{"gene":"POP1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1994,"finding":"Yeast POP1 protein (Pop1p) is a shared protein component of both RNase MRP and RNase P ribonucleoproteins, demonstrated by immunoprecipitation. The pop1-1 mutation inhibits cleavage at the A3 site in pre-rRNA (required for synthesis of the major short 5.8S rRNA form) and blocks pre-tRNA processing, phenocopying mutations in the RNA components of RNase MRP and RNase P respectively. Loss of Pop1p causes underaccumulation of the RNA components of both RNase MRP and RNase P.","method":"Immunoprecipitation of ribonucleoproteins; temperature-sensitive mutant analysis; Northern blotting of pre-rRNA and pre-tRNA processing intermediates","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP demonstrating complex membership, in vivo processing assays with defined substrates, multiple orthogonal methods in a single rigorous study","pmids":["7926742"],"is_preprint":false},{"year":2015,"finding":"Footprinting analysis revealed that yeast Pop1 (the largest protein component of RNase P/MRP) directly contacts the RNA moieties of both RNase P and RNase MRP. Pop1 interacts with conserved structural elements of both RNA components and is proposed to function as a scaffold stabilizing the global architecture of eukaryotic RNase P RNA, substituting for RNA-RNA tertiary interactions that maintain structure in bacterial RNase P.","method":"RNA footprinting (chemical and enzymatic probing) with purified Pop1 protein and RNase P/MRP RNA components","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct biochemical footprinting with purified components, but single lab, structural interpretation partly inferential from abstract","pmids":["26135751"],"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 severe skeletal dysplasia. POP1 directly interacts with the RMRP RNA domains that are affected in anauxetic dysplasia.","method":"Whole-exome sequencing; functional assays of RNase MRP complex integrity and activity in patient cells; cell proliferation assays","journal":"PLoS Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human disease mutations with functional validation of complex activity and cell proliferation, two orthogonal cellular assays, single lab","pmids":["21455487"],"is_preprint":false},{"year":2017,"finding":"POP1 mutations in human patients reduce RMRP RNA abundance and elevate pre-5.8S rRNA levels, confirming that POP1 is required for the stability/assembly of the RNase MRP complex and for its rRNA processing activity in vivo.","method":"Sanger sequencing of patient samples; quantitative RT-PCR measurement of RMRP RNA and pre-5.8S rRNA accumulation in patient cells","journal":"Clinical Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient mutation studies with functional readout of complex RNA stability and substrate accumulation; replicated across multiple families","pmids":["28067412"],"is_preprint":false},{"year":2020,"finding":"A novel homozygous R211Q POP1 mutation dramatically reduces RNase MRP RNA levels in patient lymphocytes (indicating complex instability) but does not cause accumulation of pre-5.8S rRNA substrate, suggesting this mutation dissociates RNase MRP complex stability from its rRNA processing activity and questioning ribosomal biogenesis as the sole pathophysiological basis for POP1-related skeletal dysplasia.","method":"RNA extraction from patient peripheral lymphocytes; quantitative RT-PCR for RMRP RNA and pre-5.8S rRNA","journal":"American Journal of Medical Genetics Part A","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single family, single lab, single method (RT-PCR), negative pre-rRNA accumulation result is informative but not functionally confirmed by independent assay","pmids":["32134183"],"is_preprint":false},{"year":2003,"finding":"Human POP1/ASC2 (a PYRIN-domain-only protein) associates with ASC through PAAD-PAAD (PYD-PYD) interactions and suppresses ASC-mediated NF-κB activation and pro-caspase-1 regulation. In gene transfer experiments, POP1/ASC2 suppressed cytokine-mediated NF-κB activation.","method":"Co-immunoprecipitation demonstrating PYD-PYD interaction; gene transfer/overexpression assays; NF-κB reporter assays; pro-caspase-1 activation assays","journal":"Biochemical Journal","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP establishing physical interaction, functional reporter assays in cells, multiple orthogonal methods; single lab","pmids":["12656673"],"is_preprint":false},{"year":2008,"finding":"POP1 (PYD-only protein) specifically binds the pyrin domain of ASC (ASC_PYD) with a dissociation constant of ~4 µM but does not interact with Cryopyrin. NMR and mutagenesis identified the binding interface: a negative electrostatic surface patch on ASC_PYD (helices H1 and H4) interacts with a positive electrostatic surface patch on POP1 (helices H2 and H3). Conformational changes in the ASC_PYD H2-H3 loop can modulate this interaction.","method":"In vitro binding assay with purified proteins (affinity measurement); NMR chemical shift perturbation mapping; site-directed mutagenesis of interacting residues","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins, NMR structural mapping, and mutagenesis validation of the binding interface; multiple orthogonal methods in a single rigorous study","pmids":["18362139"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of human POP1 (PYD-only protein) was solved, revealing a six-helix bundle PYD fold with distinct structural features. Based on the structure, POP1 inhibits inflammasome assembly by directly binding ASC via a PYD:PYD interaction, thereby preventing ASC recruitment to Nod-like receptors.","method":"X-ray crystallography of human POP1; structural comparison with related PYD domains","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure determined, but mechanistic inhibition inference is partly structural speculation from the abstract without mutagenesis validation reported","pmids":["25839653"],"is_preprint":false},{"year":2015,"finding":"Human POP1 (PYD-only protein) inhibits ASC-dependent inflammasome assembly by preventing inflammasome nucleation (blocking ASC polymerization), thereby suppressing caspase-1 activation, IL-1β/IL-18 processing, pyroptosis, and ASC particle release. Transgenic POP1 expression in mouse myeloid cells protected from systemic inflammation. POP1 expression is regulated by TLR and IL-1R signaling, establishing a negative feedback loop.","method":"Transgenic mouse model (human POP1 in monocytes/macrophages/DCs); NLRP3 mutation and PAMP challenge models; caspase-1 activation, cytokine, and pyroptosis assays; ASC polymerization/speck formation assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic model with defined molecular mechanism (ASC nucleation inhibition), multiple orthogonal assays (caspase-1, cytokine, pyroptosis, ASC speck), replicated across multiple disease models","pmids":["26275995"],"is_preprint":false},{"year":2022,"finding":"POP1 inhibits NLRP3 inflammasome activation specifically by interfering with the NLRP3-ASC PYD-PYD interaction within the inflammasome complex. Exogenous POP1 in mouse and human macrophages blocks MSU crystal-induced NLRP3 inflammasome assembly and reduces IL-1β/IL-18 secretion; reduced POP1 in human macrophages enhances IL-1β secretion. A cell-permeable engineered POP1 ameliorates MSU-induced inflammation in vivo.","method":"Macrophage overexpression and knockdown; MSU crystal stimulation; IL-1β/IL-18 ELISA; ASC speck formation assay; in vivo subcutaneous airpouch and ankle joint gout models; cell-permeable POP1 administration","journal":"Frontiers in Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain- and loss-of-function in primary human and mouse macrophages, in vivo models, mechanistic placement at NLRP3-ASC interaction step, multiple orthogonal readouts","pmids":["36225929"],"is_preprint":false},{"year":2024,"finding":"PGC-1α transcriptionally activates POP1 (PYD-only protein) by binding to the POP1 promoter region, and this PGC-1α→POP1 axis inactivates NLRP3 signaling to reduce inflammation in LPS-stimulated periodontal stem cells.","method":"ChIP or promoter binding assay (PGC-1α binding to POP1 promoter); POP1 knockdown epistasis; NLRP3 pathway readouts; overexpression in PDLSCs","journal":"Prostaglandins & Other Lipid Mediators","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — promoter binding assay and epistasis placing POP1 downstream of PGC-1α and upstream of NLRP3; single lab, abstract does not detail method rigor","pmids":["38763227"],"is_preprint":false},{"year":2024,"finding":"Human POP1 (RNase component) directly binds the coding sequence (CDS) region of CDKN1A mRNA and promotes its degradation in TNBC cells. This degradation depends on N6-methyladenosine (m6A) modification at position 497 of CDKN1A mRNA and recognition of this modification by YTHDF2. POP1-mediated CDKN1A mRNA degradation drives cell cycle progression and proliferation.","method":"RNA immunoprecipitation (RIP) demonstrating POP1 binding to CDKN1A CDS; m6A site mapping; YTHDF2 knockdown epistasis; in vitro and in vivo proliferation assays; m6A inhibitor (STM2457) rescue experiments","journal":"Research (Washington D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP assay for direct RNA binding, m6A site-specific mechanism, epistasis with YTHDF2, in vivo xenograft validation; single lab","pmids":["39268503"],"is_preprint":false},{"year":2023,"finding":"POP1 (RNase component) interacts with and stabilizes the telomerase RNA component (TERC), activating the telomerase complex and protecting telomeres from shortening. POP1 overexpression promotes breast cancer cell cycle progression, while POP1 silencing causes cell cycle arrest.","method":"Co-immunoprecipitation of POP1 with telomerase complex; TERC stability assay upon POP1 overexpression/knockdown; telomere length measurement; xenograft in vivo model; cell cycle analysis","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — Co-IP and functional RNA stability data with defined molecular mechanism; single lab, abstract does not detail method rigor fully","pmids":["37010429"],"is_preprint":false}],"current_model":"Human POP1 (Processing of Precursor 1) is a large, essential protein that serves as a shared structural scaffold component of both RNase MRP and RNase P ribonucleoprotein complexes, stabilizing their RNA moieties and enabling pre-rRNA (A3-site cleavage for 5.8S rRNA) and pre-tRNA processing; loss-of-function mutations cause RNase MRP complex instability and a spectrum of skeletal dysplasias. In cancer contexts, POP1 has been shown to promote proliferation by degrading CDKN1A mRNA in an m6A/YTHDF2-dependent manner and by stabilizing the telomerase RNA component TERC. A distinct human protein sharing the POP1 symbol—the PYRIN-domain-only protein POP1/ASC2—inhibits inflammasome assembly by competitively binding the pyrin domain of ASC (via a defined electrostatic interface mapped by NMR and crystallography), thereby blocking ASC-NLRP3 interaction, preventing ASC polymerization, and suppressing caspase-1 activation, IL-1β/IL-18 release, and pyroptosis; its expression is induced by TLR/IL-1R signaling, forming a negative feedback loop, and it is transcriptionally activated by PGC-1α."},"narrative":{"mechanistic_narrative":"The POP1 symbol denotes two distinct, coherent proteins in this corpus. The RNase-associated POP1 is the largest protein subunit shared by the RNase MRP and RNase P ribonucleoprotein complexes, originally defined in yeast where it co-precipitates with both enzymes and its loss blocks A3-site cleavage of pre-rRNA (5.8S rRNA maturation) and pre-tRNA processing while destabilizing the RNA moieties of both complexes [PMID:7926742]. It acts as a protein scaffold that directly contacts conserved structural elements of both RNase P and RNase MRP RNAs, substituting for the RNA-RNA tertiary interactions that maintain enzyme architecture [PMID:26135751]. In humans, compound heterozygous loss-of-function mutations impair RNase MRP integrity and activity, reduce RMRP RNA abundance, elevate pre-5.8S rRNA, and impair cell proliferation, causing severe skeletal dysplasia (anauxetic dysplasia); POP1 binds the RMRP RNA domains affected in this disease [PMID:21455487, PMID:28067412]. In cancer, this POP1 promotes proliferation through two RNA-directed activities: it binds the coding sequence of CDKN1A mRNA and drives its degradation in an m6A(position 497)/YTHDF2-dependent manner to relieve cell-cycle inhibition, and it binds and stabilizes the telomerase RNA component TERC to activate telomerase and protect telomeres [PMID:39268503, PMID:37010429]. A separate, unrelated protein sharing the POP1/ASC2 symbol is a PYRIN-domain-only protein that binds the pyrin domain of ASC through a defined PYD:PYD electrostatic interface and inhibits inflammasome assembly by blocking ASC nucleation and polymerization, thereby suppressing caspase-1 activation, IL-1β/IL-18 release, and pyroptosis [PMID:18362139, PMID:26275995]. This POP1 interferes with the NLRP3-ASC PYD-PYD interaction, its expression is induced by TLR/IL-1R signaling as a negative feedback loop, and it is transcriptionally activated by PGC-1α [PMID:26275995, PMID:36225929, PMID:38763227].","teleology":[{"year":1994,"claim":"Established that POP1 is a shared protein subunit of two distinct RNA-processing enzymes, defining its core role as a component required for both rRNA and tRNA maturation.","evidence":"Immunoprecipitation, temperature-sensitive mutant analysis, and Northern blotting of processing intermediates in yeast","pmids":["7926742"],"confidence":"High","gaps":["Did not define which RNA elements Pop1 contacts","Mechanism of how a shared subunit serves two distinct catalytic substrates not resolved"]},{"year":2003,"claim":"Identified a separate PYRIN-domain-only POP1/ASC2 that physically associates with ASC and suppresses ASC-mediated NF-κB and pro-caspase-1 signaling, opening the inflammasome-regulatory branch of the POP1 symbol.","evidence":"Co-IP demonstrating PYD-PYD interaction with NF-κB reporter and pro-caspase-1 activation assays in cells","pmids":["12656673"],"confidence":"Medium","gaps":["Binding interface not mapped at residue level","Endogenous-level relevance not established beyond overexpression"]},{"year":2008,"claim":"Mapped the POP1/ASC2-ASC binding interface at atomic resolution, showing the interaction is electrostatically driven and ASC-specific (not Cryopyrin), grounding the inhibitory mechanism structurally.","evidence":"In vitro binding (Kd ~4 µM) with purified proteins, NMR chemical shift mapping, and site-directed mutagenesis","pmids":["18362139"],"confidence":"High","gaps":["Did not show downstream consequences for inflammasome assembly in cells","Specificity profile against other PYD proteins incomplete"]},{"year":2011,"claim":"Connected human POP1 loss-of-function to disease, showing mutations impair RNase MRP integrity/activity and proliferation and cause skeletal dysplasia, establishing pathophysiological relevance of the RNase subunit role.","evidence":"Whole-exome sequencing with functional RNase MRP integrity/activity and proliferation assays in patient cells","pmids":["21455487"],"confidence":"Medium","gaps":["Did not separate rRNA-processing defect from other RNase MRP functions as the disease driver","Tissue specificity of skeletal phenotype unexplained"]},{"year":2015,"claim":"Resolved how the inflammasome-regulatory POP1 blocks signaling, demonstrating in vivo that it prevents ASC nucleation/polymerization to suppress caspase-1, cytokine release, and pyroptosis, and operates as a TLR/IL-1R-induced negative feedback loop.","evidence":"Transgenic mouse myeloid POP1 expression, NLRP3/PAMP challenge, caspase-1, cytokine, pyroptosis and ASC speck assays","pmids":["26275995"],"confidence":"High","gaps":["Stoichiometry of POP1 needed to block polymerization in vivo not defined","Selectivity across distinct inflammasome sensors not fully delineated"]},{"year":2015,"claim":"Determined the crystal structure of the PYD-only POP1, revealing a six-helix bundle fold consistent with PYD-mediated decoy inhibition of ASC recruitment.","evidence":"X-ray crystallography of human POP1 with structural comparison to related PYDs","pmids":["25839653"],"confidence":"Medium","gaps":["Inhibition inference structural, not validated by mutagenesis in this study","No co-structure with ASC"]},{"year":2015,"claim":"Provided direct biochemical evidence that the RNase POP1 contacts both RNase P and RNase MRP RNAs, supporting a scaffolding model in which protein substitutes for RNA-RNA tertiary contacts.","evidence":"Chemical and enzymatic RNA footprinting with purified Pop1 and RNase P/MRP RNA components","pmids":["26135751"],"confidence":"Medium","gaps":["Structural interpretation partly inferential","Does not resolve how Pop1 distinguishes the two RNAs"]},{"year":2017,"claim":"Confirmed across families that human POP1 mutations reduce RMRP RNA and accumulate pre-5.8S rRNA, tying complex stability directly to defective rRNA processing in vivo.","evidence":"Sanger sequencing and quantitative RT-PCR of RMRP RNA and pre-5.8S rRNA in patient cells","pmids":["28067412"],"confidence":"Medium","gaps":["Causal link from rRNA defect to skeletal phenotype not mechanistically demonstrated"]},{"year":2020,"claim":"Challenged the ribosome-biogenesis-only model by identifying a mutation that destabilizes RNase MRP without accumulating pre-5.8S rRNA, dissociating complex stability from rRNA processing activity.","evidence":"Quantitative RT-PCR of RMRP RNA and pre-5.8S rRNA in patient lymphocytes (single family)","pmids":["32134183"],"confidence":"Low","gaps":["Single family, single method, negative result not functionally confirmed by independent assay","Alternative pathogenic mechanism not identified"]},{"year":2022,"claim":"Refined the inflammasome inhibition mechanism, placing POP1 action at the NLRP3-ASC PYD-PYD interaction step and showing therapeutic potential of a cell-permeable engineered POP1 in gout models.","evidence":"Macrophage gain/loss-of-function, MSU stimulation, IL-1β/IL-18 ELISA, ASC speck assays, and in vivo gout models","pmids":["36225929"],"confidence":"High","gaps":["Pharmacokinetics and off-target effects of engineered POP1 not detailed","Effect on non-NLRP3 inflammasomes not addressed"]},{"year":2023,"claim":"Revealed an oncogenic RNA-stabilizing function, showing the RNase POP1 binds and stabilizes TERC to activate telomerase and drive breast cancer cell cycle progression.","evidence":"Co-IP with telomerase complex, TERC stability and telomere length assays, cell cycle analysis, and xenograft model","pmids":["37010429"],"confidence":"Medium","gaps":["Whether TERC stabilization requires RNase MRP/P complex context unknown","Direct versus indirect binding to TERC not fully resolved"]},{"year":2024,"claim":"Identified a second oncogenic mechanism whereby POP1 binds CDKN1A mRNA and promotes its m6A/YTHDF2-dependent degradation to relieve cell-cycle inhibition, expanding POP1 into mRNA-decay regulation.","evidence":"RIP for POP1-CDKN1A binding, m6A site mapping, YTHDF2 knockdown epistasis, STM2457 rescue, and in vivo proliferation assays in TNBC","pmids":["39268503"],"confidence":"Medium","gaps":["Whether this activity uses the RNase MRP/P catalytic machinery unknown","Generality across other m6A-marked transcripts unaddressed"]},{"year":2024,"claim":"Placed the inflammasome-regulatory POP1 in a transcriptional control circuit, showing PGC-1α binds the POP1 promoter to activate it and inactivate NLRP3 signaling.","evidence":"Promoter binding/ChIP assay, POP1 knockdown epistasis, and NLRP3 pathway readouts in LPS-stimulated periodontal stem cells","pmids":["38763227"],"confidence":"Medium","gaps":["Direct PGC-1α promoter occupancy detail limited","Single cell-type context"]},{"year":null,"claim":"It remains unresolved how the RNase-scaffold POP1 mechanistically achieves its oncogenic RNA-targeting functions (TERC stabilization, CDKN1A decay) and whether these depend on the canonical RNase MRP/P complexes or a distinct activity.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of human RNase MRP/P with POP1 reported in corpus","Link between scaffolding role and mRNA-decay/telomerase functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,2,11,12]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,8,9]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2,3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[11,12]}],"complexes":["RNase MRP","RNase P"],"partners":["RMRP","TERC","CDKN1A","YTHDF2","ASC","NLRP3","PGC-1Α"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NE79","full_name":"Popeye domain-containing protein 1","aliases":[],"length_aa":360,"mass_kda":41.5,"function":"Cell adhesion molecule involved in the establishment and/or maintenance of cell integrity. Involved in the formation and regulation of the tight junction (TJ) paracellular permeability barrier in epithelial cells (PubMed:16188940). Plays a role in VAMP3-mediated vesicular transport and recycling of different receptor molecules through its interaction with VAMP3. Plays a role in the regulation of cell shape and movement by modulating the Rho-family GTPase activity through its interaction with ARHGEF25/GEFT. Induces primordial adhesive contact and aggregation of epithelial cells in a Ca(2+)-independent manner. Also involved in striated muscle regeneration and repair and in the regulation of cell spreading (By similarity). Important for the maintenance of cardiac function. Plays a regulatory function in heart rate dynamics mediated, at least in part, through cAMP-binding and, probably, by increasing cell surface expression of the potassium channel KCNK2 and enhancing current density (PubMed:26642364). Is also a caveolae-associated protein important for the preservation of caveolae structural and functional integrity as well as for heart protection against ischemia injury","subcellular_location":"Lateral cell membrane; Cell junction, tight junction; Membrane; Cell membrane, sarcolemma; Membrane, caveola","url":"https://www.uniprot.org/uniprotkb/Q8NE79/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":153,"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":"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":114,"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":"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":69,"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":63,"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":48,"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":44,"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":21,"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":20,"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":19,"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":19,"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":"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":14,"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":6,"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":6,"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":"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":1,"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":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":17459,"output_tokens":4501,"usd":0.059946,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11537,"output_tokens":4403,"usd":0.08388,"stage2_stop_reason":"end_turn"},"total_usd":0.143826,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify which papers are about the canonical human/mammalian POP1 protein (or clear orthologs). The gene symbol \"POP1\" is used for several distinct proteins:\n\n1. **Human POP1** (Processing of Precursor 1) — core component of RNase MRP and RNase P (PMID:7926742 yeast ortholog; PMID:21455487, 28067412, 27380734, 32134183, 38351533 human disease papers; PMID:26135751 yeast biochemistry; PMID:37010429, 39268503 cancer papers)\n2. **Human POP1/ASC2** — PYRIN-domain-only protein regulating inflammasomes (PMID:12656673, 26275995, 18362139, 25839653, 36225929, 38763227, 28370480)\n3. **C. elegans POP-1** — TCF/LEF transcription factor in Wnt signaling (PMIDs: 7585963, 9458047, 11807036, 16112103, 12142026, 17567664, 16084508, 11742996, 12810601, 12651889, 31740621, 15935751)\n4. **Fission yeast Pop1** — WD-repeat F-box protein in SCF ubiquitin ligase (PMID:9203581, 9990507)\n5. **Mouse Pop1/BVES (Popeye)** — transmembrane protein in muscle (PMID:11839816, 14966204, 11839256) — this is a *different* gene (BVES/POPDC1), not the RNase MRP POP1\n6. **lnc-POP1-1** — lncRNA (PMID:34111560) — EXCLUDE\n7. **Preprint** (bio_10.1101_2024.10.30.621158) — uses \"pop1/pop2/pop3/pop4\" as population labels, not the gene — EXCLUDE\n\nThe query gene is **POP1** (human). Given the corpus is heavily weighted toward the RNase MRP/P component and the inflammasome regulator (both called POP1 in humans), I will treat both as the query gene. The C. elegans POP-1 is an ortholog of TCF/LEF, NOT of human POP1 (RNase MRP). The fission yeast Pop1 is also a different protein (F-box/WD40). Mouse BVES/Pop1 (Popeye) is a different gene entirely.\n\nI will focus on: RNase MRP/P POP1 (yeast ortholog papers included as orthologs), human inflammasome POP1/ASC2 papers, and human cancer POP1 papers. C. elegans POP-1/TCF and fission yeast Pop1/F-box are NOT orthologs of human POP1 — they are symbol collisions.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"Yeast POP1 protein (Pop1p) is a shared protein component of both RNase MRP and RNase P ribonucleoproteins, demonstrated by immunoprecipitation. The pop1-1 mutation inhibits cleavage at the A3 site in pre-rRNA (required for synthesis of the major short 5.8S rRNA form) and blocks pre-tRNA processing, phenocopying mutations in the RNA components of RNase MRP and RNase P respectively. Loss of Pop1p causes underaccumulation of the RNA components of both RNase MRP and RNase P.\",\n      \"method\": \"Immunoprecipitation of ribonucleoproteins; temperature-sensitive mutant analysis; Northern blotting of pre-rRNA and pre-tRNA processing intermediates\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP demonstrating complex membership, in vivo processing assays with defined substrates, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"7926742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Footprinting analysis revealed that yeast Pop1 (the largest protein component of RNase P/MRP) directly contacts the RNA moieties of both RNase P and RNase MRP. Pop1 interacts with conserved structural elements of both RNA components and is proposed to function as a scaffold stabilizing the global architecture of eukaryotic RNase P RNA, substituting for RNA-RNA tertiary interactions that maintain structure in bacterial RNase P.\",\n      \"method\": \"RNA footprinting (chemical and enzymatic probing) with purified Pop1 protein and RNase P/MRP RNA components\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct biochemical footprinting with purified components, but single lab, structural interpretation partly inferential from abstract\",\n      \"pmids\": [\"26135751\"],\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 severe skeletal dysplasia. POP1 directly interacts with the RMRP RNA domains that are affected in anauxetic dysplasia.\",\n      \"method\": \"Whole-exome sequencing; functional assays of RNase MRP complex integrity and activity in patient cells; cell proliferation assays\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human disease mutations with functional validation of complex activity and cell proliferation, two orthogonal cellular assays, single lab\",\n      \"pmids\": [\"21455487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"POP1 mutations in human patients reduce RMRP RNA abundance and elevate pre-5.8S rRNA levels, confirming that POP1 is required for the stability/assembly of the RNase MRP complex and for its rRNA processing activity in vivo.\",\n      \"method\": \"Sanger sequencing of patient samples; quantitative RT-PCR measurement of RMRP RNA and pre-5.8S rRNA accumulation in patient cells\",\n      \"journal\": \"Clinical Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient mutation studies with functional readout of complex RNA stability and substrate accumulation; replicated across multiple families\",\n      \"pmids\": [\"28067412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A novel homozygous R211Q POP1 mutation dramatically reduces RNase MRP RNA levels in patient lymphocytes (indicating complex instability) but does not cause accumulation of pre-5.8S rRNA substrate, suggesting this mutation dissociates RNase MRP complex stability from its rRNA processing activity and questioning ribosomal biogenesis as the sole pathophysiological basis for POP1-related skeletal dysplasia.\",\n      \"method\": \"RNA extraction from patient peripheral lymphocytes; quantitative RT-PCR for RMRP RNA and pre-5.8S rRNA\",\n      \"journal\": \"American Journal of Medical Genetics Part A\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single family, single lab, single method (RT-PCR), negative pre-rRNA accumulation result is informative but not functionally confirmed by independent assay\",\n      \"pmids\": [\"32134183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human POP1/ASC2 (a PYRIN-domain-only protein) associates with ASC through PAAD-PAAD (PYD-PYD) interactions and suppresses ASC-mediated NF-κB activation and pro-caspase-1 regulation. In gene transfer experiments, POP1/ASC2 suppressed cytokine-mediated NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation demonstrating PYD-PYD interaction; gene transfer/overexpression assays; NF-κB reporter assays; pro-caspase-1 activation assays\",\n      \"journal\": \"Biochemical Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP establishing physical interaction, functional reporter assays in cells, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"12656673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"POP1 (PYD-only protein) specifically binds the pyrin domain of ASC (ASC_PYD) with a dissociation constant of ~4 µM but does not interact with Cryopyrin. NMR and mutagenesis identified the binding interface: a negative electrostatic surface patch on ASC_PYD (helices H1 and H4) interacts with a positive electrostatic surface patch on POP1 (helices H2 and H3). Conformational changes in the ASC_PYD H2-H3 loop can modulate this interaction.\",\n      \"method\": \"In vitro binding assay with purified proteins (affinity measurement); NMR chemical shift perturbation mapping; site-directed mutagenesis of interacting residues\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins, NMR structural mapping, and mutagenesis validation of the binding interface; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"18362139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of human POP1 (PYD-only protein) was solved, revealing a six-helix bundle PYD fold with distinct structural features. Based on the structure, POP1 inhibits inflammasome assembly by directly binding ASC via a PYD:PYD interaction, thereby preventing ASC recruitment to Nod-like receptors.\",\n      \"method\": \"X-ray crystallography of human POP1; structural comparison with related PYD domains\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure determined, but mechanistic inhibition inference is partly structural speculation from the abstract without mutagenesis validation reported\",\n      \"pmids\": [\"25839653\"],\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 (blocking ASC polymerization), thereby suppressing caspase-1 activation, IL-1β/IL-18 processing, pyroptosis, and ASC particle release. Transgenic POP1 expression in mouse myeloid cells protected from systemic inflammation. POP1 expression is regulated by TLR and IL-1R signaling, establishing a negative feedback loop.\",\n      \"method\": \"Transgenic mouse model (human POP1 in monocytes/macrophages/DCs); NLRP3 mutation and PAMP challenge models; caspase-1 activation, cytokine, and pyroptosis assays; ASC polymerization/speck formation assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic model with defined molecular mechanism (ASC nucleation inhibition), multiple orthogonal assays (caspase-1, cytokine, pyroptosis, ASC speck), replicated across multiple disease models\",\n      \"pmids\": [\"26275995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"POP1 inhibits NLRP3 inflammasome activation specifically by interfering with the NLRP3-ASC PYD-PYD interaction within the inflammasome complex. Exogenous POP1 in mouse and human macrophages blocks MSU crystal-induced NLRP3 inflammasome assembly and reduces IL-1β/IL-18 secretion; reduced POP1 in human macrophages enhances IL-1β secretion. A cell-permeable engineered POP1 ameliorates MSU-induced inflammation in vivo.\",\n      \"method\": \"Macrophage overexpression and knockdown; MSU crystal stimulation; IL-1β/IL-18 ELISA; ASC speck formation assay; in vivo subcutaneous airpouch and ankle joint gout models; cell-permeable POP1 administration\",\n      \"journal\": \"Frontiers in Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain- and loss-of-function in primary human and mouse macrophages, in vivo models, mechanistic placement at NLRP3-ASC interaction step, multiple orthogonal readouts\",\n      \"pmids\": [\"36225929\"],\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, and this PGC-1α→POP1 axis inactivates NLRP3 signaling to reduce inflammation in LPS-stimulated periodontal stem cells.\",\n      \"method\": \"ChIP or promoter binding assay (PGC-1α binding to POP1 promoter); POP1 knockdown epistasis; NLRP3 pathway readouts; overexpression in PDLSCs\",\n      \"journal\": \"Prostaglandins & Other Lipid Mediators\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — promoter binding assay and epistasis placing POP1 downstream of PGC-1α and upstream of NLRP3; single lab, abstract does not detail method rigor\",\n      \"pmids\": [\"38763227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Human POP1 (RNase component) directly binds the coding sequence (CDS) region of CDKN1A mRNA and promotes its degradation in TNBC cells. This degradation depends on N6-methyladenosine (m6A) modification at position 497 of CDKN1A mRNA and recognition of this modification by YTHDF2. POP1-mediated CDKN1A mRNA degradation drives cell cycle progression and proliferation.\",\n      \"method\": \"RNA immunoprecipitation (RIP) demonstrating POP1 binding to CDKN1A CDS; m6A site mapping; YTHDF2 knockdown epistasis; in vitro and in vivo proliferation assays; m6A inhibitor (STM2457) rescue experiments\",\n      \"journal\": \"Research (Washington D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP assay for direct RNA binding, m6A site-specific mechanism, epistasis with YTHDF2, in vivo xenograft validation; single lab\",\n      \"pmids\": [\"39268503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"POP1 (RNase component) interacts with and stabilizes the telomerase RNA component (TERC), activating the telomerase complex and protecting telomeres from shortening. POP1 overexpression promotes breast cancer cell cycle progression, while POP1 silencing causes cell cycle arrest.\",\n      \"method\": \"Co-immunoprecipitation of POP1 with telomerase complex; TERC stability assay upon POP1 overexpression/knockdown; telomere length measurement; xenograft in vivo model; cell cycle analysis\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — Co-IP and functional RNA stability data with defined molecular mechanism; single lab, abstract does not detail method rigor fully\",\n      \"pmids\": [\"37010429\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human POP1 (Processing of Precursor 1) is a large, essential protein that serves as a shared structural scaffold component of both RNase MRP and RNase P ribonucleoprotein complexes, stabilizing their RNA moieties and enabling pre-rRNA (A3-site cleavage for 5.8S rRNA) and pre-tRNA processing; loss-of-function mutations cause RNase MRP complex instability and a spectrum of skeletal dysplasias. In cancer contexts, POP1 has been shown to promote proliferation by degrading CDKN1A mRNA in an m6A/YTHDF2-dependent manner and by stabilizing the telomerase RNA component TERC. A distinct human protein sharing the POP1 symbol—the PYRIN-domain-only protein POP1/ASC2—inhibits inflammasome assembly by competitively binding the pyrin domain of ASC (via a defined electrostatic interface mapped by NMR and crystallography), thereby blocking ASC-NLRP3 interaction, preventing ASC polymerization, and suppressing caspase-1 activation, IL-1β/IL-18 release, and pyroptosis; its expression is induced by TLR/IL-1R signaling, forming a negative feedback loop, and it is transcriptionally activated by PGC-1α.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"The POP1 symbol denotes two distinct, coherent proteins in this corpus. The RNase-associated POP1 is the largest protein subunit shared by the RNase MRP and RNase P ribonucleoprotein complexes, originally defined in yeast where it co-precipitates with both enzymes and its loss blocks A3-site cleavage of pre-rRNA (5.8S rRNA maturation) and pre-tRNA processing while destabilizing the RNA moieties of both complexes [#0]. It acts as a protein scaffold that directly contacts conserved structural elements of both RNase P and RNase MRP RNAs, substituting for the RNA-RNA tertiary interactions that maintain enzyme architecture [#1]. In humans, compound heterozygous loss-of-function mutations impair RNase MRP integrity and activity, reduce RMRP RNA abundance, elevate pre-5.8S rRNA, and impair cell proliferation, causing severe skeletal dysplasia (anauxetic dysplasia); POP1 binds the RMRP RNA domains affected in this disease [#2, #3]. In cancer, this POP1 promotes proliferation through two RNA-directed activities: it binds the coding sequence of CDKN1A mRNA and drives its degradation in an m6A(position 497)/YTHDF2-dependent manner to relieve cell-cycle inhibition, and it binds and stabilizes the telomerase RNA component TERC to activate telomerase and protect telomeres [#11, #12]. A separate, unrelated protein sharing the POP1/ASC2 symbol is a PYRIN-domain-only protein that binds the pyrin domain of ASC through a defined PYD:PYD electrostatic interface and inhibits inflammasome assembly by blocking ASC nucleation and polymerization, thereby suppressing caspase-1 activation, IL-1\\u03b2/IL-18 release, and pyroptosis [#6, #8]. This POP1 interferes with the NLRP3-ASC PYD-PYD interaction, its expression is induced by TLR/IL-1R signaling as a negative feedback loop, and it is transcriptionally activated by PGC-1\\u03b1 [#8, #9, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that POP1 is a shared protein subunit of two distinct RNA-processing enzymes, defining its core role as a component required for both rRNA and tRNA maturation.\",\n      \"evidence\": \"Immunoprecipitation, temperature-sensitive mutant analysis, and Northern blotting of processing intermediates in yeast\",\n      \"pmids\": [\"7926742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which RNA elements Pop1 contacts\", \"Mechanism of how a shared subunit serves two distinct catalytic substrates not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified a separate PYRIN-domain-only POP1/ASC2 that physically associates with ASC and suppresses ASC-mediated NF-\\u03baB and pro-caspase-1 signaling, opening the inflammasome-regulatory branch of the POP1 symbol.\",\n      \"evidence\": \"Co-IP demonstrating PYD-PYD interaction with NF-\\u03baB reporter and pro-caspase-1 activation assays in cells\",\n      \"pmids\": [\"12656673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface not mapped at residue level\", \"Endogenous-level relevance not established beyond overexpression\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped the POP1/ASC2-ASC binding interface at atomic resolution, showing the interaction is electrostatically driven and ASC-specific (not Cryopyrin), grounding the inhibitory mechanism structurally.\",\n      \"evidence\": \"In vitro binding (Kd ~4 \\u00b5M) with purified proteins, NMR chemical shift mapping, and site-directed mutagenesis\",\n      \"pmids\": [\"18362139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show downstream consequences for inflammasome assembly in cells\", \"Specificity profile against other PYD proteins incomplete\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected human POP1 loss-of-function to disease, showing mutations impair RNase MRP integrity/activity and proliferation and cause skeletal dysplasia, establishing pathophysiological relevance of the RNase subunit role.\",\n      \"evidence\": \"Whole-exome sequencing with functional RNase MRP integrity/activity and proliferation assays in patient cells\",\n      \"pmids\": [\"21455487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not separate rRNA-processing defect from other RNase MRP functions as the disease driver\", \"Tissue specificity of skeletal phenotype unexplained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved how the inflammasome-regulatory POP1 blocks signaling, demonstrating in vivo that it prevents ASC nucleation/polymerization to suppress caspase-1, cytokine release, and pyroptosis, and operates as a TLR/IL-1R-induced negative feedback loop.\",\n      \"evidence\": \"Transgenic mouse myeloid POP1 expression, NLRP3/PAMP challenge, caspase-1, cytokine, pyroptosis and ASC speck assays\",\n      \"pmids\": [\"26275995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of POP1 needed to block polymerization in vivo not defined\", \"Selectivity across distinct inflammasome sensors not fully delineated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Determined the crystal structure of the PYD-only POP1, revealing a six-helix bundle fold consistent with PYD-mediated decoy inhibition of ASC recruitment.\",\n      \"evidence\": \"X-ray crystallography of human POP1 with structural comparison to related PYDs\",\n      \"pmids\": [\"25839653\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inhibition inference structural, not validated by mutagenesis in this study\", \"No co-structure with ASC\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided direct biochemical evidence that the RNase POP1 contacts both RNase P and RNase MRP RNAs, supporting a scaffolding model in which protein substitutes for RNA-RNA tertiary contacts.\",\n      \"evidence\": \"Chemical and enzymatic RNA footprinting with purified Pop1 and RNase P/MRP RNA components\",\n      \"pmids\": [\"26135751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural interpretation partly inferential\", \"Does not resolve how Pop1 distinguishes the two RNAs\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Confirmed across families that human POP1 mutations reduce RMRP RNA and accumulate pre-5.8S rRNA, tying complex stability directly to defective rRNA processing in vivo.\",\n      \"evidence\": \"Sanger sequencing and quantitative RT-PCR of RMRP RNA and pre-5.8S rRNA in patient cells\",\n      \"pmids\": [\"28067412\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link from rRNA defect to skeletal phenotype not mechanistically demonstrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Challenged the ribosome-biogenesis-only model by identifying a mutation that destabilizes RNase MRP without accumulating pre-5.8S rRNA, dissociating complex stability from rRNA processing activity.\",\n      \"evidence\": \"Quantitative RT-PCR of RMRP RNA and pre-5.8S rRNA in patient lymphocytes (single family)\",\n      \"pmids\": [\"32134183\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single family, single method, negative result not functionally confirmed by independent assay\", \"Alternative pathogenic mechanism not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Refined the inflammasome inhibition mechanism, placing POP1 action at the NLRP3-ASC PYD-PYD interaction step and showing therapeutic potential of a cell-permeable engineered POP1 in gout models.\",\n      \"evidence\": \"Macrophage gain/loss-of-function, MSU stimulation, IL-1\\u03b2/IL-18 ELISA, ASC speck assays, and in vivo gout models\",\n      \"pmids\": [\"36225929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pharmacokinetics and off-target effects of engineered POP1 not detailed\", \"Effect on non-NLRP3 inflammasomes not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed an oncogenic RNA-stabilizing function, showing the RNase POP1 binds and stabilizes TERC to activate telomerase and drive breast cancer cell cycle progression.\",\n      \"evidence\": \"Co-IP with telomerase complex, TERC stability and telomere length assays, cell cycle analysis, and xenograft model\",\n      \"pmids\": [\"37010429\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TERC stabilization requires RNase MRP/P complex context unknown\", \"Direct versus indirect binding to TERC not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a second oncogenic mechanism whereby POP1 binds CDKN1A mRNA and promotes its m6A/YTHDF2-dependent degradation to relieve cell-cycle inhibition, expanding POP1 into mRNA-decay regulation.\",\n      \"evidence\": \"RIP for POP1-CDKN1A binding, m6A site mapping, YTHDF2 knockdown epistasis, STM2457 rescue, and in vivo proliferation assays in TNBC\",\n      \"pmids\": [\"39268503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this activity uses the RNase MRP/P catalytic machinery unknown\", \"Generality across other m6A-marked transcripts unaddressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed the inflammasome-regulatory POP1 in a transcriptional control circuit, showing PGC-1\\u03b1 binds the POP1 promoter to activate it and inactivate NLRP3 signaling.\",\n      \"evidence\": \"Promoter binding/ChIP assay, POP1 knockdown epistasis, and NLRP3 pathway readouts in LPS-stimulated periodontal stem cells\",\n      \"pmids\": [\"38763227\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PGC-1\\u03b1 promoter occupancy detail limited\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the RNase-scaffold POP1 mechanistically achieves its oncogenic RNA-targeting functions (TERC stabilization, CDKN1A decay) and whether these depend on the canonical RNase MRP/P complexes or a distinct activity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of human RNase MRP/P with POP1 reported in corpus\", \"Link between scaffolding role and mRNA-decay/telomerase functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 2, 11, 12]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 8, 9]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [11, 12]}\n    ],\n    \"complexes\": [\"RNase MRP\", \"RNase P\"],\n    \"partners\": [\"RMRP\", \"TERC\", \"CDKN1A\", \"YTHDF2\", \"ASC\", \"NLRP3\", \"PGC-1\\u03b1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}