Affinage

POP1

Ribonucleases P/MRP protein subunit POP1 · UniProt Q99575

Length
1024 aa
Mass
114.7 kDa
Annotated
2026-04-28
34 papers in source corpus 25 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1994 High

    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

    PMID:7926742

    Open questions at the time
    • Structural basis of POP1 interaction with the RNA subunits was unknown
    • Whether POP1 contributed catalytic or purely structural roles was unresolved
  2. 2003 Medium

    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

    PMID:12656673

    Open questions at the time
    • Only overexpression data; endogenous POP1 function unconfirmed
    • Specificity for ASC versus other PYD-containing proteins untested
    • No structural detail on the PYD-PYD interface
  3. 2008 High

    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

    PMID:18362139

    Open questions at the time
    • No full atomic-resolution structure of the POP1-ASC complex
    • In vivo relevance of specific interface residues not tested
  4. 2011 Medium

    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

    PMID:21455487

    Open questions at the time
    • Limited number of families studied
    • Relative contributions of RNase MRP versus RNase P dysfunction to skeletal phenotype unclear
  5. 2015 High

    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

    PMID:25839653 PMID:26135751 PMID:26275995

    Open questions at the time
    • Whether POP1 inhibits all ASC-dependent inflammasomes or preferentially NLRP3 was unresolved
    • Stoichiometry of POP1 relative to ASC in endogenous settings unknown
  6. 2022 High

    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

    PMID:36225929

    Open questions at the time
    • Long-term safety and specificity of cell-permeable POP1 not assessed
    • Effect on non-NLRP3 inflammasomes (AIM2, NLRC4) in vivo not tested
  7. 2024 Medium

    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

    PMID:39268503

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0003723 RNA binding 3 GO:0005198 structural molecule activity 2 GO:0140313 molecular sequestering activity 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-8953854 Metabolism of RNA 2 R-HSA-1643685 Disease 1
Partners
ASCNLRP3TERCYTHDF2
Complex memberships
RNase MRPRNase P

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 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. Temperature-sensitive mutant screening, immunoprecipitation, RNA processing assays Genes & development High 7926742
1995 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. Genetic loss-of-function, lineage analysis, sequence analysis revealing HMG box domain Cell High 7585963
1997 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. Genetic epistasis, in vivo co-immunoprecipitation, Western blot for ubiquitinated forms, 26S proteasome mutant analysis Genes & development High 9203581
1998 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. Immunofluorescence quantification of nuclear POP-1, genetic epistasis with Wnt pathway mutants, loss-of-function analysis Cell High 9458047
1998 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. Co-immunoprecipitation, genetic analysis, biochemical fractionation Genes to cells High 9990507
2001 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). Genetic epistasis, reporter gene assays, co-immunoprecipitation The EMBO journal High 11742996
2002 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. Live imaging in embryos, domain deletion analysis, in vivo chromatin binding assays Developmental biology High 12142026
2002 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. Knockout mouse model, cardiotoxin injury assay, lacZ reporter lineage tracing, immunofluorescence Molecular and cellular biology Medium 11839816
2002 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. RNAi, genetic epistasis, domain-specific allele analysis Development High 11807036
2003 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. Gene transfer/overexpression, co-immunoprecipitation, NF-κB reporter assays The Biochemical journal Medium 12656673
2003 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. In vivo mutagenesis of acetylation sites, nuclear localization assays, functional rescue experiments Genes & development High 12651889
2003 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. Cell ablation, blastomere isolation, genetic epistasis Development Medium 12810601
2005 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. Reporter gene assays, promoter mutagenesis, genetic epistasis with Wnt pathway Developmental biology High 16084508 16112103
2007 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. Fluorescent protein reporters, genetic epistasis, RNAi, quantitative imaging Development High 17567664
2008 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. In vitro binding assays with purified proteins, NMR chemical shift mapping, site-directed mutagenesis The Journal of biological chemistry High 18362139
2011 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. Whole-exome sequencing, RNase MRP activity assays, cell proliferation assays PLoS genetics Medium 21455487
2015 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. Transgenic mouse model (human POP1 in monocytes/macrophages/DCs), inflammasome assembly assays, caspase-1 activation assays, cytokine measurement Immunity High 26275995
2015 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. Footprinting analysis, RNA-protein interaction mapping RNA Medium 26135751
2015 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. X-ray crystallography, structural analysis Biochemical and biophysical research communications Medium 25839653
2019 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. Time-lapse fluorescence microscopy, lineage-specific knockout, GFP-tagging of endogenous pop-1, RNAi Development Medium 31740621
2022 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. Macrophage overexpression/knockdown, NLRP3 inflammasome assembly assays, in vivo gout models (airpouch, ankle joint), cytokine measurement Frontiers in immunology High 36225929
2023 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. Co-immunoprecipitation, knockdown/overexpression, xenograft model, telomere length assays Carcinogenesis Low 37010429
2024 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. RNA immunoprecipitation, m6A site mutagenesis, YTHDF2 knockdown, in vitro and in vivo proliferation assays, m6A inhibitor treatment Research (Washington, D.C.) Medium 39268503
2024 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. Promoter binding assay (ChIP or luciferase), overexpression/knockdown, NLRP3 pathway assays Prostaglandins & other lipid mediators Low 38763227

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 pop-1 encodes an HMG box protein required for the specification of a mesoderm precursor in early C. elegans embryos. Cell 265 7585963
1998 POP-1 and anterior-posterior fate decisions in C. elegans embryos. Cell 235 9458047
1994 The POP1 gene encodes a protein component common to the RNase MRP and RNase P ribonucleoproteins. Genes & development 202 7926742
2003 The PAAD/PYRIN-only protein POP1/ASC2 is a modulator of ASC-mediated nuclear-factor-kappa B and pro-caspase-1 regulation. The Biochemical journal 150 12656673
1997 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. Genes & development 147 9203581
2002 POP-1 controls axis formation during early gonadogenesis in C. elegans. Development (Cambridge, England) 113 11807036
2015 The PYRIN Domain-only Protein POP1 Inhibits Inflammasome Assembly and Ameliorates Inflammatory Disease. Immunity 112 26275995
1998 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. Genes to cells : devoted to molecular & cellular mechanisms 93 9990507
2005 C. elegans TCF protein, POP-1, converts from repressor to activator as a result of Wnt-induced lowering of nuclear levels. Developmental biology 91 16112103
2002 Dynamics of a developmental switch: recursive intracellular and intranuclear redistribution of Caenorhabditis elegans POP-1 parallels Wnt-inhibited transcriptional repression. Developmental biology 85 12142026
2007 Binary cell fate specification during C. elegans embryogenesis driven by reiterated reciprocal asymmetry of TCF POP-1 and its coactivator beta-catenin SYS-1. Development (Cambridge, England) 82 17567664
2005 The Wnt effector POP-1 and the PAL-1/Caudal homeoprotein collaborate with SKN-1 to activate C. elegans endoderm development. Developmental biology 80 16084508
2001 A POP-1 repressor complex restricts inappropriate cell type-specific gene transcription during Caenorhabditis elegans embryogenesis. The EMBO journal 75 11742996
2024 POP1 Facilitates Proliferation in Triple-Negative Breast Cancer via m6A-Dependent Degradation of CDKN1A mRNA. Research (Washington, D.C.) 67 39268503
2002 Mouse Pop1 is required for muscle regeneration in adult skeletal muscle. Molecular and cellular biology 66 11839816
2011 Whole-exome re-sequencing in a family quartet identifies POP1 mutations as the cause of a novel skeletal dysplasia. PLoS genetics 62 21455487
2003 Establishment of POP-1 asymmetry in early C. elegans embryos. Development (Cambridge, England) 56 12810601
2021 lncRNA lnc-POP1-1 upregulated by VN1R5 promotes cisplatin resistance in head and neck squamous cell carcinoma through interaction with MCM5. Molecular therapy : the journal of the American Society of Gene Therapy 47 34111560
2008 Mapping of POP1-binding site on pyrin domain of ASC. The Journal of biological chemistry 42 18362139
2003 Acetylation regulates subcellular localization of the Wnt signaling nuclear effector POP-1. Genes & development 40 12651889
2004 Developmental expression of Pop1/Bves. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 39 14966204
2017 Broadening the phenotypic spectrum of POP1-skeletal dysplasias: identification of POP1 mutations in a mild and severe skeletal dysplasia. Clinical genetics 20 28067412
2001 Production of monoclonal antibodies against chicken Pop1 (BVES). Hybridoma and hybridomics 19 11839256
2016 Further evidence of POP1 mutations as the cause of anauxetic dysplasia. American journal of medical genetics. Part A 18 27380734
2015 Footprinting analysis of interactions between the largest eukaryotic RNase P/MRP protein Pop1 and RNase P/MRP RNA components. RNA (New York, N.Y.) 18 26135751
2022 POP1 inhibits MSU-induced inflammasome activation and ameliorates gout. Frontiers in immunology 17 36225929
2017 POP1 might be recruiting its type-Ia interface for NLRP3-mediated PYD-PYD interaction: Insights from MD simulation. Journal of molecular recognition : JMR 13 28370480
2019 C. elegans Runx/CBFβ suppresses POP-1 TCF to convert asymmetric to proliferative division of stem cell-like seam cells. Development (Cambridge, England) 12 31740621
2015 Crystal structure of human POP1 and its distinct structural feature for PYD domain. Biochemical and biophysical research communications 7 25839653
2023 POP1 promotes the progression of breast cancer through maintaining telomere integrity. Carcinogenesis 5 37010429
2020 The novel R211Q POP1 homozygous mutation causes different pathogenesis and skeletal changes from those of previously reported POP1-associated anauxetic dysplasia. American journal of medical genetics. Part A 5 32134183
2005 Advocating asymmetry and the POP-1 paradox: noncanonical Wnt signaling in C. elegans. Cell 2 15935751
2024 PGC-1α inhibits NLRP3 signaling through transcriptional activation of POP1 to alleviate inflammation and strengthen osteogenic differentiation of lipopolysaccharide-induced human periodontal stem cells. Prostaglandins & other lipid mediators 1 38763227
2024 Novel phenotype associated with homozygous likely pathogenic variant in the POP1 gene. Clinical genetics 0 38351533