{"gene":"LENG8","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2025,"finding":"LENG8 forms a novel nuclear complex called TREX-2.1 (composed of LENG8, PCID2, and DSS1) that facilitates release of the DEAD-box ATPase DDX39B (UAP56) from mRNPs. Cryo-EM structures of TREX-2.1/DDX39B revealed a conserved 'trigger loop' in LENG8 that is critical for DDX39B regulation, analogous to the trigger loop in GANP within the canonical TREX-2 complex.","method":"Cryo-EM structure determination, co-immunoprecipitation, RNA sequencing from LENG8 knockdown cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures with functional mutagenesis, complemented by knockdown transcriptomics; single lab but multiple orthogonal methods","pmids":["40595470"],"is_preprint":false},{"year":2026,"finding":"LENG8 is a conserved RNA nuclear retention and degradation factor. It is recruited to pre-mRNAs by splicing factors including the U1 snRNP, forms the REX (Repressor of EXport) complex with PCID2 and SEM1, and acts as a dominant-negative factor against the mRNA export factor TREX-2 to cause nuclear RNA retention. LENG8 also promotes nuclear RNA degradation by recruiting the PAXT adaptor complex and the RNA exosome. Loss of LENG8 causes cytoplasmic leakage of misprocessed mRNAs (intronically polyadenylated, intron-retained) and noncoding RNAs.","method":"LENG8 knockdown/depletion with transcriptomic readout, co-immunoprecipitation, RNA nuclear retention assays, functional complex reconstitution","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD + transcriptomics, Co-IP, retention assays), replicated across preprint and peer-reviewed publication, functionally validated pathway placement","pmids":["41861815","40832163"],"is_preprint":false},{"year":2026,"finding":"Biochemical and structural analysis showed that the LENG8-PCID2 complex (human) operates as an mRNP decay connector, coupling nuclear mRNPs to the RNA-degrading exosome via the PAXT adaptor. LENG8-PCID2 uniquely associates with early splicing factors through direct interaction with U1A and RRP1B, distinguishing it from the GANP-PCID2 export complex. The yeast ortholog of this pathway (Thp3-Csn12 coupling Mud2-Bbp with the nuclear exosome) reveals evolutionary conservation of the spliceosome-exosome mRNP decay pathway.","method":"Biochemical reconstitution, structural analysis, direct binding assays (pulldown/Co-IP with U1A and RRP1B)","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical and structural approaches, direct interaction mapping, cross-species conservation validated experimentally","pmids":["42140674"],"is_preprint":false},{"year":2026,"finding":"PCID2 scaffolds mutually exclusive subcomplexes with GANP, LENG8, and SAC3D1. LENG8 localizes to nuclear speckles and interacts extensively with mRNA processing factors. LENG8 depletion alters mRNA processing and polyadenylation site usage, indicating LENG8 acts upstream of the canonical TREX-2 complex in mRNA processing.","method":"Interactome characterization, subcellular localization (nuclear speckle), LENG8 depletion with mRNA processing and polyadenylation site usage readout","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interactome mapping plus localization and depletion phenotype, single lab, preprint not yet peer-reviewed","pmids":["42039562"],"is_preprint":true},{"year":2025,"finding":"The LENG8-PCID2-SEM1 (LENG8-PS) trimer is structurally and functionally equivalent to the GANP-PCID2-SEM1 trimer of TREX-2. Mutagenesis and transcriptomic data demonstrate that LENG8-PS, as the core of a PAXT-associated TREX-2-like module, competes with NPC-associated TREX-2 (GANP-PS) for UAP56-bound RNPs, directing them toward nuclear decay instead of export. Nuclear fate of polyadenylated RNPs is governed by the opposing actions of nucleoplasmic PAXT (containing LENG8-PS) and NPC-associated TREX-2.","method":"Mutagenesis, transcriptomics, structural equivalence assessment, competition assays between PAXT and TREX-2 modules","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus transcriptomics, preprint, single lab, mechanistically detailed but not yet peer-reviewed","pmids":["bio_10.1101_2025.09.16.676470"],"is_preprint":true}],"current_model":"LENG8 is a conserved nuclear RNA quality-control factor that forms the REX/TREX-2.1 complex with PCID2 and SEM1, is recruited to pre-mRNAs via U1 snRNP and other splicing factors, acts as a dominant-negative competitor of the mRNA export factor TREX-2 to retain misprocessed and noncoding RNAs in the nucleus, and promotes their degradation by recruiting the PAXT adaptor and the RNA exosome, thereby ensuring only correctly processed RNAs are exported to the cytoplasm."},"narrative":{"mechanistic_narrative":"LENG8 is a conserved nuclear RNA quality-control factor that governs the fate of polyadenylated RNPs by directing misprocessed and noncoding transcripts toward nuclear retention and degradation rather than cytoplasmic export [PMID:41861815, PMID:40832163]. It assembles with PCID2 and SEM1/DSS1 into a TREX-2-like trimer (variously termed REX or TREX-2.1) that is structurally and functionally equivalent to the canonical GANP-PCID2-SEM1 export complex, but acts as its dominant-negative counterpart: LENG8-PS competes with NPC-associated TREX-2 for UAP56(DDX39B)-bound RNPs and steers them to decay [PMID:40595470, PMID:41861815, PMID:40832163, PMID:bio_10.1101_2025.09.16.676470]. Cryo-EM of the LENG8-containing complex bound to DDX39B revealed a conserved 'trigger loop' in LENG8, analogous to that of GANP, that is critical for regulating release of the DEAD-box ATPase from mRNPs [PMID:40595470]. LENG8 is recruited to pre-mRNAs through direct interactions with early splicing factors including the U1 snRNP component U1A and with RRP1B, a feature that distinguishes the LENG8-PCID2 complex from the GANP export complex [PMID:41861815, PMID:40832163, PMID:42140674]. Having engaged these substrates, LENG8 couples them to the RNA exosome by recruiting the PAXT adaptor, and its loss causes cytoplasmic leakage of intronically polyadenylated, intron-retained, and noncoding RNAs [PMID:41861815, PMID:40832163, PMID:42140674]. This spliceosome-coupled mRNP decay pathway is evolutionarily conserved, with the yeast Thp3-Csn12 module performing the analogous coupling of splicing factors to the nuclear exosome [PMID:42140674].","teleology":[{"year":2025,"claim":"Established that LENG8 forms a defined nuclear trimeric complex and directly regulates the export ATPase DDX39B, answering how this previously uncharacterized factor engages the mRNA export machinery.","evidence":"Cryo-EM of the LENG8/PCID2/DSS1-DDX39B complex with functional mutagenesis of the LENG8 'trigger loop', plus LENG8 knockdown RNA-seq","pmids":["40595470"],"confidence":"High","gaps":["Whether trigger-loop activity promotes ATPase stimulation or RNP release was defined structurally but not in a reconstituted kinetic assay","The set of physiological RNA substrates whose DDX39B handling depends on LENG8 was not exhaustively mapped"]},{"year":2026,"claim":"Defined LENG8 as a dominant-negative export antagonist and active degradation factor, resolving how it converts an export-like complex into a retention-and-decay machine.","evidence":"LENG8 depletion with transcriptomics, Co-IP, RNA nuclear retention assays and complex reconstitution identifying the REX (LENG8-PCID2-SEM1) complex, U1 snRNP recruitment, and PAXT/exosome coupling","pmids":["41861815","40832163"],"confidence":"High","gaps":["How LENG8 discriminates misprocessed from correctly processed transcripts at the molecular level is not resolved","The stoichiometry and dynamics of competition between LENG8-PS and GANP-PS in cells were not directly measured"]},{"year":2026,"claim":"Mapped the direct splicing-factor contacts that recruit LENG8-PCID2 to early mRNPs and demonstrated evolutionary conservation, distinguishing the decay connector from the GANP export complex.","evidence":"Biochemical reconstitution, structural analysis and direct pulldown/Co-IP with U1A and RRP1B, plus characterization of the yeast Thp3-Csn12 ortholog pathway","pmids":["42140674"],"confidence":"High","gaps":["The structural basis of U1A and RRP1B binding to LENG8-PCID2 was not determined at high resolution","How early spliceosome engagement is temporally coordinated with exosome recruitment is unresolved"]},{"year":2026,"claim":"Showed that PCID2 scaffolds mutually exclusive GANP, LENG8, and SAC3D1 subcomplexes and that LENG8 acts upstream in mRNA processing, framing how a shared scaffold partitions distinct nuclear RNA fates.","evidence":"Interactome characterization, nuclear speckle localization, and LENG8 depletion with mRNA processing and polyadenylation site-usage readout (preprint)","pmids":["42039562"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Mechanism determining which PCID2 subcomplex assembles on a given transcript is unknown","The functional role of the SAC3D1-PCID2 subcomplex relative to LENG8 was not defined"]},{"year":2025,"claim":"Provided mechanistic detail that LENG8-PS and GANP-PS compete for the same UAP56-bound RNPs, establishing a competition model for nuclear RNA fate determination.","evidence":"Mutagenesis, transcriptomics and competition assays between PAXT-associated LENG8-PS and NPC-associated TREX-2 modules (preprint)","pmids":["bio_10.1101_2025.09.16.676470"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","The kinetic parameters governing the competition outcome were not quantified","How spatial separation (nucleoplasm vs NPC) biases the competition in vivo is not directly shown"]},{"year":null,"claim":"How LENG8 distinguishes correctly processed from aberrant transcripts and what controls the partitioning of substrates between export and decay remains the central open question.","evidence":"","pmids":[],"confidence":"High","gaps":["No molecular discriminator of 'misprocessed' RNA defined","Regulation of LENG8-PS versus GANP-PS abundance and localization in different conditions is unknown","Physiological consequences of LENG8 loss at the organismal level not characterized in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,4]}],"complexes":["REX/TREX-2.1 (LENG8-PCID2-SEM1/DSS1)","PAXT","nuclear RNA exosome"],"partners":["PCID2","SEM1","DDX39B","U1A","RRP1B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96PV6","full_name":"Leukocyte receptor cluster member 8","aliases":[],"length_aa":800,"mass_kda":88.2,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q96PV6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/LENG8","classification":"Common Essential","n_dependent_lines":697,"n_total_lines":1208,"dependency_fraction":0.5769867549668874},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX39B","stoichiometry":0.2},{"gene":"HNRNPL","stoichiometry":0.2},{"gene":"SEM1","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LENG8","total_profiled":1310},"omim":[{"mim_id":"616575","title":"LEUKOCYTE RECEPTOR CLUSTER GENE 8; LENG8","url":"https://www.omim.org/entry/616575"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LENG8"},"hgnc":{"alias_symbol":["KIAA1932","MGC40108","pp13842"],"prev_symbol":[]},"alphafold":{"accession":"Q96PV6","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PV6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PV6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PV6-F1-predicted_aligned_error_v6.png","plddt_mean":55.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LENG8","jax_strain_url":"https://www.jax.org/strain/search?query=LENG8"},"sequence":{"accession":"Q96PV6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96PV6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96PV6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PV6"}},"corpus_meta":[{"pmid":"26910819","id":"PMC_26910819","title":"Early Loss of Blood-Brain Barrier Integrity Precedes NOX2 Elevation in the Prefrontal Cortex of an Animal Model of Psychosis.","date":"2016","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/26910819","citation_count":47,"is_preprint":false},{"pmid":"40595470","id":"PMC_40595470","title":"Structural mechanism of DDX39B regulation by human TREX-2 and a related complex in mRNP remodeling.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40595470","citation_count":14,"is_preprint":false},{"pmid":"30216441","id":"PMC_30216441","title":"Screening the full leucocyte receptor complex genomic region revealed associations with pemphigus that might be explained by gene regulation.","date":"2018","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30216441","citation_count":14,"is_preprint":false},{"pmid":"25160908","id":"PMC_25160908","title":"Breed-specific transcriptome response of spleen from six to eight week old piglet after infection with Streptococcus suis type 2.","date":"2014","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/25160908","citation_count":11,"is_preprint":false},{"pmid":"40832163","id":"PMC_40832163","title":"LENG8 mediates RNA nuclear retention and degradation in eukaryotes.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40832163","citation_count":2,"is_preprint":false},{"pmid":"41861815","id":"PMC_41861815","title":"LENG8 mediates RNA nuclear retention and degradation in eukaryotes.","date":"2026","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/41861815","citation_count":2,"is_preprint":false},{"pmid":"37435641","id":"PMC_37435641","title":"Potential susceptibility genes in patients with stage III and IV periodontitis: A whole-exome sequencing pilot study.","date":"2024","source":"Biomolecules & biomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/37435641","citation_count":1,"is_preprint":false},{"pmid":"41997106","id":"PMC_41997106","title":"LENG8: The nuclear sentry guarding against aberrant RNA leakage.","date":"2026","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/41997106","citation_count":0,"is_preprint":false},{"pmid":"42140674","id":"PMC_42140674","title":"Evolutionarily conserved spliceosome-exosome pathway in nuclear mRNA surveillance.","date":"2026","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/42140674","citation_count":0,"is_preprint":false},{"pmid":"42039562","id":"PMC_42039562","title":"TREX2 component PCID2 scaffolds alternative SAC3-based subcomplexes with distinct RNA processing and export function.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42039562","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.16.676470","title":"Molecular basis of polyadenylated RNA fate determination in the nucleus","date":"2025-09-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.16.676470","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7122,"output_tokens":1640,"usd":0.022983,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8371,"output_tokens":2736,"usd":0.055128,"stage2_stop_reason":"end_turn"},"total_usd":0.078111,"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\": 2025,\n      \"finding\": \"LENG8 forms a novel nuclear complex called TREX-2.1 (composed of LENG8, PCID2, and DSS1) that facilitates release of the DEAD-box ATPase DDX39B (UAP56) from mRNPs. Cryo-EM structures of TREX-2.1/DDX39B revealed a conserved 'trigger loop' in LENG8 that is critical for DDX39B regulation, analogous to the trigger loop in GANP within the canonical TREX-2 complex.\",\n      \"method\": \"Cryo-EM structure determination, co-immunoprecipitation, RNA sequencing from LENG8 knockdown cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures with functional mutagenesis, complemented by knockdown transcriptomics; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40595470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LENG8 is a conserved RNA nuclear retention and degradation factor. It is recruited to pre-mRNAs by splicing factors including the U1 snRNP, forms the REX (Repressor of EXport) complex with PCID2 and SEM1, and acts as a dominant-negative factor against the mRNA export factor TREX-2 to cause nuclear RNA retention. LENG8 also promotes nuclear RNA degradation by recruiting the PAXT adaptor complex and the RNA exosome. Loss of LENG8 causes cytoplasmic leakage of misprocessed mRNAs (intronically polyadenylated, intron-retained) and noncoding RNAs.\",\n      \"method\": \"LENG8 knockdown/depletion with transcriptomic readout, co-immunoprecipitation, RNA nuclear retention assays, functional complex reconstitution\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD + transcriptomics, Co-IP, retention assays), replicated across preprint and peer-reviewed publication, functionally validated pathway placement\",\n      \"pmids\": [\"41861815\", \"40832163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Biochemical and structural analysis showed that the LENG8-PCID2 complex (human) operates as an mRNP decay connector, coupling nuclear mRNPs to the RNA-degrading exosome via the PAXT adaptor. LENG8-PCID2 uniquely associates with early splicing factors through direct interaction with U1A and RRP1B, distinguishing it from the GANP-PCID2 export complex. The yeast ortholog of this pathway (Thp3-Csn12 coupling Mud2-Bbp with the nuclear exosome) reveals evolutionary conservation of the spliceosome-exosome mRNP decay pathway.\",\n      \"method\": \"Biochemical reconstitution, structural analysis, direct binding assays (pulldown/Co-IP with U1A and RRP1B)\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical and structural approaches, direct interaction mapping, cross-species conservation validated experimentally\",\n      \"pmids\": [\"42140674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PCID2 scaffolds mutually exclusive subcomplexes with GANP, LENG8, and SAC3D1. LENG8 localizes to nuclear speckles and interacts extensively with mRNA processing factors. LENG8 depletion alters mRNA processing and polyadenylation site usage, indicating LENG8 acts upstream of the canonical TREX-2 complex in mRNA processing.\",\n      \"method\": \"Interactome characterization, subcellular localization (nuclear speckle), LENG8 depletion with mRNA processing and polyadenylation site usage readout\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interactome mapping plus localization and depletion phenotype, single lab, preprint not yet peer-reviewed\",\n      \"pmids\": [\"42039562\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The LENG8-PCID2-SEM1 (LENG8-PS) trimer is structurally and functionally equivalent to the GANP-PCID2-SEM1 trimer of TREX-2. Mutagenesis and transcriptomic data demonstrate that LENG8-PS, as the core of a PAXT-associated TREX-2-like module, competes with NPC-associated TREX-2 (GANP-PS) for UAP56-bound RNPs, directing them toward nuclear decay instead of export. Nuclear fate of polyadenylated RNPs is governed by the opposing actions of nucleoplasmic PAXT (containing LENG8-PS) and NPC-associated TREX-2.\",\n      \"method\": \"Mutagenesis, transcriptomics, structural equivalence assessment, competition assays between PAXT and TREX-2 modules\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus transcriptomics, preprint, single lab, mechanistically detailed but not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.16.676470\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"LENG8 is a conserved nuclear RNA quality-control factor that forms the REX/TREX-2.1 complex with PCID2 and SEM1, is recruited to pre-mRNAs via U1 snRNP and other splicing factors, acts as a dominant-negative competitor of the mRNA export factor TREX-2 to retain misprocessed and noncoding RNAs in the nucleus, and promotes their degradation by recruiting the PAXT adaptor and the RNA exosome, thereby ensuring only correctly processed RNAs are exported to the cytoplasm.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LENG8 is a conserved nuclear RNA quality-control factor that governs the fate of polyadenylated RNPs by directing misprocessed and noncoding transcripts toward nuclear retention and degradation rather than cytoplasmic export [#1]. It assembles with PCID2 and SEM1/DSS1 into a TREX-2-like trimer (variously termed REX or TREX-2.1) that is structurally and functionally equivalent to the canonical GANP-PCID2-SEM1 export complex, but acts as its dominant-negative counterpart: LENG8-PS competes with NPC-associated TREX-2 for UAP56(DDX39B)-bound RNPs and steers them to decay [#0, #1, #4]. Cryo-EM of the LENG8-containing complex bound to DDX39B revealed a conserved 'trigger loop' in LENG8, analogous to that of GANP, that is critical for regulating release of the DEAD-box ATPase from mRNPs [#0]. LENG8 is recruited to pre-mRNAs through direct interactions with early splicing factors including the U1 snRNP component U1A and with RRP1B, a feature that distinguishes the LENG8-PCID2 complex from the GANP export complex [#1, #2]. Having engaged these substrates, LENG8 couples them to the RNA exosome by recruiting the PAXT adaptor, and its loss causes cytoplasmic leakage of intronically polyadenylated, intron-retained, and noncoding RNAs [#1, #2]. This spliceosome-coupled mRNP decay pathway is evolutionarily conserved, with the yeast Thp3-Csn12 module performing the analogous coupling of splicing factors to the nuclear exosome [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"Established that LENG8 forms a defined nuclear trimeric complex and directly regulates the export ATPase DDX39B, answering how this previously uncharacterized factor engages the mRNA export machinery.\",\n      \"evidence\": \"Cryo-EM of the LENG8/PCID2/DSS1-DDX39B complex with functional mutagenesis of the LENG8 'trigger loop', plus LENG8 knockdown RNA-seq\",\n      \"pmids\": [\"40595470\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether trigger-loop activity promotes ATPase stimulation or RNP release was defined structurally but not in a reconstituted kinetic assay\",\n        \"The set of physiological RNA substrates whose DDX39B handling depends on LENG8 was not exhaustively mapped\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined LENG8 as a dominant-negative export antagonist and active degradation factor, resolving how it converts an export-like complex into a retention-and-decay machine.\",\n      \"evidence\": \"LENG8 depletion with transcriptomics, Co-IP, RNA nuclear retention assays and complex reconstitution identifying the REX (LENG8-PCID2-SEM1) complex, U1 snRNP recruitment, and PAXT/exosome coupling\",\n      \"pmids\": [\"41861815\", \"40832163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How LENG8 discriminates misprocessed from correctly processed transcripts at the molecular level is not resolved\",\n        \"The stoichiometry and dynamics of competition between LENG8-PS and GANP-PS in cells were not directly measured\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Mapped the direct splicing-factor contacts that recruit LENG8-PCID2 to early mRNPs and demonstrated evolutionary conservation, distinguishing the decay connector from the GANP export complex.\",\n      \"evidence\": \"Biochemical reconstitution, structural analysis and direct pulldown/Co-IP with U1A and RRP1B, plus characterization of the yeast Thp3-Csn12 ortholog pathway\",\n      \"pmids\": [\"42140674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The structural basis of U1A and RRP1B binding to LENG8-PCID2 was not determined at high resolution\",\n        \"How early spliceosome engagement is temporally coordinated with exosome recruitment is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed that PCID2 scaffolds mutually exclusive GANP, LENG8, and SAC3D1 subcomplexes and that LENG8 acts upstream in mRNA processing, framing how a shared scaffold partitions distinct nuclear RNA fates.\",\n      \"evidence\": \"Interactome characterization, nuclear speckle localization, and LENG8 depletion with mRNA processing and polyadenylation site-usage readout (preprint)\",\n      \"pmids\": [\"42039562\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint not yet peer-reviewed\",\n        \"Mechanism determining which PCID2 subcomplex assembles on a given transcript is unknown\",\n        \"The functional role of the SAC3D1-PCID2 subcomplex relative to LENG8 was not defined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided mechanistic detail that LENG8-PS and GANP-PS compete for the same UAP56-bound RNPs, establishing a competition model for nuclear RNA fate determination.\",\n      \"evidence\": \"Mutagenesis, transcriptomics and competition assays between PAXT-associated LENG8-PS and NPC-associated TREX-2 modules (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.16.676470\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint not yet peer-reviewed\",\n        \"The kinetic parameters governing the competition outcome were not quantified\",\n        \"How spatial separation (nucleoplasm vs NPC) biases the competition in vivo is not directly shown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LENG8 distinguishes correctly processed from aberrant transcripts and what controls the partitioning of substrates between export and decay remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No molecular discriminator of 'misprocessed' RNA defined\",\n        \"Regulation of LENG8-PS versus GANP-PS abundance and localization in different conditions is unknown\",\n        \"Physiological consequences of LENG8 loss at the organismal level not characterized in the corpus\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0016607\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [\n      \"REX/TREX-2.1 (LENG8-PCID2-SEM1/DSS1)\",\n      \"PAXT\",\n      \"nuclear RNA exosome\"\n    ],\n    \"partners\": [\n      \"PCID2\",\n      \"SEM1\",\n      \"DDX39B\",\n      \"U1A\",\n      \"RRP1B\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}