POP1

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).

1. 1994 High

   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

   PMID:7926742

   Open questions at the time

   • Did not define which RNA elements Pop1 contacts
   • Mechanism of how a shared subunit serves two distinct catalytic substrates not resolved
2. 2003 Medium

   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

   PMID:12656673

   Open questions at the time

   • Binding interface not mapped at residue level
   • Endogenous-level relevance not established beyond overexpression
3. 2008 High

   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

   PMID:18362139

   Open questions at the time

   • Did not show downstream consequences for inflammasome assembly in cells
   • Specificity profile against other PYD proteins incomplete
4. 2011 Medium

   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

   PMID:21455487

   Open questions at the time

   • Did not separate rRNA-processing defect from other RNase MRP functions as the disease driver
   • Tissue specificity of skeletal phenotype unexplained
5. 2015 High

   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

   PMID:26275995

   Open questions at the time

   • Stoichiometry of POP1 needed to block polymerization in vivo not defined
   • Selectivity across distinct inflammasome sensors not fully delineated
6. 2015 Medium

   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

   PMID:25839653

   Open questions at the time

   • Inhibition inference structural, not validated by mutagenesis in this study
   • No co-structure with ASC
7. 2015 Medium

   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

   PMID:26135751

   Open questions at the time

   • Structural interpretation partly inferential
   • Does not resolve how Pop1 distinguishes the two RNAs
8. 2017 Medium

   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

   PMID:28067412

   Open questions at the time

   • Causal link from rRNA defect to skeletal phenotype not mechanistically demonstrated
9. 2020 Low

   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)

   PMID:32134183

   Open questions at the time

   • Single family, single method, negative result not functionally confirmed by independent assay
   • Alternative pathogenic mechanism not identified
10. 2022 High

    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

    PMID:36225929

    Open questions at the time

    • Pharmacokinetics and off-target effects of engineered POP1 not detailed
    • Effect on non-NLRP3 inflammasomes not addressed
11. 2023 Medium

    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

    PMID:37010429

    Open questions at the time

    • Whether TERC stabilization requires RNase MRP/P complex context unknown
    • Direct versus indirect binding to TERC not fully resolved
12. 2024 Medium

    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

    PMID:39268503

    Open questions at the time

    • Whether this activity uses the RNase MRP/P catalytic machinery unknown
    • Generality across other m6A-marked transcripts unaddressed
13. 2024 Medium

    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

    PMID:38763227

    Open questions at the time

    • Direct PGC-1α promoter occupancy detail limited
    • Single cell-type context

• 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.
• No structure of human RNase MRP/P with POP1 reported in corpus
• Link between scaffolding role and mRNA-decay/telomerase functions undefined