Affinage

LSM12

Protein LSM12 · UniProt Q3MHD2

Length
195 aa
Mass
21.7 kDa
Annotated
2026-06-10
11 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LSM12 is a Sm-like (Lsm) domain protein with dual roles in acidic-store Ca2+ signaling and RNA-associated regulation (PMID:34362892, PMID:28388438). As a high-affinity NAADP receptor, recombinant LSM12 directly binds NAADP through its Lsm domain, associates with the two-pore channels TPC1 and TPC2, and is required for NAADP-evoked Ca2+ release from endolysosomal organelles (PMID:34362892, PMID:37607218). Mechanistically, LSM12 acts as a competitive antagonist of PI(3,5)P2-dependent TPC gating, and NAADP binding to LSM12 relieves this inhibition to permit channel activation (PMID:42039649); this signaling axis also supports endolysosomal trafficking of pseudotyped coronavirus particles (PMID:37607218). Independently, LSM12 functions as a molecular adaptor within the ATAXIN-2 complex, recruiting TWENTY-FOUR (TYF) to co-activate translation of the clock gene period and maintain circadian periodicity in Drosophila, consistent with its conserved physical interaction with the ATAXIN-2 ortholog Pbp1 and its localization to stress granules in yeast (PMID:28388438, PMID:20368989). In human cells LSM12 posttranscriptionally upregulates EPAC1 to sustain the nucleocytoplasmic RAN gradient and counteract C9ORF72 poly(GR)-induced nucleocytoplasmic transport defects (PMID:33362237). Additional reported activities include regulation of alternative splicing of USO1 and ARRB1 (PMID:35449073, PMID:40425760) and modulation of β-catenin stability in WNT signaling (PMID:37303493).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2010 Medium

    Establishing where LSM12 acts and with whom: it was placed in the RNA-granule/ATAXIN-2 axis by showing it localizes to stress granules and binds the yeast ATAXIN-2 ortholog Pbp1.

    Evidence Live fluorescence imaging, genetic deletion/overexpression, and physical interaction in yeast

    PMID:20368989

    Open questions at the time
    • Functional consequence of LSM12 in stress granules undefined
    • No molecular substrate or RNA target identified
    • Mammalian relevance not tested in this study
  2. 2017 High

    Resolved how LSM12 contributes to ATAXIN-2 function: it serves as an adaptor recruiting TYF to drive translation of specific mRNAs, linking it to circadian timekeeping.

    Evidence Genetic epistasis, reciprocal co-IP, and behavioral rhythmicity assays in Drosophila

    PMID:28388438

    Open questions at the time
    • Translational targets beyond period not mapped
    • Adaptor mechanism not reconstituted biochemically
    • Conservation of TYF-recruitment role in mammals untested
  3. 2018 Medium

    Extended LSM12's interaction repertoire to DNA-damage tolerance, showing it modulates Polη ubiquitination state.

    Evidence Co-IP, deletion/overexpression, and ubiquitination assays in yeast

    PMID:30366994

    Open questions at the time
    • Whether this role is conserved in human cells unknown
    • Direct vs indirect effect on Ubp3 deubiquitination unresolved
    • Connection to LSM12's RNA/Ca2+ roles unclear
  4. 2020 Medium

    Identified a neuroprotective role: LSM12 posttranscriptionally upregulates EPAC1 to maintain the RAN gradient and counter C9ORF72 poly(GR) toxicity.

    Evidence siRNA knockdown, iPSC-neuron overexpression, RAN-gradient and TDP-43 localization readouts in human cells

    PMID:33362237

    Open questions at the time
    • Mechanism by which LSM12 raises EPAC1 not defined
    • Single-lab finding
    • Direct RNA target binding not demonstrated
  5. 2021 High

    Defined the founding molecular function: LSM12 is a direct NAADP-binding protein and an essential component for TPC activation and endolysosomal Ca2+ release.

    Evidence Affinity purification, quantitative proteomics, direct binding, colocalization, and Ca2+ assays with knockdown/knockout

    PMID:34362892

    Open questions at the time
    • Stoichiometry of LSM12-TPC-NAADP complex unresolved
    • Relationship to JPT2 not addressed
    • Structural basis of NAADP binding unknown
  6. 2023 High

    Independently confirmed NAADP receptor activity and extended it to a physiological context: LSM12 supports coronavirus endolysosomal trafficking.

    Evidence Recombinant binding assays, endogenous reciprocal co-IP, knockout/rescue, Ca2+ imaging in human cells

    PMID:37607218

    Open questions at the time
    • Functional interplay between LSM12 and JPT2 not resolved
    • Structural mechanism of TPC association undefined
  7. 2026 Medium

    Provided the gating mechanism: LSM12 competitively inhibits PI(3,5)P2-evoked TPC currents and NAADP binding reverses this inhibition, explaining how NAADP licenses channel opening.

    Evidence Electrophysiology with purified protein, acute PIP2 sequestration, and Ca2+ imaging (preprint)

    PMID:42039649

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Structural details of competitive inhibition unresolved
    • Generality across TPC isoforms and tissues untested
  8. 2022 Medium

    Linked LSM12 to alternative splicing control, showing it governs USO1 exon 15 inclusion with oncogenic consequences.

    Evidence Transcriptome sequencing, splicing PCR, knockdown/overexpression, and tumor assays in OSCC

    PMID:35449073

    Open questions at the time
    • Direct LSM12 binding to USO1 pre-mRNA not shown
    • Mechanism connecting Lsm domain to splicing undefined
  9. 2023 Low

    Proposed a role in WNT signaling via stabilization of β-catenin in colorectal cancer.

    Evidence Computational interaction simulation, co-IP/pulldown, stability assay, xenograft

    PMID:37303493

    Open questions at the time
    • Single co-IP plus simulation without reciprocal validation
    • Direct binding not biochemically confirmed
    • Mechanism of stability regulation unknown
  10. 2025 Low

    Added ARRB1 splicing regulation and identified upstream control of LSM12 itself by SAMD4A-mediated mRNA degradation.

    Evidence RNA-seq, splicing analysis, RNA-binding assay, functional cell assays

    PMID:40425760

    Open questions at the time
    • Direct LSM12 binding to ARRB1 pre-mRNA not validated
    • Single lab
    • Functional significance of ARRB1 isoform shift unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single Lsm-domain protein integrates NAADP/TPC Ca2+ signaling, ATAXIN-2-dependent translational control, and alternative splicing remains unresolved.
  • No structural model unifying NAADP binding and RNA/protein adaptor functions
  • Whether splicing and Ca2+ roles share a common mechanism unknown
  • Tissue-specific division of these functions uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0045182 translation regulator activity 1 GO:0060090 molecular adaptor activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005764 lysosome 2 GO:0005768 endosome 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-8953854 Metabolism of RNA 2 R-HSA-9909396 Circadian clock 1
Partners
ATXN2CTNNB1EPAC1PBP1RAD30TPC1TPC2TYF
Complex memberships
ATAXIN-2 (ATX2-LSM12-TYF) complexLSM12-TPC1/TPC2 NAADP receptor complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 LSM12 directly binds NAADP via its Lsm domain, colocalizes with TPC2, and is essential for NAADP-evoked TPC activation and Ca2+ mobilization from acidic endolysosomal organelles. LSM12 was identified as complexed with NAADP, TPC1, and TPC2 by affinity purification and quantitative proteomic analysis. Affinity purification, quantitative proteomics, co-immunoprecipitation, colocalization imaging, functional Ca2+ mobilization assays, knockdown/knockout Nature communications High 34362892
2023 Recombinant LSM12 binds NAADP with high affinity and endogenous LSM12 independently associates with TPC1 and TPC2; LSM12 is required (alongside JPT2) for NAADP-evoked Ca2+ signaling and endolysosomal trafficking of pseudotyped coronavirus particles in human cells. Recombinant protein binding assays, co-immunoprecipitation of endogenous proteins, knockout and rescue analyses, functional Ca2+ imaging Science signaling High 37607218
2026 LSM12 acts as a potent antagonist of PI(3,5)P2-dependent TPC activation: purified LSM12 strongly inhibits PI(3,5)P2-evoked TPC1 and TPC2 currents, reduces TPC2 apparent sensitivity to PI(3,5)P2 via a competitive mechanism dependent on Lsm12-TPC interaction, and NAADP binding to LSM12 specifically and dose-dependently reverses this inhibition to permit TPC channel activation. Electrophysiology (channel currents), purified recombinant protein, endogenous knockdown, acute PI(3,5)P2 sequestration, Ca2+ imaging bioRxivpreprint Medium 42039649
2017 Drosophila LSM12 acts as a molecular adaptor for recruitment of 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-hr circadian periodicity. Genetic interaction/epistasis analysis, co-immunoprecipitation, behavioral rhythmicity assays, loss-of-function Molecular cell High 28388438
2020 LSM12 posttranscriptionally upregulates EPAC1 expression; the LSM12-EPAC1 pathway sustains the nucleocytoplasmic RAN gradient and suppresses NCT dysfunction caused by C9ORF72-derived poly(GR) protein. LSM12 depletion aggravates poly(GR)-induced NCT impairment and promotes nuclear accumulation of poly(GR) granules. siRNA knockdown in human neuroblastoma cells, lentiviral overexpression in C9-ALS iPSC-derived neurons, RAN gradient measurement, TDP-43 localization assay, caspase-3 activation assay PLoS biology Medium 33362237
2010 Yeast Lsm12 localizes to stress granules (but not constitutively to P-bodies). Deletion or overexpression of Lsm12 does not dramatically affect stress granule or P-body formation. Lsm12 physically interacts with the Pbp1 protein (yeast ortholog of Ataxin-2). Fluorescence microscopy (live imaging), genetic deletion, overexpression, stress granule formation assay PloS one Medium 20368989
2018 Yeast Lsm12 physically interacts with the UBZ domain of DNA polymerase η (Polη/Rad30) and enhances Polη deubiquitination through Ubp3, thereby promoting Polη recruitment under oxidative stress. Co-immunoprecipitation (physical interaction), gene deletion/overexpression, ubiquitination assays, transcriptome analysis Applied and environmental microbiology Medium 30366994
2022 LSM12 regulates alternative splicing of USO1 exon 15: LSM12 overexpression causes inclusion of USO1 exon 15, while LSM12 knockdown induces exon 15 skipping. The exon 15-retained USO1 isoform promotes malignant phenotypes in OSCC cells. Whole transcriptome sequencing, PCR and sequencing of alternative splicing, siRNA knockdown, overexpression, cell proliferation/migration/invasion assays, in vivo tumor formation Journal of experimental & clinical cancer research Medium 35449073
2023 LSM12 directly binds to CTNNB1 (β-Catenin) and regulates its protein stability, affecting formation of the CTNNB1-LEF1-TCF1 transcriptional complex and downstream WNT signaling in colorectal cancer cells. Protein interaction simulation, co-immunoprecipitation/biochemical pulldown, protein stability assay, siRNA knockdown, in vivo xenograft Oncology research Low 37303493
2025 LSM12 regulates alternative splicing of ARRB1, increasing exon 13-skipped splicing. SAMD4A directly binds LSM12 mRNA and accelerates its degradation (upstream regulation of LSM12 itself). High-throughput omics/RNA-seq, alternative splicing analysis, RNA-binding protein interaction assay (SAMD4A-LSM12 mRNA), functional cell assays Communications biology Low 40425760

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Localization to, and effects of Pbp1, Pbp4, Lsm12, Dhh1, and Pab1 on stress granules in Saccharomyces cerevisiae. PloS one 110 20368989
2021 Lsm12 is an NAADP receptor and a two-pore channel regulatory protein required for calcium mobilization from acidic organelles. Nature communications 78 34362892
2017 LSM12 and ME31B/DDX6 Define Distinct Modes of Posttranscriptional Regulation by ATAXIN-2 Protein Complex in Drosophila Circadian Pacemaker Neurons. Molecular cell 54 28388438
2023 Convergent activation of two-pore channels mediated by the NAADP-binding proteins JPT2 and LSM12. Science signaling 23 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)P2 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

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