reveals a six-helix bundle PYD domain; POP1 directly binds ASC via PYD:PYD interaction, preventing ASC recruitment to Nod-like receptors and thereby inhibiting inflammasome assembly.\",\n      \"method\": \"X-ray crystallography, structural analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure determined, but limited functional mutagenesis validation in same paper\",\n      \"pmids\": [\"25839653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In C. elegans seam cells, high nuclear POP-1 levels induce differentiation while low nuclear POP-1 promotes self-renewal; before symmetric division, RNT-1 (Runx) and BRO-1 (CBFβ) downregulate pop-1 expression to reduce POP-1 below the threshold needed for its repressor function, converting asymmetric (differentiative) to symmetric (proliferative) division.\",\n      \"method\": \"Time-lapse fluorescence microscopy, lineage-specific knockout, GFP-tagging of endogenous pop-1, RNAi\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — endogenous tagging, KO with defined phenotype, epistasis\",\n      \"pmids\": [\"31740621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Human POP1 (PYD-only protein) inhibits NLRP3 inflammasome activation by interfering with the NLRP3-ASC PYD-PYD interaction within the inflammasome complex; reduced POP1 expression in human macrophages enhances IL-1β secretion; a cell-permeable version of POP1 ameliorates MSU crystal-induced inflammation in vivo.\",\n      \"method\": \"Macrophage overexpression/knockdown, NLRP3 inflammasome assembly assays, in vivo gout models (airpouch, ankle joint), cytokine measurement\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain and loss of function with defined mechanism, in vivo validation, multiple readouts\",\n      \"pmids\": [\"36225929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Human POP1 (RNase MRP component) promotes breast cancer cell proliferation by interacting with and stabilizing the telomerase RNA component TERC, thereby protecting telomeres from shortening.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/overexpression, xenograft model, telomere length assays\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single co-IP, limited mechanistic validation\",\n      \"pmids\": [\"37010429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Human POP1 (RNase MRP component) directly binds the coding sequence (CDS) region of CDKN1A mRNA and promotes its degradation in a manner dependent on N6-methyladenosine (m6A) modification at position 497 of CDKN1A and recognition of this mark by YTHDF2.\",\n      \"method\": \"RNA immunoprecipitation, m6A site mutagenesis, YTHDF2 knockdown, in vitro and in vivo proliferation assays, m6A inhibitor treatment\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-IP with mutagenesis of m6A site, multiple orthogonal approaches in single lab\",\n      \"pmids\": [\"39268503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PGC-1α transcriptionally activates POP1 (PYD-only protein) by binding to the POP1 promoter region; this PGC-1α→POP1 axis inactivates NLRP3 signaling to reduce inflammation in LPS-treated periodontal stem cells.\",\n      \"method\": \"Promoter binding assay (ChIP or luciferase), overexpression/knockdown, NLRP3 pathway assays\",\n      \"journal\": \"Prostaglandins & other lipid mediators\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single study with limited mechanistic detail on promoter binding\",\n      \"pmids\": [\"38763227\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"POP1 refers to multiple distinct proteins: (1) the human/yeast RNase MRP/RNase P core protein component that scaffolds RNA architecture and is required for pre-rRNA and pre-tRNA processing, with mutations causing skeletal dysplasia; (2) the human PYD-only protein (inflammasome regulator) that inhibits NLRP3 inflammasome assembly by competitively binding the ASC pyrin domain via defined electrostatic surface patches, thereby blocking caspase-1 activation and IL-1β/IL-18 release; and (3) the C. elegans TCF/LEF homolog that acts as a Wnt-regulated nuclear effector, switching between repressor (via HDA-1/UNC-37 recruitment) and activator states depending on its nuclear concentration and interaction with beta-catenin SYS-1, to specify anterior-posterior cell fate asymmetry throughout development.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Human POP1 designates two distinct gene products: (1) a core protein subunit of the RNase MRP and RNase P ribonucleoprotein complexes, and (2) a PYD-only protein that regulates inflammasome signaling. As an RNase MRP/P component, POP1 scaffolds the RNA architecture of both complexes and is required for pre-rRNA cleavage and pre-tRNA processing; compound heterozygous loss-of-function mutations in this gene cause anauxetic dysplasia, a skeletal dysplasia, by impairing RNase MRP integrity and cell proliferation [PMID:7926742, PMID:21455487, PMID:26135751]. POP1 also binds CDKN1A mRNA and promotes its m6A/YTHDF2-dependent degradation, and interacts with TERC to stabilize telomerase RNA [PMID:39268503, PMID:37010429]. As the PYD-only inflammasome regulator, POP1 adopts a six-helix bundle pyrin domain fold and competitively binds the ASC pyrin domain via complementary electrostatic surfaces, thereby blocking ASC recruitment to NLRP3, preventing inflammasome nucleation, caspase-1 activation, and IL-1β/IL-18 release [PMID:18362139, PMID:25839653, PMID:26275995, PMID:36225929].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Identification of yeast POP1 as a shared subunit of RNase MRP and RNase P established that a single protein bridges both RNA-processing ribonucleoproteins and is essential for pre-rRNA and pre-tRNA maturation.\",\n      \"evidence\": \"Temperature-sensitive mutant screening, immunoprecipitation of both complexes, and RNA processing assays in S. cerevisiae\",\n      \"pmids\": [\"7926742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of POP1 interaction with the RNA subunits was unknown\", \"Whether POP1 contributed catalytic or purely structural roles was unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery that human POP1 (PYD-only protein) binds ASC via pyrin-pyrin domain interactions and suppresses NF-κB activation and caspase-1 regulation revealed a new class of endogenous inflammasome inhibitors.\",\n      \"evidence\": \"Co-immunoprecipitation and NF-κB reporter assays in transfected cells\",\n      \"pmids\": [\"12656673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only overexpression data; endogenous POP1 function unconfirmed\", \"Specificity for ASC versus other PYD-containing proteins untested\", \"No structural detail on the PYD-PYD interface\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"NMR mapping and mutagenesis defined the molecular interface between POP1 and ASC, showing that complementary electrostatic patches (negative on ASC helices H1/H4, positive on POP1 helices H2/H3) mediate binding with micromolar affinity, explaining POP1's selectivity for ASC over Cryopyrin.\",\n      \"evidence\": \"In vitro binding with purified proteins, NMR chemical shift perturbation, site-directed mutagenesis\",\n      \"pmids\": [\"18362139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full atomic-resolution structure of the POP1-ASC complex\", \"In vivo relevance of specific interface residues not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linking compound heterozygous POP1 mutations to anauxetic dysplasia demonstrated that RNase MRP integrity in humans depends on POP1 and that its loss causes a Mendelian skeletal dysplasia.\",\n      \"evidence\": \"Whole-exome sequencing of patients, RNase MRP activity and integrity assays, cell proliferation assays\",\n      \"pmids\": [\"21455487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited number of families studied\", \"Relative contributions of RNase MRP versus RNase P dysfunction to skeletal phenotype unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Three converging studies established POP1's structural basis and in vivo inflammasome-regulatory function: crystal structure revealed a canonical six-helix PYD fold, footprinting showed yeast Pop1 scaffolds RNase P RNA architecture, and a transgenic mouse model demonstrated that POP1 blocks inflammasome nucleation, caspase-1 activation, IL-1β/IL-18 release, and pyroptosis in a feedback loop regulated by TLR/IL-1R signaling.\",\n      \"evidence\": \"X-ray crystallography of human POP1 PYD; RNA footprinting of yeast Pop1-RNA interactions; transgenic mice expressing human POP1 in myeloid cells with inflammasome functional assays\",\n      \"pmids\": [\"25839653\", \"26135751\", \"26275995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether POP1 inhibits all ASC-dependent inflammasomes or preferentially NLRP3 was unresolved\", \"Stoichiometry of POP1 relative to ASC in endogenous settings unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Gain- and loss-of-function experiments in human macrophages plus in vivo gout models showed POP1 specifically interferes with the NLRP3-ASC PYD-PYD interaction, and a cell-permeable POP1 peptide ameliorates MSU crystal-induced inflammation, validating POP1 as a therapeutic concept.\",\n      \"evidence\": \"Macrophage knockdown/overexpression, NLRP3 assembly assays, in vivo airpouch and ankle joint gout models\",\n      \"pmids\": [\"36225929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term safety and specificity of cell-permeable POP1 not assessed\", \"Effect on non-NLRP3 inflammasomes (AIM2, NLRC4) in vivo not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"POP1 (RNase MRP component) was shown to bind CDKN1A mRNA and promote its degradation via m6A modification at position 497 recognized by YTHDF2, revealing an RNA-regulatory function beyond canonical rRNA/tRNA processing.\",\n      \"evidence\": \"RNA immunoprecipitation, m6A site mutagenesis, YTHDF2 knockdown, proliferation assays\",\n      \"pmids\": [\"39268503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether POP1 directly reads or merely facilitates YTHDF2 access to m6A is unclear\", \"Broader mRNA target repertoire of POP1 uncharacterized\", \"Single-lab finding awaiting independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the full scope of POP1's mRNA targets beyond CDKN1A and TERC, whether the RNase MRP scaffolding and mRNA-decay functions are mechanistically coupled, the stoichiometry and dynamics of POP1 inhibition within native inflammasome assemblies, and whether POP1 therapeutics can selectively modulate specific inflammasome subtypes in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No genome-wide mapping of POP1-bound mRNAs\", \"No cryo-EM structure of POP1 within a fully assembled human RNase MRP complex\", \"Therapeutic window for POP1-based inflammasome inhibition undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 17, 22]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 14, 16, 20]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [16, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 14, 16, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [\n      \"RNase MRP\",\n      \"RNase P\"\n    ],\n    \"partners\": [\n      \"ASC\",\n      \"NLRP3\",\n      \"TERC\",\n      \"YTHDF2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}