{"gene":"LSM12","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2010,"finding":"Yeast Lsm12 localizes to stress granules (not P-bodies) and physically interacts with Pbp1 (the yeast ortholog of Ataxin-2); deletion or over-expression of Lsm12 did not dramatically affect stress granule or P-body formation, indicating Lsm12 is a stress granule component but not a critical assembly factor.","method":"Fluorescence microscopy of GFP-tagged Lsm12 under stress conditions; genetic deletion and over-expression analysis in S. cerevisiae","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with genetic perturbation, single lab","pmids":["20368989"],"is_preprint":false},{"year":2017,"finding":"In Drosophila circadian pacemaker neurons, LSM12 acts as a molecular adaptor that recruits TWENTY-FOUR (TYF) to the ATAXIN-2 (ATX2) complex; the ATX2-LSM12-TYF complex stimulates TYF-dependent translation of the clock gene period (per) to maintain 24-hour circadian periodicity.","method":"Co-immunoprecipitation, genetic epistasis in Drosophila, behavioral circadian rhythm assays, translational reporter assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, genetic epistasis, functional phenotype (circadian period), multiple orthogonal methods in single rigorous study","pmids":["28388438"],"is_preprint":false},{"year":2018,"finding":"In S. cerevisiae, Lsm12 physically interacts with the UBZ domain of DNA polymerase η (Polη/Rad30) and promotes Polη deubiquitination via Ubp3, thereby enhancing Polη recruitment under oxidative stress to support genome stability.","method":"Co-immunoprecipitation/pull-down, genetic deletion and over-expression, transcriptome analysis, growth/survival assays under H2O2 treatment","journal":"Applied and environmental microbiology","confidence":"Medium","confidence_rationale":"Tier 2 — physical interaction mapped to UBZ domain, deubiquitination assay, genetic rescue, single lab","pmids":["30366994"],"is_preprint":false},{"year":2020,"finding":"Human LSM12 posttranscriptionally up-regulates EPAC1 expression; the LSM12-EPAC1 pathway sustains the nucleocytoplasmic RAN gradient and suppresses nucleocytoplasmic transport (NCT) dysfunction caused by C9ORF72-derived poly(GR) protein. LSM12 depletion aggravates poly(GR)-induced NCT impairment and nuclear integrity loss, while LSM12 or EPAC1 overexpression rescues the RAN gradient, reduces TDP-43 mislocalization, and suppresses caspase-3 activation in C9-ALS patient iPSC-derived neurons.","method":"siRNA knockdown, lentiviral overexpression, nucleocytoplasmic transport assays, RAN gradient measurement, caspase-3 activation assay, C9-ALS iPSC-derived neurons","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function and gain-of-function with multiple orthogonal phenotypic readouts, validated in patient-derived neurons","pmids":["33362237"],"is_preprint":false},{"year":2021,"finding":"Human Lsm12 is an NAADP receptor: it directly binds NAADP via its Lsm domain, co-purifies with TPC1 and TPC2, colocalizes with TPC2 on acidic organelles, and is essential for NAADP-evoked TPC activation and Ca2+ mobilization from endolysosomes. Affinity purification of NAADP-interacting proteins and TPC interactors both identified Lsm12.","method":"Affinity purification with NAADP ligand, quantitative proteomics, co-immunoprecipitation with TPC1/TPC2, colocalization (fluorescence microscopy), siRNA knockdown with Ca2+ imaging, in vitro NAADP-binding assay with Lsm domain","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — direct NAADP-binding mapped to Lsm domain, reciprocal co-IP with TPCs, functional Ca2+ release assay with KD, multiple orthogonal methods","pmids":["34362892"],"is_preprint":false},{"year":2022,"finding":"Human LSM12 regulates alternative splicing of USO1 exon 15; LSM12 overexpression causes inclusion of USO1 exon 15, while knockdown induces exon 15 skipping. The exon-15-retained USO1 isoform promotes malignant phenotypes in OSCC cells. LSM12 overexpression promotes cell proliferation, migration, and invasion, while knockdown inhibits tumor formation in vivo.","method":"Whole transcriptome sequencing, PCR/sequencing of alternative splicing, siRNA knockdown and overexpression, cell proliferation/migration/invasion assays, xenograft tumor formation in vivo","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 — alternative splicing mechanism linked to specific exon identified by sequencing plus functional rescue with isoforms, single lab","pmids":["35449073"],"is_preprint":false},{"year":2023,"finding":"Human LSM12 directly binds to CTNNB1 (β-Catenin) and regulates its protein stability, thereby affecting CTNNB1-LEF1-TCF1 transcriptional complex formation and downstream WNT signaling pathway activity in colorectal cancer cells.","method":"Protein interaction simulation (docking), co-immunoprecipitation, protein stability assays, WNT pathway reporter assays, siRNA knockdown with in vivo xenograft","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP binding to β-Catenin with pathway functional readout, single lab","pmids":["37303493"],"is_preprint":false},{"year":2023,"finding":"Both LSM12 and JPT2 independently bind NAADP with high affinity and independently associate with TPC1 and TPC2; knockout/rescue analyses show both NAADP-binding proteins are required for NAADP-evoked Ca2+ signaling and contribute to endolysosomal trafficking of pseudotyped coronavirus particles, demonstrating convergent regulation of TPC-dependent Ca2+ release.","method":"Recombinant protein NAADP-binding assays, Co-IP of endogenous proteins with TPC1/TPC2, CRISPR knockout, rescue transfection, Ca2+ imaging, viral particle trafficking assay","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding assay with recombinant proteins, CRISPR KO with rescue, multiple functional readouts, independent replication of NAADP-receptor role","pmids":["37607218"],"is_preprint":false},{"year":2025,"finding":"LSM12 regulates alternative splicing of ARRB1 exon 13 in lung squamous cell carcinoma cells; LSM12 overexpression increases exon 13-skipped splicing of ARRB1. Additionally, SAMD4A directly binds to LSM12 mRNA and accelerates its degradation. LSM12 overexpression promotes proliferation, migration, invasion, and tumor growth in vivo.","method":"High-throughput RNA-seq omics, RT-PCR validation of alternative splicing, RNA immunoprecipitation (SAMD4A binding to LSM12 mRNA), siRNA/overexpression functional assays, xenograft mouse model","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — splicing regulation mechanistically linked to specific exon, upstream mRNA stability regulation identified, single lab","pmids":["40425760"],"is_preprint":false},{"year":2026,"finding":"Lsm12 acts as a potent competitive antagonist of PI(3,5)P2-dependent TPC activation: purified Lsm12 strongly inhibits PI(3,5)P2-evoked currents of both TPC1 and TPC2, reducing apparent TPC2 sensitivity to PI(3,5)P2 through a mechanism dependent on Lsm12-TPC interaction and concentrations of both Lsm12 and PI(3,5)P2. NAADP specifically and dose-dependently reverses Lsm12-mediated inhibition, restoring TPC currents only in the presence of PI(3,5)P2 or an intact PI(3,5)P2-binding site, establishing a gating model where Lsm12 tonically restrains PI(3,5)P2-dependent TPC gating and NAADP binding to Lsm12 relieves this inhibition.","method":"Electrophysiology (whole-endolysosome patch clamp), purified recombinant Lsm12 in vitro channel activity assay, NAADP dose-response, PI(3,5)P2 sequestration (acute depletion), mutagenesis of TPC2 PI(3,5)P2-binding site, Ca2+ imaging","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro electrophysiology with purified protein, mutagenesis, dose-response, multiple orthogonal methods in single study","pmids":["42039649"],"is_preprint":true}],"current_model":"LSM12 is a multifunctional Sm-like domain protein that acts as an NAADP receptor (binding NAADP via its Lsm domain) and TPC regulatory protein — tonically inhibiting PI(3,5)P2-dependent TPC gating until NAADP binding relieves this inhibition to trigger Ca2+ release from acidic organelles — while also serving as a molecular adaptor in the ATAXIN-2 complex to stimulate period mRNA translation for circadian rhythms, posttranscriptionally upregulating EPAC1 to sustain the nucleocytoplasmic RAN gradient (neuroprotective against C9-ALS pathology), and regulating alternative splicing of targets including USO1 and ARRB1."},"narrative":{"teleology":[{"year":2010,"claim":"Identifying LSM12 as a stress granule component interacting with Pbp1/Ataxin-2 in yeast established its initial link to RNA granule biology and the Ataxin-2 network.","evidence":"GFP-tagged Lsm12 fluorescence microscopy and genetic deletion/overexpression in S. cerevisiae","pmids":["20368989"],"confidence":"Medium","gaps":["Functional consequence of LSM12–Pbp1 interaction unknown","No mammalian validation","Role in mRNA metabolism not tested"]},{"year":2017,"claim":"Demonstrating that LSM12 bridges ATAXIN-2 to TYF to stimulate period mRNA translation in circadian pacemaker neurons revealed LSM12's first defined molecular function as a translational adaptor controlling a physiological process.","evidence":"Reciprocal co-immunoprecipitation, genetic epistasis, circadian behavioral assays, and translational reporters in Drosophila","pmids":["28388438"],"confidence":"High","gaps":["Whether this adaptor function is conserved in mammalian circadian clocks is untested","Direct RNA-binding capacity of LSM12 not addressed"]},{"year":2018,"claim":"Finding that yeast Lsm12 promotes DNA polymerase η deubiquitination via Ubp3 under oxidative stress expanded its functional repertoire to genome maintenance.","evidence":"Co-immunoprecipitation/pull-down, genetic deletion and overexpression, growth assays under H₂O₂ in S. cerevisiae","pmids":["30366994"],"confidence":"Medium","gaps":["Not validated in mammalian cells","Mechanism by which LSM12 promotes Ubp3-dependent deubiquitination is unclear","Single-lab finding"]},{"year":2020,"claim":"Showing that LSM12 posttranscriptionally upregulates EPAC1 to sustain the RAN gradient and protect against C9ORF72 poly(GR)-induced nucleocytoplasmic transport defects linked LSM12 to ALS-relevant neuroprotection.","evidence":"siRNA knockdown, lentiviral overexpression, RAN gradient and NCT assays, caspase-3 activation in C9-ALS iPSC-derived neurons","pmids":["33362237"],"confidence":"High","gaps":["Mechanism of posttranscriptional EPAC1 upregulation not defined","Whether this pathway operates in non-ALS neurons is unknown"]},{"year":2021,"claim":"Identifying LSM12 as a direct NAADP receptor that binds NAADP via its Lsm domain and is required for TPC-dependent endolysosomal Ca²⁺ release fundamentally reframed understanding of NAADP signaling.","evidence":"NAADP affinity purification, quantitative proteomics, co-IP with TPC1/TPC2, siRNA knockdown with Ca²⁺ imaging, in vitro binding assay","pmids":["34362892"],"confidence":"High","gaps":["Structural basis of NAADP binding to Lsm domain unknown","Relative contributions of LSM12 versus JPT2 not resolved"]},{"year":2022,"claim":"Discovery that LSM12 regulates alternative splicing of USO1 exon 15 to promote malignant phenotypes in oral squamous cell carcinoma revealed a splicing-regulatory role with oncogenic consequences.","evidence":"RNA-seq, PCR/sequencing of alternative splicing events, knockdown/overexpression functional assays, xenograft model","pmids":["35449073"],"confidence":"Medium","gaps":["Mechanism by which LSM12 influences spliceosome activity is undefined","Single cancer type studied"]},{"year":2023,"claim":"Independent confirmation that both LSM12 and JPT2 bind NAADP with high affinity and are each required for NAADP-evoked Ca²⁺ signaling and endolysosomal viral trafficking established a convergent two-receptor model for TPC regulation.","evidence":"Recombinant protein binding assays, CRISPR knockout/rescue, Ca²⁺ imaging, pseudotyped coronavirus trafficking assay","pmids":["37607218"],"confidence":"High","gaps":["Whether LSM12 and JPT2 form a complex together on TPCs is unresolved","Stoichiometry of LSM12–TPC association unknown"]},{"year":2025,"claim":"Demonstration that LSM12 regulates ARRB1 exon 13 alternative splicing in lung squamous cell carcinoma, with SAMD4A controlling LSM12 mRNA stability, placed LSM12 within a defined upstream regulatory circuit.","evidence":"RNA-seq, RT-PCR splicing validation, RNA immunoprecipitation for SAMD4A–LSM12 mRNA binding, xenograft model","pmids":["40425760"],"confidence":"Medium","gaps":["Splicing targets beyond USO1 and ARRB1 not systematically catalogued","Whether SAMD4A regulation of LSM12 operates in non-cancer contexts is untested"]},{"year":2026,"claim":"Reconstituted electrophysiology demonstrated that LSM12 tonically inhibits PI(3,5)P₂-dependent TPC gating and that NAADP binding to LSM12 relieves this inhibition, providing a complete mechanistic model for NAADP–TPC signal transduction.","evidence":"Whole-endolysosome patch clamp with purified recombinant LSM12, NAADP dose-response, PI(3,5)P₂ depletion, TPC2 mutagenesis (preprint)","pmids":["42039649"],"confidence":"High","gaps":["Preprint; not yet peer-reviewed","Structural basis of LSM12–TPC interaction at atomic resolution lacking","In vivo physiological confirmation of tonic inhibition model pending"]},{"year":null,"claim":"How LSM12's NAADP-receptor and translational/splicing-adaptor functions are coordinated across cellular compartments, and whether its diverse roles are mediated by distinct protein pools or a shared molecular switch, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of full-length LSM12 with NAADP or TPC","Relative partitioning of LSM12 between endolysosomal and cytoplasmic functions not quantified","Systematic identification of RNA targets not performed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,7,9]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[4,7,9]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[4,7,9]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,7,9]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[4,7,9]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5,8]}],"complexes":["ATAXIN-2–LSM12–TYF complex","TPC1/TPC2–LSM12 complex"],"partners":["TPC1","TPC2","ATX2","JPT2","EPAC1","CTNNB1","PBP1","SAMD4A"],"other_free_text":[]},"mechanistic_narrative":"LSM12 is a multifunctional Sm-like domain protein that serves as an NAADP receptor and regulatory subunit of two-pore channel (TPC) Ca²⁺ signaling, while also functioning as a translational and splicing adaptor in diverse cellular contexts. LSM12 directly binds NAADP via its Lsm domain, associates with TPC1 and TPC2 on acidic organelles, and is essential for NAADP-evoked endolysosomal Ca²⁺ release; it tonically inhibits PI(3,5)P₂-dependent TPC gating, and NAADP binding to LSM12 relieves this inhibition [PMID:34362892, PMID:37607218, PMID:42039649]. In Drosophila circadian neurons, LSM12 acts as a molecular adaptor recruiting TWENTY-FOUR to the ATAXIN-2 complex to stimulate period mRNA translation and maintain circadian periodicity [PMID:28388438], and in human neurons it posttranscriptionally upregulates EPAC1 to sustain the RAN nucleocytoplasmic gradient and protect against C9ORF72-associated ALS pathology [PMID:33362237]. LSM12 also regulates alternative splicing of specific targets including USO1 and ARRB1, promoting oncogenic phenotypes in squamous and oral carcinoma cells [PMID:35449073, PMID:40425760]."},"prefetch_data":{"uniprot":{"accession":"Q3MHD2","full_name":"Protein LSM12","aliases":[],"length_aa":195,"mass_kda":21.7,"function":"Nicotinic acid adenine dinucleotide phosphate (NAADP) binding protein (PubMed:34362892). Confers NAADP sensitivity to the two pore channel complex (TPCs) by acting as TPC accessory protein necessary for NAADP-evoked Ca(2+) release (PubMed:34362892)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q3MHD2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LSM12","classification":"Not Classified","n_dependent_lines":683,"n_total_lines":1208,"dependency_fraction":0.5653973509933775},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ATXN2L","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DDX6","stoichiometry":0.2},{"gene":"EIF3G","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LSM12","total_profiled":1310},"omim":[{"mim_id":"611793","title":"LSM12, S. CEREVISIAE, HOMOLOG OF; LSM12","url":"https://www.omim.org/entry/611793"},{"mim_id":"611792","title":"ZINC FINGER CCHC DOMAIN-CONTAINING PROTEIN 4; ZCCHC4","url":"https://www.omim.org/entry/611792"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LSM12"},"hgnc":{"alias_symbol":["FLJ30656"],"prev_symbol":[]},"alphafold":{"accession":"Q3MHD2","domains":[{"cath_id":"2.30.30.100","chopping":"12-69","consensus_level":"high","plddt":93.9638,"start":12,"end":69},{"cath_id":"-","chopping":"94-184","consensus_level":"high","plddt":96.0782,"start":94,"end":184}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q3MHD2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q3MHD2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q3MHD2-F1-predicted_aligned_error_v6.png","plddt_mean":90.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LSM12","jax_strain_url":"https://www.jax.org/strain/search?query=LSM12"},"sequence":{"accession":"Q3MHD2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q3MHD2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q3MHD2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q3MHD2"}},"corpus_meta":[{"pmid":"20368989","id":"PMC_20368989","title":"Localization to, and effects of Pbp1, Pbp4, Lsm12, Dhh1, and Pab1 on stress granules in Saccharomyces cerevisiae.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20368989","citation_count":108,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34362892","id":"PMC_34362892","title":"Lsm12 is an NAADP receptor and a two-pore channel regulatory protein required for calcium mobilization from acidic organelles.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34362892","citation_count":74,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28388438","id":"PMC_28388438","title":"LSM12 and ME31B/DDX6 Define Distinct Modes of Posttranscriptional Regulation by ATAXIN-2 Protein Complex in Drosophila Circadian Pacemaker Neurons.","date":"2017","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/28388438","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37607218","id":"PMC_37607218","title":"Convergent activation of two-pore channels mediated by the NAADP-binding proteins JPT2 and LSM12.","date":"2023","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/37607218","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33362237","id":"PMC_33362237","title":"LSM12-EPAC1 defines a neuroprotective pathway that sustains the nucleocytoplasmic RAN gradient.","date":"2020","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/33362237","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35449073","id":"PMC_35449073","title":"Identification of RNA-splicing factor Lsm12 as a novel tumor-associated gene and a potent biomarker in Oral Squamous Cell Carcinoma (OSCC).","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/35449073","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30366994","id":"PMC_30366994","title":"Lsm12 Mediates Deubiquitination of DNA Polymerase η To Help Saccharomyces cerevisiae Resist Oxidative Stress.","date":"2018","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30366994","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40425760","id":"PMC_40425760","title":"LSM12 promotes the lung squamous cell carcinoma progression through mediating alternative splicing of ARRB1.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/40425760","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37303493","id":"PMC_37303493","title":"LSM12 facilitates the progression of colorectal cancer by activating the WNT/CTNNB1 signaling pathway.","date":"2023","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/37303493","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41080638","id":"PMC_41080638","title":"Functional characterization of LSM12 as a driver in uveal melanoma oncogenesis.","date":"2025","source":"Advances in ophthalmology practice and research","url":"https://pubmed.ncbi.nlm.nih.gov/41080638","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"42039649","id":"PMC_42039649","title":"NAADP elicits two-pore channel currents by lifting Lsm12-mediated inhibition of PI(3,5)P 2 activation.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42039649","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.11.11.687795","title":"JPT2/HN1L functions as an NAADP-binding protein in a cell-type specific manner","date":"2025-11-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.11.687795","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.06.02.657355","title":"Genome-wide CRISPR/Cas9 knockout screen identifies host factors essential for Bovine Parainfluenza Virus Type 3 replication","date":"2025-06-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.02.657355","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.03.06.641895","title":"ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation","date":"2025-03-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.06.641895","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":"16169070","id":"PMC_16169070","title":"A human protein-protein interaction network: a resource for annotating the proteome.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16169070","citation_count":1704,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21906983","id":"PMC_21906983","title":"Systematic and quantitative assessment of the ubiquitin-modified proteome.","date":"2011","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/21906983","citation_count":1334,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29507755","citation_count":829,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21890473","id":"PMC_21890473","title":"A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.","date":"2011","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/21890473","citation_count":749,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17353931","id":"PMC_17353931","title":"Large-scale mapping of human protein-protein interactions by mass spectrometry.","date":"2007","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/17353931","citation_count":733,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22190034","id":"PMC_22190034","title":"Global landscape of HIV-human protein complexes.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22190034","citation_count":593,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29395067","id":"PMC_29395067","title":"High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies.","date":"2018","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/29395067","citation_count":580,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28302793","id":"PMC_28302793","title":"Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15.","date":"2017","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28302793","citation_count":533,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33080218","id":"PMC_33080218","title":"SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses.","date":"2020","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33080218","citation_count":449,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20020773","id":"PMC_20020773","title":"Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery.","date":"2010","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/20020773","citation_count":422,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34079125","id":"PMC_34079125","title":"A proximity-dependent biotinylation map of a human cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21145461","id":"PMC_21145461","title":"Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.","date":"2010","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/21145461","citation_count":318,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21139048","id":"PMC_21139048","title":"Mass spectrometric analysis of lysine ubiquitylation reveals promiscuity at site level.","date":"2010","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/21139048","citation_count":262,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15252450","id":"PMC_15252450","title":"Lineage-specific gene duplication and loss in human and great ape evolution.","date":"2004","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/15252450","citation_count":224,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25281560","id":"PMC_25281560","title":"Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes.","date":"2014","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/25281560","citation_count":215,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19738201","id":"PMC_19738201","title":"Proteomic analysis of integrin-associated complexes identifies RCC2 as a dual regulator of Rac1 and Arf6.","date":"2009","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/19738201","citation_count":207,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32203420","id":"PMC_32203420","title":"Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions.","date":"2020","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32203420","citation_count":194,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30995489","id":"PMC_30995489","title":"Genome-Wide CRISPR-Cas9 Screens Expose Genetic Vulnerabilities and Mechanisms of Temozolomide Sensitivity in Glioblastoma Stem Cells.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30995489","citation_count":178,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30833792","id":"PMC_30833792","title":"A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape.","date":"2019","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30833792","citation_count":159,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16196087","id":"PMC_16196087","title":"Large-scale analysis of the human ubiquitin-related proteome.","date":"2005","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/16196087","citation_count":154,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29117863","id":"PMC_29117863","title":"RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination.","date":"2017","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/29117863","citation_count":135,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8973,"output_tokens":2818,"usd":0.034595},"stage2":{"model":"claude-opus-4-6","input_tokens":6165,"output_tokens":2948,"usd":0.156787},"total_usd":0.393612,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":21340,"output_tokens":2915,"usd":0.053872},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6491,"output_tokens":2658,"usd":0.148358}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"Yeast Lsm12 protein accumulates in stress granules under stress conditions and physically interacts with Pbp1 (yeast ortholog of Ataxin-2); deletion or over-expression of Lsm12 does not dramatically affect stress granule or P-body formation, indicating Lsm12 is a component but not a driver of stress granule assembly.\",\n      \"method\": \"Fluorescence microscopy (GFP-tagged Lsm12), genetic deletion and overexpression, interaction established by prior co-immunoprecipitation data\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by live imaging and genetic loss/gain-of-function, but functional consequence of Lsm12 localization is limited (no strong phenotype)\",\n      \"pmids\": [\"20368989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Drosophila LSM12 acts as a molecular adaptor that recruits TWENTY-FOUR (TYF) to the ATAXIN-2 (ATX2) complex; the ATX2-LSM12-TYF complex stimulates TYF-dependent translation of the clock gene period (per) to maintain circadian periodicity. LSM12 is distinct from ME31B/DDX6, which mediates ATX2 association with NOT1 for gene silencing.\",\n      \"method\": \"Co-immunoprecipitation, genetic epistasis in Drosophila circadian neurons, behavioral rhythm assays, loss-of-function (RNAi), translation reporter assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, genetic epistasis, and functional translational readout, replicated across multiple assays in a single rigorous study\",\n      \"pmids\": [\"28388438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Yeast Lsm12 physically interacts with the UBZ domain of DNA polymerase η (Polη/Rad30) and promotes Polη deubiquitination through Ubp3, consequently enhancing Polη recruitment under oxidative stress to support translesion DNA synthesis and genome stability.\",\n      \"method\": \"Co-immunoprecipitation/pulldown (Lsm12–Polη interaction), genetic deletion and overexpression phenotypic assays (H2O2 survival, DNA damage markers), deubiquitination assays with Ubp3\",\n      \"journal\": \"Applied and environmental microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein interaction plus biochemical deubiquitination assay; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30366994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LSM12 posttranscriptionally upregulates EPAC1 expression; the LSM12-EPAC1 pathway sustains the nucleocytoplasmic RAN gradient and suppresses nucleocytoplasmic transport (NCT) defects caused by C9ORF72-derived poly(GR) protein. EPAC1 depletion biochemically dissociates RAN-importin β1 from the cytoplasmic nuclear pore complex, dissipating the RAN gradient.\",\n      \"method\": \"siRNA knockdown of LSM12 in human neuroblastoma cells, lentiviral overexpression in C9-ALS iPSC-derived neurons, NCT reporter assays, immunofluorescence (RAN gradient, TDP-43 localization), caspase-3 activation assays, co-immunoprecipitation (RAN-importin β1-NPC)\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD, OE, biochemical dissociation, iPSN validation), clear mechanistic pathway placement\",\n      \"pmids\": [\"33362237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LSM12 is an NAADP receptor: it directly binds NAADP via its Lsm domain, co-localizes with TPC2 on acidic organelles, and is required for NAADP-evoked TPC activation and Ca2+ mobilization from endolysosomes. LSM12 forms a complex with TPC1 and TPC2, and mediates the apparent association of NAADP with isolated TPC2-containing membranes.\",\n      \"method\": \"Affinity purification with NAADP-conjugated beads, quantitative proteomics, co-immunoprecipitation (LSM12-TPC1/TPC2), colocalization (confocal microscopy), siRNA knockdown with Ca2+ imaging, Lsm domain binding assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — affinity purification, direct binding assay, co-IP, functional Ca2+ mobilization, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"34362892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LSM12 regulates alternative splicing of USO1 exon 15 in oral squamous cell carcinoma cells; overexpression causes exon 15 inclusion while knockdown induces exon 15 skipping, and the exon 15-retained USO1 isoform promotes malignant cell phenotypes.\",\n      \"method\": \"siRNA knockdown and overexpression, whole transcriptome sequencing, PCR and sequencing of alternative splicing, cell proliferation/invasion assays, in vivo tumor formation\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — splicing regulation demonstrated by transcriptome and PCR, but mechanism of how LSM12 drives splicing is not resolved; single lab\",\n      \"pmids\": [\"35449073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Recombinant LSM12 binds NAADP with high affinity; endogenous LSM12 independently associates with TPC1 and TPC2; LSM12 knockout abolishes NAADP-evoked Ca2+ signaling and endolysosomal trafficking of pseudotyped coronavirus particles, and these defects are rescued by LSM12 re-expression.\",\n      \"method\": \"Recombinant protein NAADP-binding assay, co-immunoprecipitation (endogenous LSM12-TPC1/TPC2), CRISPR knockout, Ca2+ imaging, viral particle trafficking assay, rescue overexpression\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro binding assay with recombinant protein, KO + rescue, multiple functional readouts; replicates and extends prior finding\",\n      \"pmids\": [\"37607218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LSM12 directly binds β-catenin (CTNNB1) and regulates its protein stability, thereby affecting CTNNB1-LEF1-TCF1 transcriptional complex formation and WNT downstream signaling in colorectal cancer cells.\",\n      \"method\": \"Protein interaction simulation, co-immunoprecipitation (LSM12-CTNNB1), siRNA knockdown, protein stability assays, reporter assays for WNT target genes, in vivo tumor growth assays\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus functional assays; single lab, mechanism of stability regulation not fully resolved\",\n      \"pmids\": [\"37303493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LSM12 regulates alternative splicing of ARRB1 exon 13 (increasing exon 13 skipping) in lung squamous cell carcinoma cells; SAMD4A directly binds LSM12 mRNA and promotes its degradation, placing SAMD4A upstream of LSM12 in this pathway.\",\n      \"method\": \"High-throughput omics/RNA-seq for splicing events, siRNA knockdown and overexpression, RIP or RNA pulldown (SAMD4A-LSM12 mRNA), in vivo xenograft assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — splicing regulated shown by omics plus functional assays; SAMD4A-mRNA interaction shown by direct binding; single lab\",\n      \"pmids\": [\"40425760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Purified LSM12 acts as a potent inhibitor of PI(3,5)P2-dependent TPC1 and TPC2 channel activation; NAADP binding to LSM12 relieves this inhibition in a competitive mechanism dependent on PI(3,5)P2 concentration and LSM12-TPC interaction, thereby permitting channel opening and Ca2+ release from acidic stores.\",\n      \"method\": \"Patch-clamp electrophysiology on endolysosomes (TPC currents), purified recombinant Lsm12 addition, acute PI(3,5)P2 sequestration, mutagenesis of PI(3,5)P2-binding site on TPC2, endogenous Lsm12 manipulation in cells, NAADP dose-response\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro electrophysiology reconstitution with purified protein, mutagenesis, and pharmacological competition; rigorous mechanistic dissection\",\n      \"pmids\": [\"42039649\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"LSM12 is a multifunctional Sm-like protein that acts primarily as an NAADP receptor: its Lsm domain directly binds NAADP and forms a complex with endolysosomal two-pore channels (TPC1/TPC2), where it tonically inhibits PI(3,5)P2-dependent channel gating and NAADP binding relieves this inhibition to trigger Ca2+ release from acidic stores; additionally, LSM12 serves as a molecular adaptor linking ATAXIN-2 to translational co-activators (e.g., TYF) for target mRNA translation, posttranscriptionally upregulates EPAC1 to sustain the nucleocytoplasmic RAN gradient, and regulates alternative splicing of specific pre-mRNAs (USO1, ARRB1) in cancer contexts.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"Yeast Lsm12 localizes to stress granules (not P-bodies) and physically interacts with Pbp1 (the yeast ortholog of Ataxin-2); deletion or over-expression of Lsm12 did not dramatically affect stress granule or P-body formation, indicating Lsm12 is a stress granule component but not a critical assembly factor.\",\n      \"method\": \"Fluorescence microscopy of GFP-tagged Lsm12 under stress conditions; genetic deletion and over-expression analysis in S. cerevisiae\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with genetic perturbation, single lab\",\n      \"pmids\": [\"20368989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Drosophila circadian pacemaker neurons, LSM12 acts as a molecular adaptor that recruits TWENTY-FOUR (TYF) to the ATAXIN-2 (ATX2) complex; the ATX2-LSM12-TYF complex stimulates TYF-dependent translation of the clock gene period (per) to maintain 24-hour circadian periodicity.\",\n      \"method\": \"Co-immunoprecipitation, genetic epistasis in Drosophila, behavioral circadian rhythm assays, translational reporter assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, genetic epistasis, functional phenotype (circadian period), multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"28388438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In S. cerevisiae, Lsm12 physically interacts with the UBZ domain of DNA polymerase η (Polη/Rad30) and promotes Polη deubiquitination via Ubp3, thereby enhancing Polη recruitment under oxidative stress to support genome stability.\",\n      \"method\": \"Co-immunoprecipitation/pull-down, genetic deletion and over-expression, transcriptome analysis, growth/survival assays under H2O2 treatment\",\n      \"journal\": \"Applied and environmental microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — physical interaction mapped to UBZ domain, deubiquitination assay, genetic rescue, single lab\",\n      \"pmids\": [\"30366994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human LSM12 posttranscriptionally up-regulates EPAC1 expression; the LSM12-EPAC1 pathway sustains the nucleocytoplasmic RAN gradient and suppresses nucleocytoplasmic transport (NCT) dysfunction caused by C9ORF72-derived poly(GR) protein. LSM12 depletion aggravates poly(GR)-induced NCT impairment and nuclear integrity loss, while LSM12 or EPAC1 overexpression rescues the RAN gradient, reduces TDP-43 mislocalization, and suppresses caspase-3 activation in C9-ALS patient iPSC-derived neurons.\",\n      \"method\": \"siRNA knockdown, lentiviral overexpression, nucleocytoplasmic transport assays, RAN gradient measurement, caspase-3 activation assay, C9-ALS iPSC-derived neurons\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function and gain-of-function with multiple orthogonal phenotypic readouts, validated in patient-derived neurons\",\n      \"pmids\": [\"33362237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human Lsm12 is an NAADP receptor: it directly binds NAADP via its Lsm domain, co-purifies with TPC1 and TPC2, colocalizes with TPC2 on acidic organelles, and is essential for NAADP-evoked TPC activation and Ca2+ mobilization from endolysosomes. Affinity purification of NAADP-interacting proteins and TPC interactors both identified Lsm12.\",\n      \"method\": \"Affinity purification with NAADP ligand, quantitative proteomics, co-immunoprecipitation with TPC1/TPC2, colocalization (fluorescence microscopy), siRNA knockdown with Ca2+ imaging, in vitro NAADP-binding assay with Lsm domain\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct NAADP-binding mapped to Lsm domain, reciprocal co-IP with TPCs, functional Ca2+ release assay with KD, multiple orthogonal methods\",\n      \"pmids\": [\"34362892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Human LSM12 regulates alternative splicing of USO1 exon 15; LSM12 overexpression causes inclusion of USO1 exon 15, while knockdown induces exon 15 skipping. The exon-15-retained USO1 isoform promotes malignant phenotypes in OSCC cells. LSM12 overexpression promotes cell proliferation, migration, and invasion, while knockdown inhibits tumor formation in vivo.\",\n      \"method\": \"Whole transcriptome sequencing, PCR/sequencing of alternative splicing, siRNA knockdown and overexpression, cell proliferation/migration/invasion assays, xenograft tumor formation in vivo\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — alternative splicing mechanism linked to specific exon identified by sequencing plus functional rescue with isoforms, single lab\",\n      \"pmids\": [\"35449073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Human LSM12 directly binds to CTNNB1 (β-Catenin) and regulates its protein stability, thereby affecting CTNNB1-LEF1-TCF1 transcriptional complex formation and downstream WNT signaling pathway activity in colorectal cancer cells.\",\n      \"method\": \"Protein interaction simulation (docking), co-immunoprecipitation, protein stability assays, WNT pathway reporter assays, siRNA knockdown with in vivo xenograft\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP binding to β-Catenin with pathway functional readout, single lab\",\n      \"pmids\": [\"37303493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Both LSM12 and JPT2 independently bind NAADP with high affinity and independently associate with TPC1 and TPC2; knockout/rescue analyses show both NAADP-binding proteins are required for NAADP-evoked Ca2+ signaling and contribute to endolysosomal trafficking of pseudotyped coronavirus particles, demonstrating convergent regulation of TPC-dependent Ca2+ release.\",\n      \"method\": \"Recombinant protein NAADP-binding assays, Co-IP of endogenous proteins with TPC1/TPC2, CRISPR knockout, rescue transfection, Ca2+ imaging, viral particle trafficking assay\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding assay with recombinant proteins, CRISPR KO with rescue, multiple functional readouts, independent replication of NAADP-receptor role\",\n      \"pmids\": [\"37607218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LSM12 regulates alternative splicing of ARRB1 exon 13 in lung squamous cell carcinoma cells; LSM12 overexpression increases exon 13-skipped splicing of ARRB1. Additionally, SAMD4A directly binds to LSM12 mRNA and accelerates its degradation. LSM12 overexpression promotes proliferation, migration, invasion, and tumor growth in vivo.\",\n      \"method\": \"High-throughput RNA-seq omics, RT-PCR validation of alternative splicing, RNA immunoprecipitation (SAMD4A binding to LSM12 mRNA), siRNA/overexpression functional assays, xenograft mouse model\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — splicing regulation mechanistically linked to specific exon, upstream mRNA stability regulation identified, single lab\",\n      \"pmids\": [\"40425760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Lsm12 acts as a potent competitive antagonist of PI(3,5)P2-dependent TPC activation: purified Lsm12 strongly inhibits PI(3,5)P2-evoked currents of both TPC1 and TPC2, reducing apparent TPC2 sensitivity to PI(3,5)P2 through a mechanism dependent on Lsm12-TPC interaction and concentrations of both Lsm12 and PI(3,5)P2. NAADP specifically and dose-dependently reverses Lsm12-mediated inhibition, restoring TPC currents only in the presence of PI(3,5)P2 or an intact PI(3,5)P2-binding site, establishing a gating model where Lsm12 tonically restrains PI(3,5)P2-dependent TPC gating and NAADP binding to Lsm12 relieves this inhibition.\",\n      \"method\": \"Electrophysiology (whole-endolysosome patch clamp), purified recombinant Lsm12 in vitro channel activity assay, NAADP dose-response, PI(3,5)P2 sequestration (acute depletion), mutagenesis of TPC2 PI(3,5)P2-binding site, Ca2+ imaging\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro electrophysiology with purified protein, mutagenesis, dose-response, multiple orthogonal methods in single study\",\n      \"pmids\": [\"42039649\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"LSM12 is a multifunctional Sm-like domain protein that acts as an NAADP receptor (binding NAADP via its Lsm domain) and TPC regulatory protein — tonically inhibiting PI(3,5)P2-dependent TPC gating until NAADP binding relieves this inhibition to trigger Ca2+ release from acidic organelles — while also serving as a molecular adaptor in the ATAXIN-2 complex to stimulate period mRNA translation for circadian rhythms, posttranscriptionally upregulating EPAC1 to sustain the nucleocytoplasmic RAN gradient (neuroprotective against C9-ALS pathology), and regulating alternative splicing of targets including USO1 and ARRB1.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LSM12 is an Sm-like domain protein that functions as a direct NAADP receptor and tonic inhibitor of endolysosomal two-pore channels (TPC1/TPC2), integrating second-messenger signaling with Ca²⁺ release from acidic stores. Its Lsm domain binds NAADP with high affinity; in the basal state LSM12 inhibits PI(3,5)P₂-dependent TPC gating, and NAADP binding relieves this inhibition, permitting channel opening, Ca²⁺ mobilization, and endolysosomal trafficking events including coronavirus particle transit [PMID:34362892, PMID:37607218, PMID:42039649]. Beyond Ca²⁺ signaling, LSM12 serves as a molecular adaptor that bridges ATAXIN-2 to translational co-activators such as TYF to stimulate target mRNA translation, posttranscriptionally upregulates EPAC1 to maintain the nucleocytoplasmic RAN gradient, and regulates alternative splicing of specific pre-mRNAs [PMID:28388438, PMID:33362237, PMID:35449073].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing LSM12 as a stress-granule-associated Sm-like protein that interacts with the ATAXIN-2 ortholog Pbp1, placing it in the mRNP granule biology without assigning a required role in granule assembly.\",\n      \"evidence\": \"GFP-tagged Lsm12 imaging in yeast under stress, deletion/overexpression with no dramatic granule phenotype\",\n      \"pmids\": [\"20368989\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether LSM12 performs any essential function inside stress granules remained unknown\",\n        \"Functional consequence of the Pbp1/ATAXIN-2 interaction was not determined\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining LSM12 as a molecular adaptor that recruits translational co-activator TYF to the ATAXIN-2 complex, thereby stimulating target mRNA translation — demonstrated via circadian period mRNA in Drosophila clock neurons.\",\n      \"evidence\": \"Reciprocal co-IP, RNAi epistasis, translation reporters, and behavioral rhythm assays in Drosophila\",\n      \"pmids\": [\"28388438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether this adaptor role is conserved in mammals was not tested\",\n        \"The RNA-binding specificity that targets specific mRNAs was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealing that yeast Lsm12 promotes translesion DNA synthesis by binding Pol η and facilitating its Ubp3-dependent deubiquitination under oxidative stress, extending LSM12 function to genome maintenance.\",\n      \"evidence\": \"Co-IP/pulldown of Lsm12–Pol η, deubiquitination assays with Ubp3, H₂O₂ survival phenotypes in yeast\",\n      \"pmids\": [\"30366994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether this function is conserved in mammalian cells was not tested\",\n        \"Structural basis of the Lsm12–UBZ interaction was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that LSM12 posttranscriptionally upregulates EPAC1 to maintain the nucleocytoplasmic RAN gradient, providing a mechanism by which LSM12 suppresses nucleocytoplasmic transport defects caused by C9ORF72-derived dipeptide repeats in ALS/FTD models.\",\n      \"evidence\": \"siRNA knockdown and lentiviral overexpression in neuroblastoma cells and C9-ALS iPSC-derived neurons, NCT reporters, RAN gradient imaging\",\n      \"pmids\": [\"33362237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The mechanism by which LSM12 posttranscriptionally regulates EPAC1 levels was not identified\",\n        \"Whether NAADP-receptor activity contributes to the NCT phenotype was unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying LSM12 as a direct NAADP receptor: its Lsm domain binds NAADP, it complexes with TPC1/TPC2 on acidic organelles, and it is required for NAADP-evoked Ca²⁺ release — resolving a long-standing question about the molecular identity of the NAADP binding site.\",\n      \"evidence\": \"NAADP-affinity purification with proteomics, co-IP of LSM12–TPC1/TPC2, siRNA knockdown with Ca²⁺ imaging, Lsm domain binding assay\",\n      \"pmids\": [\"34362892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether LSM12 inhibits or activates TPCs in the basal state was not resolved\",\n        \"High-resolution structural basis of NAADP–Lsm domain interaction was not determined\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extending LSM12 to alternative splicing regulation, showing it controls USO1 exon 15 inclusion in oral squamous cell carcinoma with functional consequences for malignant phenotypes.\",\n      \"evidence\": \"siRNA knockdown and overexpression, RNA-seq, PCR-based splicing analysis, cell proliferation/invasion and xenograft assays\",\n      \"pmids\": [\"35449073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which LSM12 directs exon inclusion (direct RNA binding vs. cofactor recruitment) was not resolved\",\n        \"Not independently confirmed outside a single lab\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirming and extending LSM12 as the essential NAADP receptor with recombinant protein binding data, CRISPR knockout, and rescue — and linking the pathway to endolysosomal trafficking of pseudotyped coronavirus particles.\",\n      \"evidence\": \"Recombinant LSM12 NAADP-binding assay, CRISPR KO plus rescue, Ca²⁺ imaging, viral particle trafficking assay\",\n      \"pmids\": [\"37607218\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The structural mechanism of NAADP-dependent TPC gating was still unresolved\",\n        \"Whether LSM12 has NAADP-independent roles at TPCs was unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reporting that LSM12 directly binds β-catenin and regulates its stability, modulating WNT signaling output in colorectal cancer cells.\",\n      \"evidence\": \"Co-IP of LSM12–CTNNB1, siRNA knockdown, protein stability and WNT reporter assays, xenograft tumor growth\",\n      \"pmids\": [\"37303493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single Co-IP without reciprocal validation; mechanism of β-catenin stability regulation not defined\",\n        \"Not independently replicated\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing that LSM12 regulates ARRB1 exon 13 alternative splicing in lung squamous cell carcinoma, and that SAMD4A directly binds LSM12 mRNA to promote its degradation, establishing an upstream regulatory axis.\",\n      \"evidence\": \"RNA-seq splicing analysis, siRNA knockdown/overexpression, RIP or RNA pulldown for SAMD4A–LSM12 mRNA, xenograft assays\",\n      \"pmids\": [\"40425760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which LSM12 alters splicing (direct vs. indirect) remains unresolved\",\n        \"Single lab finding\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolving the biophysical mechanism: purified LSM12 tonically inhibits PI(3,5)P₂-dependent TPC activation, and NAADP competitively relieves this inhibition, establishing LSM12 as a gating switch rather than a simple NAADP-to-channel relay.\",\n      \"evidence\": \"Patch-clamp electrophysiology on endolysosomes with purified recombinant LSM12, PI(3,5)P₂ sequestration, TPC2 PI(3,5)P₂-site mutagenesis, NAADP dose-response (preprint)\",\n      \"pmids\": [\"42039649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Preprint; awaits peer review\",\n        \"High-resolution structure of LSM12–TPC complex not yet available\",\n        \"In vivo physiological validation of the tonic-inhibition model in intact tissues remains to be performed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LSM12's NAADP-receptor function relates to its translational adaptor, splicing-regulatory, and nucleocytoplasmic transport roles remains unresolved — whether these represent independent functions of distinct LSM12 pools or are mechanistically connected is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No study has addressed whether LSM12's multiple functions are mutually exclusive or operate in the same cellular contexts\",\n        \"Structural basis of NAADP binding to the Lsm domain is unknown at atomic resolution\",\n        \"No Mendelian disease link or in vivo mammalian loss-of-function model has been reported\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 6, 9]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [4, 6, 9]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [4, 6, 9]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [4, 6, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"complexes\": [\n      \"LSM12–TPC1/TPC2 complex\",\n      \"ATX2–LSM12–TYF complex\"\n    ],\n    \"partners\": [\n      \"TPC1\",\n      \"TPC2\",\n      \"ATXN2\",\n      \"EPAC1\",\n      \"CTNNB1\",\n      \"SAMD4A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"LSM12 is a multifunctional Sm-like domain protein that serves as an NAADP receptor and regulatory subunit of two-pore channel (TPC) Ca²⁺ signaling, while also functioning as a translational and splicing adaptor in diverse cellular contexts. LSM12 directly binds NAADP via its Lsm domain, associates with TPC1 and TPC2 on acidic organelles, and is essential for NAADP-evoked endolysosomal Ca²⁺ release; it tonically inhibits PI(3,5)P₂-dependent TPC gating, and NAADP binding to LSM12 relieves this inhibition [PMID:34362892, PMID:37607218, PMID:42039649]. In Drosophila circadian neurons, LSM12 acts as a molecular adaptor recruiting TWENTY-FOUR to the ATAXIN-2 complex to stimulate period mRNA translation and maintain circadian periodicity [PMID:28388438], and in human neurons it posttranscriptionally upregulates EPAC1 to sustain the RAN nucleocytoplasmic gradient and protect against C9ORF72-associated ALS pathology [PMID:33362237]. LSM12 also regulates alternative splicing of specific targets including USO1 and ARRB1, promoting oncogenic phenotypes in squamous and oral carcinoma cells [PMID:35449073, PMID:40425760].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying LSM12 as a stress granule component interacting with Pbp1/Ataxin-2 in yeast established its initial link to RNA granule biology and the Ataxin-2 network.\",\n      \"evidence\": \"GFP-tagged Lsm12 fluorescence microscopy and genetic deletion/overexpression in S. cerevisiae\",\n      \"pmids\": [\"20368989\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of LSM12–Pbp1 interaction unknown\", \"No mammalian validation\", \"Role in mRNA metabolism not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that LSM12 bridges ATAXIN-2 to TYF to stimulate period mRNA translation in circadian pacemaker neurons revealed LSM12's first defined molecular function as a translational adaptor controlling a physiological process.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, genetic epistasis, circadian behavioral assays, and translational reporters in Drosophila\",\n      \"pmids\": [\"28388438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this adaptor function is conserved in mammalian circadian clocks is untested\", \"Direct RNA-binding capacity of LSM12 not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Finding that yeast Lsm12 promotes DNA polymerase η deubiquitination via Ubp3 under oxidative stress expanded its functional repertoire to genome maintenance.\",\n      \"evidence\": \"Co-immunoprecipitation/pull-down, genetic deletion and overexpression, growth assays under H₂O₂ in S. cerevisiae\",\n      \"pmids\": [\"30366994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not validated in mammalian cells\", \"Mechanism by which LSM12 promotes Ubp3-dependent deubiquitination is unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing that LSM12 posttranscriptionally upregulates EPAC1 to sustain the RAN gradient and protect against C9ORF72 poly(GR)-induced nucleocytoplasmic transport defects linked LSM12 to ALS-relevant neuroprotection.\",\n      \"evidence\": \"siRNA knockdown, lentiviral overexpression, RAN gradient and NCT assays, caspase-3 activation in C9-ALS iPSC-derived neurons\",\n      \"pmids\": [\"33362237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of posttranscriptional EPAC1 upregulation not defined\", \"Whether this pathway operates in non-ALS neurons is unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying LSM12 as a direct NAADP receptor that binds NAADP via its Lsm domain and is required for TPC-dependent endolysosomal Ca²⁺ release fundamentally reframed understanding of NAADP signaling.\",\n      \"evidence\": \"NAADP affinity purification, quantitative proteomics, co-IP with TPC1/TPC2, siRNA knockdown with Ca²⁺ imaging, in vitro binding assay\",\n      \"pmids\": [\"34362892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of NAADP binding to Lsm domain unknown\", \"Relative contributions of LSM12 versus JPT2 not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery that LSM12 regulates alternative splicing of USO1 exon 15 to promote malignant phenotypes in oral squamous cell carcinoma revealed a splicing-regulatory role with oncogenic consequences.\",\n      \"evidence\": \"RNA-seq, PCR/sequencing of alternative splicing events, knockdown/overexpression functional assays, xenograft model\",\n      \"pmids\": [\"35449073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which LSM12 influences spliceosome activity is undefined\", \"Single cancer type studied\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Independent confirmation that both LSM12 and JPT2 bind NAADP with high affinity and are each required for NAADP-evoked Ca²⁺ signaling and endolysosomal viral trafficking established a convergent two-receptor model for TPC regulation.\",\n      \"evidence\": \"Recombinant protein binding assays, CRISPR knockout/rescue, Ca²⁺ imaging, pseudotyped coronavirus trafficking assay\",\n      \"pmids\": [\"37607218\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LSM12 and JPT2 form a complex together on TPCs is unresolved\", \"Stoichiometry of LSM12–TPC association unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstration that LSM12 regulates ARRB1 exon 13 alternative splicing in lung squamous cell carcinoma, with SAMD4A controlling LSM12 mRNA stability, placed LSM12 within a defined upstream regulatory circuit.\",\n      \"evidence\": \"RNA-seq, RT-PCR splicing validation, RNA immunoprecipitation for SAMD4A–LSM12 mRNA binding, xenograft model\",\n      \"pmids\": [\"40425760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Splicing targets beyond USO1 and ARRB1 not systematically catalogued\", \"Whether SAMD4A regulation of LSM12 operates in non-cancer contexts is untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Reconstituted electrophysiology demonstrated that LSM12 tonically inhibits PI(3,5)P₂-dependent TPC gating and that NAADP binding to LSM12 relieves this inhibition, providing a complete mechanistic model for NAADP–TPC signal transduction.\",\n      \"evidence\": \"Whole-endolysosome patch clamp with purified recombinant LSM12, NAADP dose-response, PI(3,5)P₂ depletion, TPC2 mutagenesis (preprint)\",\n      \"pmids\": [\"42039649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint; not yet peer-reviewed\", \"Structural basis of LSM12–TPC interaction at atomic resolution lacking\", \"In vivo physiological confirmation of tonic inhibition model pending\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LSM12's NAADP-receptor and translational/splicing-adaptor functions are coordinated across cellular compartments, and whether its diverse roles are mediated by distinct protein pools or a shared molecular switch, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of full-length LSM12 with NAADP or TPC\", \"Relative partitioning of LSM12 between endolysosomal and cytoplasmic functions not quantified\", \"Systematic identification of RNA targets not performed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 7, 9]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [4, 7, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [4, 7, 9]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7, 9]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [4, 7, 9]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"complexes\": [\n      \"ATAXIN-2–LSM12–TYF complex\",\n      \"TPC1/TPC2–LSM12 complex\"\n    ],\n    \"partners\": [\n      \"TPC1\",\n      \"TPC2\",\n      \"ATX2\",\n      \"JPT2\",\n      \"EPAC1\",\n      \"CTNNB1\",\n      \"PBP1\",\n      \"SAMD4A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}