Affinage

LSM12

Protein LSM12 · UniProt Q3MHD2

Round 2 corrected
Length
195 aa
Mass
21.7 kDa
Annotated
2026-04-28
41 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2010 Medium

    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

    PMID:20368989

    Open questions at the time
    • Functional consequence of LSM12–Pbp1 interaction unknown
    • No mammalian validation
    • Role in mRNA metabolism not tested
  2. 2017 High

    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

    PMID:28388438

    Open questions at the time
    • Whether this adaptor function is conserved in mammalian circadian clocks is untested
    • Direct RNA-binding capacity of LSM12 not addressed
  3. 2018 Medium

    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

    PMID:30366994

    Open questions at the time
    • Not validated in mammalian cells
    • Mechanism by which LSM12 promotes Ubp3-dependent deubiquitination is unclear
    • Single-lab finding
  4. 2020 High

    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

    PMID:33362237

    Open questions at the time
    • Mechanism of posttranscriptional EPAC1 upregulation not defined
    • Whether this pathway operates in non-ALS neurons is unknown
  5. 2021 High

    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

    PMID:34362892

    Open questions at the time
    • Structural basis of NAADP binding to Lsm domain unknown
    • Relative contributions of LSM12 versus JPT2 not resolved
  6. 2022 Medium

    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

    PMID:35449073

    Open questions at the time
    • Mechanism by which LSM12 influences spliceosome activity is undefined
    • Single cancer type studied
  7. 2023 High

    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

    PMID:37607218

    Open questions at the time
    • Whether LSM12 and JPT2 form a complex together on TPCs is unresolved
    • Stoichiometry of LSM12–TPC association unknown
  8. 2025 Medium

    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

    PMID:40425760

    Open questions at the time
    • Splicing targets beyond USO1 and ARRB1 not systematically catalogued
    • Whether SAMD4A regulation of LSM12 operates in non-cancer contexts is untested
  9. 2026 High

    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)

    PMID:42039649

    Open questions at the time
    • Preprint; not yet peer-reviewed
    • Structural basis of LSM12–TPC interaction at atomic resolution lacking
    • In vivo physiological confirmation of tonic inhibition model pending

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140299 molecular sensor activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005764 lysosome 3 GO:0005768 endosome 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-382551 Transport of small molecules 3 R-HSA-8953854 Metabolism of RNA 2 R-HSA-9609507 Protein localization 1
Partners
ATX2CTNNB1EPAC1JPT2PBP1SAMD4ATPC1TPC2
Complex memberships
ATAXIN-2–LSM12–TYF complexTPC1/TPC2–LSM12 complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 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. Fluorescence microscopy of GFP-tagged Lsm12 under stress conditions; genetic deletion and over-expression analysis in S. cerevisiae PloS one Medium 20368989
2017 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. Co-immunoprecipitation, genetic epistasis in Drosophila, behavioral circadian rhythm assays, translational reporter assays Molecular cell High 28388438
2018 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. Co-immunoprecipitation/pull-down, genetic deletion and over-expression, transcriptome analysis, growth/survival assays under H2O2 treatment Applied and environmental microbiology Medium 30366994
2020 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. siRNA knockdown, lentiviral overexpression, nucleocytoplasmic transport assays, RAN gradient measurement, caspase-3 activation assay, C9-ALS iPSC-derived neurons PLoS biology High 33362237
2021 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. 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 Nature communications High 34362892
2022 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. Whole transcriptome sequencing, PCR/sequencing of alternative splicing, siRNA knockdown and overexpression, cell proliferation/migration/invasion assays, xenograft tumor formation in vivo Journal of experimental & clinical cancer research : CR Medium 35449073
2023 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. Protein interaction simulation (docking), co-immunoprecipitation, protein stability assays, WNT pathway reporter assays, siRNA knockdown with in vivo xenograft Oncology research Medium 37303493
2023 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. Recombinant protein NAADP-binding assays, Co-IP of endogenous proteins with TPC1/TPC2, CRISPR knockout, rescue transfection, Ca2+ imaging, viral particle trafficking assay Science signaling High 37607218
2025 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. 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 Communications biology Medium 40425760
2026 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. 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 bioRxivpreprint High 42039649

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2011 Systematic and quantitative assessment of the ubiquitin-modified proteome. Molecular cell 1334 21906983
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2011 A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles. Molecular & cellular proteomics : MCP 749 21890473
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 Global landscape of HIV-human protein complexes. Nature 593 22190034
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2020 SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses. Cell 449 33080218
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. Journal of proteome research 422 20020773
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2010 Mass spectrometric analysis of lysine ubiquitylation reveals promiscuity at site level. Molecular & cellular proteomics : MCP 262 21139048
2004 Lineage-specific gene duplication and loss in human and great ape evolution. PLoS biology 224 15252450
2014 Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes. Journal of proteomics 215 25281560
2009 Proteomic analysis of integrin-associated complexes identifies RCC2 as a dual regulator of Rac1 and Arf6. Science signaling 207 19738201
2020 Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology 194 32203420
2019 Genome-Wide CRISPR-Cas9 Screens Expose Genetic Vulnerabilities and Mechanisms of Temozolomide Sensitivity in Glioblastoma Stem Cells. Cell reports 178 30995489
2019 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nature immunology 159 30833792
2005 Large-scale analysis of the human ubiquitin-related proteome. Proteomics 154 16196087
2017 RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC biology 135 29117863
2010 Localization to, and effects of Pbp1, Pbp4, Lsm12, Dhh1, and Pab1 on stress granules in Saccharomyces cerevisiae. PloS one 108 20368989
2021 Lsm12 is an NAADP receptor and a two-pore channel regulatory protein required for calcium mobilization from acidic organelles. Nature communications 74 34362892
2017 LSM12 and ME31B/DDX6 Define Distinct Modes of Posttranscriptional Regulation by ATAXIN-2 Protein Complex in Drosophila Circadian Pacemaker Neurons. Molecular cell 53 28388438
2023 Convergent activation of two-pore channels mediated by the NAADP-binding proteins JPT2 and LSM12. Science signaling 19 37607218
2020 LSM12-EPAC1 defines a neuroprotective pathway that sustains the nucleocytoplasmic RAN gradient. PLoS biology 18 33362237
2022 Identification of RNA-splicing factor Lsm12 as a novel tumor-associated gene and a potent biomarker in Oral Squamous Cell Carcinoma (OSCC). Journal of experimental & clinical cancer research : CR 16 35449073
2018 Lsm12 Mediates Deubiquitination of DNA Polymerase η To Help Saccharomyces cerevisiae Resist Oxidative Stress. Applied and environmental microbiology 10 30366994
2025 LSM12 promotes the lung squamous cell carcinoma progression through mediating alternative splicing of ARRB1. Communications biology 2 40425760
2023 LSM12 facilitates the progression of colorectal cancer by activating the WNT/CTNNB1 signaling pathway. Oncology research 2 37303493
2026 NAADP elicits two-pore channel currents by lifting Lsm12-mediated inhibition of PI(3,5)P 2 activation. bioRxiv : the preprint server for biology 0 42039649
2025 Functional characterization of LSM12 as a driver in uveal melanoma oncogenesis. Advances in ophthalmology practice and research 0 41080638