{"gene":"LSM14A","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2006,"finding":"RAP55 (LSM14A) localizes to P-bodies in resting cells and to stress granules after arsenite-induced stress. The FDF motif and two RGG-rich domains are necessary and sufficient for P-body targeting, while the second RGG domain is necessary and sufficient for stress granule localization. siRNA-mediated knockdown of RAP55 results in loss of P-bodies, placing RAP55 upstream of the 5'-decapping step in mRNA degradation.","method":"siRNA knockdown, GFP-tagged domain deletion mutants, immunofluorescence colocalization with DCP1a and Ge-1, arsenite-stress assay","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA KD, domain mapping, colocalization), replicated by subsequent studies","pmids":["16484376"],"is_preprint":false},{"year":2006,"finding":"Xenopus RAP55 (xRAP55/LSM14A ortholog) is a component of maternal mRNPs that directly represses translation in vitro and in oocytes when tethered to a reporter mRNA. The N-terminal LSm domain is required for P-body localization and translational repression. xRAP55 cooperates with the DEAD-box protein Xp54 to repress translation, and associates with PRMT1.","method":"Affinity purification of xRAP55 complexes from Xenopus oocytes, in vitro translation assay with recombinant protein, tethering assay in oocytes, domain deletion analysis, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro translation repression, tethering assay, domain mapping, multiple orthogonal methods in single study","pmids":["17074753"],"is_preprint":false},{"year":2012,"finding":"LSM14A binds to synthetic or viral RNA and DNA, mediates IRF3 activation and IFN-β induction, and is essential for early-phase IFN-β induction after RNA or DNA virus infection. LSM14A-mediated IFN-β induction requires RIG-I-VISA (for RNA viruses) or MITA (for DNA viruses). Viral infection causes translocation of LSM14A to peroxisomes, where RIG-I, VISA, and MITA are located.","method":"RNA/DNA binding assays, siRNA knockdown of LSM14A, IFN-β reporter assays, viral infection experiments, subcellular fractionation/immunofluorescence showing peroxisomal translocation, epistasis with RIG-I/VISA/MITA knockdowns","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (binding assay, siRNA KD, reporter assay, genetic epistasis, localization), replicated across subsequent studies","pmids":["22745163"],"is_preprint":false},{"year":2012,"finding":"PRMT1 asymmetrically dimethylates multiple arginine residues of RAP55A (LSM14A). Knockdown of PRMT1 impairs localization of RAP55A to P-bodies while other P-body components are retained, establishing PRMT1 as a writer required for RAP55A P-body targeting. RAP55A overexpression induces formation of large mRNP granules containing both P-body and stress granule components.","method":"siRNA knockdown of PRMT1, immunofluorescence, mass spectrometry identification of asymmetric dimethylarginine on RAP55A, co-immunoprecipitation of PRMT1/PRMT5 with RAP55A","journal":"RNA biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, MS identification of PTM sites, siRNA functional rescue, multiple orthogonal methods in single study","pmids":["22614839"],"is_preprint":false},{"year":2012,"finding":"Influenza A NS1 protein interacts with RAP55 (LSM14A) via its RNA-binding (R38, K41) and PKR-interaction (I123, M124, K126, N127) sites. NS1 interaction with RAP55 inhibits RAP55 expression and disrupts P-body/stress granule formation. Overexpression of RAP55 suppresses influenza virus replication, while dominant-negative RAP55 blocks NS1 colocalization to P-bodies.","method":"Co-immunoprecipitation, colocalization assays, siRNA knockdown of RAP55, site-directed mutagenesis of NS1, overexpression and dominant-negative mutant analysis","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, mutagenesis of interaction sites, functional KD and OE with specific readouts, multiple orthogonal methods","pmids":["22973032"],"is_preprint":false},{"year":2016,"finding":"LSM14A deficiency specifically downregulates MITA/STING protein level in dendritic cells (but not in macrophages or fibroblasts) by impairing nuclear mRNA precursor processing of MITA/STING, thereby impairing antiviral innate and adaptive immune responses in a cell-type-specific manner.","method":"LSm14a-deficient (knockout) mice, cell-type-specific analysis, nuclear mRNA precursor processing assays, IFN induction assays after HSV-1, MHV-68, VSV infection","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse model, cell-type-specific mechanistic dissection, mRNA processing assay linking LSm14A to MITA/STING level","pmids":["27183626"],"is_preprint":false},{"year":2021,"finding":"SFTSV nonstructural protein NSs interacts with LSM14A via a newly identified LRRD motif on NSs. This interaction inhibits downstream IRF3 phosphorylation and dimerization, suppressing IFN-β induction. Viral RNA is bound to the LSm14A-NSs protein complex during the interaction.","method":"Co-immunoprecipitation, colocalization, siRNA knockdown of NSs, proteomic screening, IRF3 phosphorylation/dimerization assays, viral replication assays","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, motif mutagenesis identification, IRF3 functional assay, single lab","pmids":["34244294"],"is_preprint":false},{"year":2015,"finding":"RAP55/LSM14A localizes to the mitotic spindle during mitosis in HeLa cells. Depletion of RAP55/LSM14A destabilizes spindle assembly and arrests cells in mitosis. In vitro binding assay demonstrates that RAP55/LSM14A binds directly to tubulin.","method":"GFP-tagged protein expression in HeLa cells, immunofluorescence during mitosis, siRNA depletion, in vitro tubulin-binding assay","journal":"Acta biochimica Polonica","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro binding assay and localization with functional KD phenotype, but single lab, single study with limited orthogonal validation","pmids":["26339800"],"is_preprint":false},{"year":2024,"finding":"LSM14A stabilizes DDX5 protein in the cytoplasm during the G1/S phase, regulating CDK4 and P21 levels to promote glioblastoma cell proliferation and migration. METTL1 modulates LSM14A expression via mRNA m7G methylation. LSM14A interacts with DDX5 as identified by mass spectrometry and co-immunoprecipitation.","method":"Co-immunoprecipitation, mass spectrometry, protein half-life assay, MeRIP analysis, CCK8/EdU/colony formation/transwell assays, in vivo xenograft model","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, MS identification of DDX5 interaction, protein stability assay, MeRIP for m7G methylation, multiple functional readouts, single lab","pmids":["39040050"],"is_preprint":false},{"year":2026,"finding":"LSM14A's antiviral innate immune function does not require its localization to P-bodies or peroxisomes. Instead, an unbiased interactomic analysis after Sendai virus infection revealed a distinct cohort of LSM14A-associated proteins assembling outside P-bodies and peroxisomes that are essential for LSM14A-dependent amplification of antiviral signaling.","method":"Interactomic/proteomic analysis (systems-level), functional interrogation of interactors, localization experiments, Sendai virus infection model","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — interactomic analysis with functional validation of interactors, preprint not yet peer-reviewed, single lab","pmids":["42182482"],"is_preprint":true},{"year":2025,"finding":"LSM14A is expressed in mouse testis germ cells from spermatogonia to elongating spermatids and localizes to the cytoplasm. Germ cell-specific conditional knockout of Lsm14a in mice did not affect spermatogenesis, sperm morphology, motility, or male fertility, nor did it significantly affect P-body formation in testes.","method":"Conditional knockout mouse model, histological examination, sperm morphology/motility analysis, immunofluorescence for P-body markers","journal":"Cells & development","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean genetic KO with specific phenotypic readouts, but negative result (dispensable), single lab","pmids":["41237998"],"is_preprint":false}],"current_model":"LSM14A (RAP55) is an RNA-binding protein with an N-terminal LSm domain and C-terminal RGG/FDF motifs that localizes to cytoplasmic P-bodies (requiring its FDF and RGG domains) and stress granules (requiring its second RGG domain), where it represses mRNA translation in cooperation with the DEAD-box helicase DDX6/Xp54; its P-body localization is regulated by PRMT1-mediated asymmetric arginine dimethylation; upon viral infection, LSM14A translocates to peroxisomes and acts as a sensor for both viral RNA and DNA, initiating IFN-β induction through RIG-I-VISA (RNA viruses) or MITA/STING (DNA viruses) pathways, with recent evidence indicating its innate immune function is mediated through a specialized interaction network outside canonical P-bodies and peroxisomes; in specific cell types (dendritic cells), LSM14A also promotes MITA/STING expression by supporting nuclear mRNA precursor processing; additionally, LSM14A stabilizes DDX5 to regulate cell cycle progression, and binds tubulin to contribute to mitotic spindle stability."},"narrative":{"mechanistic_narrative":"LSM14A (RAP55) is a cytoplasmic RNA-binding protein that controls mRNA fate and serves as a viral nucleic-acid sensor in innate immunity [PMID:16484376, PMID:22745163]. In resting cells it nucleates P-bodies and relocates to stress granules under arsenite stress, with its FDF and two RGG-rich domains directing P-body targeting and the second RGG domain driving stress-granule localization; its loss eliminates P-bodies, placing it upstream of 5'-decapping in mRNA turnover [PMID:16484376]. Through its N-terminal LSm domain it directly represses translation, acting on bound mRNAs in cooperation with the DEAD-box helicase Xp54/DDX6 [PMID:17074753]. P-body targeting is governed by PRMT1-mediated asymmetric dimethylation of multiple arginine residues, which is selectively required for LSM14A recruitment while other P-body components remain [PMID:22614839]. Upon viral infection, LSM14A binds both viral RNA and DNA and translocates to peroxisomes to drive early IRF3 activation and IFN-β induction via RIG-I-VISA for RNA viruses or MITA/STING for DNA viruses [PMID:22745163]; in dendritic cells it additionally supports MITA/STING expression by promoting nuclear mRNA precursor processing [PMID:27183626]. This antiviral function is antagonized by viral proteins including influenza NS1 and SFTSV NSs, which bind LSM14A to disrupt granule formation and block IRF3 phosphorylation [PMID:22973032, PMID:34244294]. Beyond RNA regulation and immunity, LSM14A stabilizes DDX5 to modulate CDK4/p21 and promote cell-cycle progression [PMID:39040050] and binds tubulin to support mitotic spindle stability [PMID:26339800].","teleology":[{"year":2006,"claim":"Established LSM14A as a core P-body and stress-granule protein and mapped the domains that target it to each, defining it as a structural organizer of mRNA-regulatory granules upstream of decapping.","evidence":"siRNA knockdown, GFP-tagged domain-deletion mutants, and colocalization with DCP1a/Ge-1 in stress assays","pmids":["16484376"],"confidence":"High","gaps":["Did not define the mRNAs regulated","Mechanistic link between granule loss and decapping not resolved"]},{"year":2006,"claim":"Showed the protein directly represses translation through its LSm domain in cooperation with the DEAD-box helicase Xp54, providing the biochemical basis for its repressive function in mRNPs.","evidence":"Affinity purification, in vitro translation and oocyte tethering assays, domain mapping, and Co-IP in Xenopus","pmids":["17074753"],"confidence":"High","gaps":["Human ortholog repression not reconstituted in this study","Mechanism of Xp54 cooperation at molecular level unresolved"]},{"year":2012,"claim":"Identified PRMT1 as the writer of asymmetric arginine dimethylation that is specifically required for LSM14A P-body targeting, revealing post-translational control of its granule localization.","evidence":"PRMT1 siRNA knockdown, mass-spec identification of dimethylarginine sites, and Co-IP","pmids":["22614839"],"confidence":"High","gaps":["Functional consequence of methylation on translation repression untested","Role of PRMT5 left unclear"]},{"year":2012,"claim":"Recast LSM14A as a viral RNA/DNA sensor that initiates early IFN-β induction by translocating to peroxisomes and signaling through RIG-I-VISA or MITA, linking an mRNA-regulatory protein to innate immune sensing.","evidence":"RNA/DNA binding assays, siRNA knockdown, IFN-β reporter assays, viral infection, fractionation, and genetic epistasis","pmids":["22745163"],"confidence":"High","gaps":["How sensing connects mechanistically to RIG-I/MITA at peroxisomes unresolved","Relationship to its P-body function unclear"]},{"year":2012,"claim":"Demonstrated that influenza NS1 targets LSM14A to disrupt granules and suppress its antiviral activity, establishing LSM14A as a restriction factor counteracted by viruses.","evidence":"Co-IP, colocalization, NS1 site-directed mutagenesis, and knockdown/overexpression viral replication assays","pmids":["22973032"],"confidence":"High","gaps":["Direct link between granule disruption and IFN suppression not dissected"]},{"year":2015,"claim":"Extended LSM14A function beyond mRNA control to mitosis, showing it binds tubulin and is required for spindle stability.","evidence":"GFP localization, siRNA depletion with mitotic-arrest phenotype, and in vitro tubulin binding in HeLa cells","pmids":["26339800"],"confidence":"Medium","gaps":["Single lab, limited orthogonal validation","How an RNA-binding granule protein stabilizes the spindle mechanistically unknown"]},{"year":2016,"claim":"Revealed a cell-type-specific role in which LSM14A sustains MITA/STING protein by supporting its nuclear mRNA precursor processing in dendritic cells, distinguishing this from its cytoplasmic sensing role.","evidence":"Lsm14a knockout mice, cell-type-specific analysis, mRNA processing assays, and IFN induction after multiple viral infections","pmids":["27183626"],"confidence":"High","gaps":["Mechanism of nuclear mRNA processing by a cytoplasmic protein unresolved","Why effect is dendritic-cell specific unexplained"]},{"year":2021,"claim":"Identified a second viral antagonist, SFTSV NSs, that binds LSM14A via an LRRD motif to block IRF3 phosphorylation/dimerization, reinforcing LSM14A as a node viruses target to suppress IFN.","evidence":"Co-IP, colocalization, proteomic screening, motif mutagenesis, and IRF3 phosphorylation/dimerization assays","pmids":["34244294"],"confidence":"Medium","gaps":["Single lab","Whether NSs blocks RNA binding versus signaling step not fully separated"]},{"year":2024,"claim":"Linked LSM14A to cell-cycle control by showing it stabilizes DDX5 to regulate CDK4/p21 and promote glioblastoma proliferation, with its own expression set by METTL1-dependent m7G methylation.","evidence":"Co-IP, mass spec, protein half-life and MeRIP assays, proliferation/migration readouts, and xenograft model","pmids":["39040050"],"confidence":"Medium","gaps":["Single lab","Mechanism by which LSM14A stabilizes DDX5 unresolved","Generalizability beyond glioblastoma untested"]},{"year":2026,"claim":"Challenged the granule/peroxisome model of LSM14A antiviral signaling by showing its immune amplification depends on a distinct cohort of interactors assembling outside P-bodies and peroxisomes.","evidence":"Unbiased interactomic analysis after Sendai virus infection with functional interrogation of interactors (preprint)","pmids":["42182482"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed, single lab","Identity and architecture of the signaling complex not fully defined"]},{"year":2025,"claim":"Tested the in vivo requirement of LSM14A in germ cells and found it dispensable for spermatogenesis and male fertility, bounding its essential roles to other tissues/contexts.","evidence":"Germ-cell-specific conditional knockout mice with histology, sperm analysis, and P-body marker immunofluorescence","pmids":["41237998"],"confidence":"Medium","gaps":["Negative result; possible redundancy with paralogs not addressed","Single lab"]},{"year":null,"claim":"The molecular composition and architecture of the non-canonical signaling complex that drives LSM14A antiviral amplification, and how it integrates with its granule and translational-repression activities, remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the antiviral complex","Connection between mRNA-repression, sensing, and mitotic functions unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[1]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,8,10]},{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[2]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,5,6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[7,8]}],"complexes":["P-body","stress granule"],"partners":["DDX6","PRMT1","DDX5","RIG-I","VISA","MITA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8ND56","full_name":"Protein LSM14 homolog A","aliases":["Protein FAM61A","Protein SCD6 homolog","Putative alpha-synuclein-binding protein","AlphaSNBP","RNA-associated protein 55A","hRAP55","hRAP55A"],"length_aa":463,"mass_kda":50.5,"function":"Essential for formation of P-bodies, cytoplasmic structures that provide storage sites for translationally inactive mRNAs and protect them from degradation (PubMed:16484376, PubMed:17074753, PubMed:29510985). Acts as a repressor of mRNA translation (PubMed:29510985). May play a role in mitotic spindle assembly (PubMed:26339800)","subcellular_location":"Cytoplasm, P-body; Cytoplasm, cytoskeleton, spindle; Cytoplasm, Stress granule","url":"https://www.uniprot.org/uniprotkb/Q8ND56/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LSM14A","classification":"Not Classified","n_dependent_lines":130,"n_total_lines":1208,"dependency_fraction":0.1076158940397351},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000257103","cell_line_id":"CID001688","localizations":[{"compartment":"big_aggregates","grade":3}],"interactors":[{"gene":"DDX6","stoichiometry":10.0},{"gene":"FXR2","stoichiometry":10.0},{"gene":"PRMT1","stoichiometry":4.0},{"gene":"LSM14B","stoichiometry":4.0},{"gene":"ARHGAP18","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2},{"gene":"SYNCRIP","stoichiometry":0.2},{"gene":"EIF4E","stoichiometry":0.2},{"gene":"IGF2BP3","stoichiometry":0.2},{"gene":"HNRNPR","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001688","total_profiled":1310},"omim":[{"mim_id":"620424","title":"ZYGOTE ARREST 1-LIKE; ZAR1L","url":"https://www.omim.org/entry/620424"},{"mim_id":"618653","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH IMPAIRED LANGUAGE AND DYSMORPHIC FACIES; IDDILF","url":"https://www.omim.org/entry/618653"},{"mim_id":"613026","title":"CHROMOSOME 19q13.11 DELETION SYNDROME, DISTAL","url":"https://www.omim.org/entry/613026"},{"mim_id":"610677","title":"LSM14A mRNA PROCESSING BODY ASSEMBLY FACTOR; LSM14A","url":"https://www.omim.org/entry/610677"},{"mim_id":"600326","title":"DEAD-BOX HELICASE 6; DDX6","url":"https://www.omim.org/entry/600326"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytoplasmic bodies","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LSM14A"},"hgnc":{"alias_symbol":["DKFZP434D1335","RAP55A","RAP55"],"prev_symbol":["C19orf13","FAM61A"]},"alphafold":{"accession":"Q8ND56","domains":[{"cath_id":"2.30.30.100","chopping":"11-69","consensus_level":"high","plddt":96.7642,"start":11,"end":69}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8ND56","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8ND56-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8ND56-F1-predicted_aligned_error_v6.png","plddt_mean":59.16},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LSM14A","jax_strain_url":"https://www.jax.org/strain/search?query=LSM14A"},"sequence":{"accession":"Q8ND56","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8ND56.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8ND56/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8ND56"}},"corpus_meta":[{"pmid":"16484376","id":"PMC_16484376","title":"RNA-associated protein 55 (RAP55) localizes to mRNA processing bodies and stress granules.","date":"2006","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/16484376","citation_count":147,"is_preprint":false},{"pmid":"22745163","id":"PMC_22745163","title":"LSm14A is a processing body-associated sensor of viral nucleic acids that initiates cellular antiviral response in the early phase of viral infection.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22745163","citation_count":130,"is_preprint":false},{"pmid":"17074753","id":"PMC_17074753","title":"RAP55, a cytoplasmic mRNP component, represses translation in Xenopus oocytes.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17074753","citation_count":98,"is_preprint":false},{"pmid":"22973032","id":"PMC_22973032","title":"The NS1 protein of influenza A virus interacts with cellular processing bodies and stress granules through RNA-associated protein 55 (RAP55) during virus infection.","date":"2012","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/22973032","citation_count":59,"is_preprint":false},{"pmid":"22614839","id":"PMC_22614839","title":"PRMT1 is required for RAP55 to localize to processing bodies.","date":"2012","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/22614839","citation_count":44,"is_preprint":false},{"pmid":"18723115","id":"PMC_18723115","title":"RAP55: insights into an evolutionarily conserved protein family.","date":"2008","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18723115","citation_count":42,"is_preprint":false},{"pmid":"27183626","id":"PMC_27183626","title":"LSm14A Plays a Critical Role in Antiviral Immune Responses by Regulating MITA Level in a Cell-Specific Manner.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 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infection of blue eggshell layers with Newcastle disease viruses.","date":"2019","source":"The Journal of veterinary medical science","url":"https://pubmed.ncbi.nlm.nih.gov/31534060","citation_count":4,"is_preprint":false},{"pmid":"41237998","id":"PMC_41237998","title":"LSM14A, an LSM family protein, is dispensable for spermatogenesis and male fertility in mice.","date":"2025","source":"Cells & development","url":"https://pubmed.ncbi.nlm.nih.gov/41237998","citation_count":0,"is_preprint":false},{"pmid":"41679563","id":"PMC_41679563","title":"Silencer-regulated circLSM14A inhibits autophagy of pulmonary artery smooth muscle cells through parental protein LSM14A.","date":"2026","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41679563","citation_count":0,"is_preprint":false},{"pmid":"42182482","id":"PMC_42182482","title":"The enteroviral protease target LSM14A operates outside of P-bodies to augment antiviral innate immunity.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42182482","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.08.669445","title":"Cross-kingdom miRNA delivery by Panax notoginseng-derived EVs restores neuronal function after ischemic injury","date":"2025-08-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.08.669445","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11076,"output_tokens":3176,"usd":0.040434,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10569,"output_tokens":3711,"usd":0.07281,"stage2_stop_reason":"end_turn"},"total_usd":0.113244,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"RAP55 (LSM14A) localizes to P-bodies in resting cells and to stress granules after arsenite-induced stress. The FDF motif and two RGG-rich domains are necessary and sufficient for P-body targeting, while the second RGG domain is necessary and sufficient for stress granule localization. siRNA-mediated knockdown of RAP55 results in loss of P-bodies, placing RAP55 upstream of the 5'-decapping step in mRNA degradation.\",\n      \"method\": \"siRNA knockdown, GFP-tagged domain deletion mutants, immunofluorescence colocalization with DCP1a and Ge-1, arsenite-stress assay\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA KD, domain mapping, colocalization), replicated by subsequent studies\",\n      \"pmids\": [\"16484376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Xenopus RAP55 (xRAP55/LSM14A ortholog) is a component of maternal mRNPs that directly represses translation in vitro and in oocytes when tethered to a reporter mRNA. The N-terminal LSm domain is required for P-body localization and translational repression. xRAP55 cooperates with the DEAD-box protein Xp54 to repress translation, and associates with PRMT1.\",\n      \"method\": \"Affinity purification of xRAP55 complexes from Xenopus oocytes, in vitro translation assay with recombinant protein, tethering assay in oocytes, domain deletion analysis, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro translation repression, tethering assay, domain mapping, multiple orthogonal methods in single study\",\n      \"pmids\": [\"17074753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LSM14A binds to synthetic or viral RNA and DNA, mediates IRF3 activation and IFN-β induction, and is essential for early-phase IFN-β induction after RNA or DNA virus infection. LSM14A-mediated IFN-β induction requires RIG-I-VISA (for RNA viruses) or MITA (for DNA viruses). Viral infection causes translocation of LSM14A to peroxisomes, where RIG-I, VISA, and MITA are located.\",\n      \"method\": \"RNA/DNA binding assays, siRNA knockdown of LSM14A, IFN-β reporter assays, viral infection experiments, subcellular fractionation/immunofluorescence showing peroxisomal translocation, epistasis with RIG-I/VISA/MITA knockdowns\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (binding assay, siRNA KD, reporter assay, genetic epistasis, localization), replicated across subsequent studies\",\n      \"pmids\": [\"22745163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PRMT1 asymmetrically dimethylates multiple arginine residues of RAP55A (LSM14A). Knockdown of PRMT1 impairs localization of RAP55A to P-bodies while other P-body components are retained, establishing PRMT1 as a writer required for RAP55A P-body targeting. RAP55A overexpression induces formation of large mRNP granules containing both P-body and stress granule components.\",\n      \"method\": \"siRNA knockdown of PRMT1, immunofluorescence, mass spectrometry identification of asymmetric dimethylarginine on RAP55A, co-immunoprecipitation of PRMT1/PRMT5 with RAP55A\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, MS identification of PTM sites, siRNA functional rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"22614839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Influenza A NS1 protein interacts with RAP55 (LSM14A) via its RNA-binding (R38, K41) and PKR-interaction (I123, M124, K126, N127) sites. NS1 interaction with RAP55 inhibits RAP55 expression and disrupts P-body/stress granule formation. Overexpression of RAP55 suppresses influenza virus replication, while dominant-negative RAP55 blocks NS1 colocalization to P-bodies.\",\n      \"method\": \"Co-immunoprecipitation, colocalization assays, siRNA knockdown of RAP55, site-directed mutagenesis of NS1, overexpression and dominant-negative mutant analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, mutagenesis of interaction sites, functional KD and OE with specific readouts, multiple orthogonal methods\",\n      \"pmids\": [\"22973032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LSM14A deficiency specifically downregulates MITA/STING protein level in dendritic cells (but not in macrophages or fibroblasts) by impairing nuclear mRNA precursor processing of MITA/STING, thereby impairing antiviral innate and adaptive immune responses in a cell-type-specific manner.\",\n      \"method\": \"LSm14a-deficient (knockout) mice, cell-type-specific analysis, nuclear mRNA precursor processing assays, IFN induction assays after HSV-1, MHV-68, VSV infection\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse model, cell-type-specific mechanistic dissection, mRNA processing assay linking LSm14A to MITA/STING level\",\n      \"pmids\": [\"27183626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SFTSV nonstructural protein NSs interacts with LSM14A via a newly identified LRRD motif on NSs. This interaction inhibits downstream IRF3 phosphorylation and dimerization, suppressing IFN-β induction. Viral RNA is bound to the LSm14A-NSs protein complex during the interaction.\",\n      \"method\": \"Co-immunoprecipitation, colocalization, siRNA knockdown of NSs, proteomic screening, IRF3 phosphorylation/dimerization assays, viral replication assays\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, motif mutagenesis identification, IRF3 functional assay, single lab\",\n      \"pmids\": [\"34244294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RAP55/LSM14A localizes to the mitotic spindle during mitosis in HeLa cells. Depletion of RAP55/LSM14A destabilizes spindle assembly and arrests cells in mitosis. In vitro binding assay demonstrates that RAP55/LSM14A binds directly to tubulin.\",\n      \"method\": \"GFP-tagged protein expression in HeLa cells, immunofluorescence during mitosis, siRNA depletion, in vitro tubulin-binding assay\",\n      \"journal\": \"Acta biochimica Polonica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro binding assay and localization with functional KD phenotype, but single lab, single study with limited orthogonal validation\",\n      \"pmids\": [\"26339800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LSM14A stabilizes DDX5 protein in the cytoplasm during the G1/S phase, regulating CDK4 and P21 levels to promote glioblastoma cell proliferation and migration. METTL1 modulates LSM14A expression via mRNA m7G methylation. LSM14A interacts with DDX5 as identified by mass spectrometry and co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, protein half-life assay, MeRIP analysis, CCK8/EdU/colony formation/transwell assays, in vivo xenograft model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, MS identification of DDX5 interaction, protein stability assay, MeRIP for m7G methylation, multiple functional readouts, single lab\",\n      \"pmids\": [\"39040050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LSM14A's antiviral innate immune function does not require its localization to P-bodies or peroxisomes. Instead, an unbiased interactomic analysis after Sendai virus infection revealed a distinct cohort of LSM14A-associated proteins assembling outside P-bodies and peroxisomes that are essential for LSM14A-dependent amplification of antiviral signaling.\",\n      \"method\": \"Interactomic/proteomic analysis (systems-level), functional interrogation of interactors, localization experiments, Sendai virus infection model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — interactomic analysis with functional validation of interactors, preprint not yet peer-reviewed, single lab\",\n      \"pmids\": [\"42182482\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LSM14A is expressed in mouse testis germ cells from spermatogonia to elongating spermatids and localizes to the cytoplasm. Germ cell-specific conditional knockout of Lsm14a in mice did not affect spermatogenesis, sperm morphology, motility, or male fertility, nor did it significantly affect P-body formation in testes.\",\n      \"method\": \"Conditional knockout mouse model, histological examination, sperm morphology/motility analysis, immunofluorescence for P-body markers\",\n      \"journal\": \"Cells & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean genetic KO with specific phenotypic readouts, but negative result (dispensable), single lab\",\n      \"pmids\": [\"41237998\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LSM14A (RAP55) is an RNA-binding protein with an N-terminal LSm domain and C-terminal RGG/FDF motifs that localizes to cytoplasmic P-bodies (requiring its FDF and RGG domains) and stress granules (requiring its second RGG domain), where it represses mRNA translation in cooperation with the DEAD-box helicase DDX6/Xp54; its P-body localization is regulated by PRMT1-mediated asymmetric arginine dimethylation; upon viral infection, LSM14A translocates to peroxisomes and acts as a sensor for both viral RNA and DNA, initiating IFN-β induction through RIG-I-VISA (RNA viruses) or MITA/STING (DNA viruses) pathways, with recent evidence indicating its innate immune function is mediated through a specialized interaction network outside canonical P-bodies and peroxisomes; in specific cell types (dendritic cells), LSM14A also promotes MITA/STING expression by supporting nuclear mRNA precursor processing; additionally, LSM14A stabilizes DDX5 to regulate cell cycle progression, and binds tubulin to contribute to mitotic spindle stability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LSM14A (RAP55) is a cytoplasmic RNA-binding protein that controls mRNA fate and serves as a viral nucleic-acid sensor in innate immunity [#0, #2]. In resting cells it nucleates P-bodies and relocates to stress granules under arsenite stress, with its FDF and two RGG-rich domains directing P-body targeting and the second RGG domain driving stress-granule localization; its loss eliminates P-bodies, placing it upstream of 5'-decapping in mRNA turnover [#0]. Through its N-terminal LSm domain it directly represses translation, acting on bound mRNAs in cooperation with the DEAD-box helicase Xp54/DDX6 [#1]. P-body targeting is governed by PRMT1-mediated asymmetric dimethylation of multiple arginine residues, which is selectively required for LSM14A recruitment while other P-body components remain [#3]. Upon viral infection, LSM14A binds both viral RNA and DNA and translocates to peroxisomes to drive early IRF3 activation and IFN-\\u03b2 induction via RIG-I-VISA for RNA viruses or MITA/STING for DNA viruses [#2]; in dendritic cells it additionally supports MITA/STING expression by promoting nuclear mRNA precursor processing [#5]. This antiviral function is antagonized by viral proteins including influenza NS1 and SFTSV NSs, which bind LSM14A to disrupt granule formation and block IRF3 phosphorylation [#4, #6]. Beyond RNA regulation and immunity, LSM14A stabilizes DDX5 to modulate CDK4/p21 and promote cell-cycle progression [#8] and binds tubulin to support mitotic spindle stability [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established LSM14A as a core P-body and stress-granule protein and mapped the domains that target it to each, defining it as a structural organizer of mRNA-regulatory granules upstream of decapping.\",\n      \"evidence\": \"siRNA knockdown, GFP-tagged domain-deletion mutants, and colocalization with DCP1a/Ge-1 in stress assays\",\n      \"pmids\": [\"16484376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the mRNAs regulated\", \"Mechanistic link between granule loss and decapping not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed the protein directly represses translation through its LSm domain in cooperation with the DEAD-box helicase Xp54, providing the biochemical basis for its repressive function in mRNPs.\",\n      \"evidence\": \"Affinity purification, in vitro translation and oocyte tethering assays, domain mapping, and Co-IP in Xenopus\",\n      \"pmids\": [\"17074753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human ortholog repression not reconstituted in this study\", \"Mechanism of Xp54 cooperation at molecular level unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified PRMT1 as the writer of asymmetric arginine dimethylation that is specifically required for LSM14A P-body targeting, revealing post-translational control of its granule localization.\",\n      \"evidence\": \"PRMT1 siRNA knockdown, mass-spec identification of dimethylarginine sites, and Co-IP\",\n      \"pmids\": [\"22614839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of methylation on translation repression untested\", \"Role of PRMT5 left unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Recast LSM14A as a viral RNA/DNA sensor that initiates early IFN-\\u03b2 induction by translocating to peroxisomes and signaling through RIG-I-VISA or MITA, linking an mRNA-regulatory protein to innate immune sensing.\",\n      \"evidence\": \"RNA/DNA binding assays, siRNA knockdown, IFN-\\u03b2 reporter assays, viral infection, fractionation, and genetic epistasis\",\n      \"pmids\": [\"22745163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How sensing connects mechanistically to RIG-I/MITA at peroxisomes unresolved\", \"Relationship to its P-body function unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that influenza NS1 targets LSM14A to disrupt granules and suppress its antiviral activity, establishing LSM14A as a restriction factor counteracted by viruses.\",\n      \"evidence\": \"Co-IP, colocalization, NS1 site-directed mutagenesis, and knockdown/overexpression viral replication assays\",\n      \"pmids\": [\"22973032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link between granule disruption and IFN suppression not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended LSM14A function beyond mRNA control to mitosis, showing it binds tubulin and is required for spindle stability.\",\n      \"evidence\": \"GFP localization, siRNA depletion with mitotic-arrest phenotype, and in vitro tubulin binding in HeLa cells\",\n      \"pmids\": [\"26339800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, limited orthogonal validation\", \"How an RNA-binding granule protein stabilizes the spindle mechanistically unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a cell-type-specific role in which LSM14A sustains MITA/STING protein by supporting its nuclear mRNA precursor processing in dendritic cells, distinguishing this from its cytoplasmic sensing role.\",\n      \"evidence\": \"Lsm14a knockout mice, cell-type-specific analysis, mRNA processing assays, and IFN induction after multiple viral infections\",\n      \"pmids\": [\"27183626\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of nuclear mRNA processing by a cytoplasmic protein unresolved\", \"Why effect is dendritic-cell specific unexplained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a second viral antagonist, SFTSV NSs, that binds LSM14A via an LRRD motif to block IRF3 phosphorylation/dimerization, reinforcing LSM14A as a node viruses target to suppress IFN.\",\n      \"evidence\": \"Co-IP, colocalization, proteomic screening, motif mutagenesis, and IRF3 phosphorylation/dimerization assays\",\n      \"pmids\": [\"34244294\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether NSs blocks RNA binding versus signaling step not fully separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked LSM14A to cell-cycle control by showing it stabilizes DDX5 to regulate CDK4/p21 and promote glioblastoma proliferation, with its own expression set by METTL1-dependent m7G methylation.\",\n      \"evidence\": \"Co-IP, mass spec, protein half-life and MeRIP assays, proliferation/migration readouts, and xenograft model\",\n      \"pmids\": [\"39040050\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism by which LSM14A stabilizes DDX5 unresolved\", \"Generalizability beyond glioblastoma untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Challenged the granule/peroxisome model of LSM14A antiviral signaling by showing its immune amplification depends on a distinct cohort of interactors assembling outside P-bodies and peroxisomes.\",\n      \"evidence\": \"Unbiased interactomic analysis after Sendai virus infection with functional interrogation of interactors (preprint)\",\n      \"pmids\": [\"42182482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed, single lab\", \"Identity and architecture of the signaling complex not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Tested the in vivo requirement of LSM14A in germ cells and found it dispensable for spermatogenesis and male fertility, bounding its essential roles to other tissues/contexts.\",\n      \"evidence\": \"Germ-cell-specific conditional knockout mice with histology, sperm analysis, and P-body marker immunofluorescence\",\n      \"pmids\": [\"41237998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result; possible redundancy with paralogs not addressed\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular composition and architecture of the non-canonical signaling complex that drives LSM14A antiviral amplification, and how it integrates with its granule and translational-repression activities, remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the antiviral complex\", \"Connection between mRNA-repression, sensing, and mitotic functions unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 8, 10]},\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 5, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [\"P-body\", \"stress granule\"],\n    \"partners\": [\"DDX6\", \"PRMT1\", \"DDX5\", \"RIG-I\", \"VISA\", \"MITA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}