{"gene":"ELP2","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2000,"finding":"ELP2 encodes the 90-kDa WD40-repeat subunit of the yeast Elongator complex and elongating RNA polymerase II holoenzyme; deletion of ELP2 causes temperature and salt sensitivity, and genetic double/triple ELP deletions phenocopy single deletions, providing epistasis evidence that ELP subunits function together in one complex.","method":"Yeast genetics, protein biochemistry (Elongator complex purification), genetic epistasis with multiple ELP gene deletions","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — original discovery with biochemical complex purification plus genetic epistasis, foundational paper with >50 citations","pmids":["10777588"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of Elp2 reveals two seven-bladed WD40 β-propellers; structure-guided mutagenesis shows WD40 fold integrity is required for Elp2 binding to Elp1 and Elp3 subunits. Elp2 also binds microtubules in vitro and in vivo through conserved alkaline residues, and Elp2 mutations impair histone H3 acetylation activity of Elongator in vivo.","method":"X-ray crystallography, structure-guided mutagenesis, Co-IP/pulldown for Elp1/Elp3 binding, microtubule co-sedimentation assay, histone acetylation assay","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis plus multiple orthogonal biochemical assays in one study","pmids":["25960406"],"is_preprint":false},{"year":2021,"finding":"Biallelic ELP2 mutations reduce Elongator complex activity and impair tRNA modification, leading to perturbed protein homeostasis, impaired neurogenesis, myelin loss, and neurodegeneration; mouse models recapitulate microcephaly and white matter tract loss.","method":"Mouse knock-in models of patient variants, tRNA modification assays, brain MRI/tractography, neurogenesis assays, protein homeostasis analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (animal model, tRNA modification biochemistry, imaging) in a single rigorous study","pmids":["33976153"],"is_preprint":false},{"year":2011,"finding":"ELP2 (Elp2/StIP1) mediates 4-phenylbutyrate-induced Hsp70 expression in cystic fibrosis epithelial cells via STAT3 activation; Elp2 depletion reduces Hsp70 protein levels and blocks 4PBA-stimulated Hsp70 promoter activity, while Elp2 overexpression increases Hsp70 promoter activity.","method":"siRNA knockdown, luciferase reporter assay, Western blot, EMSA (nuclear STAT3-binding to Hsp70 promoter)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (siRNA, reporter assay, EMSA) but single lab","pmids":["22069317"],"is_preprint":false},{"year":2015,"finding":"STIP (ELP2) acts as a nuclear scaffold linking USP7 to the p53-Mdm2 pathway; STIP co-immunoprecipitates with USP7 and colocalizes in the nucleoplasm, and mediates assembly of separate ternary complexes STIP-USP7-Mdm2 and STIP-USP7-p53, facilitating USP7-dependent stabilization of both Mdm2 and p53.","method":"Co-immunoprecipitation, co-localization by immunofluorescence, overexpression and knockdown studies, Western blot for protein stability","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 — reciprocal Co-IP with functional follow-up (overexpression/KD effects on Mdm2/p53 levels), single lab","pmids":["26460617"],"is_preprint":false},{"year":2007,"finding":"STIP (ELP2 ortholog) localizes to the nucleus and forms large rod-like polymers in mammalian cells; deletion mutant mapping identified regions required for nuclear import and polymer assembly; RNAi knockdown in C. elegans causes embryonic lethality at ~16-cell stage, rescued by Drosophila and human transgenes, demonstrating conserved essential nuclear function.","method":"Reporter constructs, deletion mutant analysis, RNAi knockdown in C. elegans, transgenic rescue with Drosophila/human genes, Western blot","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic rescue across species and deletion mapping, but single lab","pmids":["17289020"],"is_preprint":false},{"year":2016,"finding":"STIP (ELP2) interacts with PP1γ (protein phosphatase 1 gamma) and suppresses its phosphatase activity, leading to hyper-activation of ERK1/2 signaling; STIP knockdown reduces p-ERK1/2 levels in a phosphatase-dependent manner.","method":"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, phosphatase inhibitor (Calyculin A) rescue experiments, Western blot","journal":"Current molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 — Co-IP and functional rescue but single lab, single study with limited mechanistic depth","pmids":["27758712"],"is_preprint":false},{"year":2023,"finding":"ELP2 associates with STAT3 and NLRP3 as shown by co-immunoprecipitation; forced ELP2 expression promotes NLRP3 inflammasome activation, caspase-dependent pyroptosis (via GSDMD/GSDME), and osteoblast differentiation inhibition in response to TNF-α.","method":"Co-immunoprecipitation, protein docking model, siRNA knockdown, overexpression, Western blot for NLRP3/GSDMD/GSDME","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 — Co-IP with functional follow-up but single lab, relies partly on computational docking","pmids":["37830762"],"is_preprint":false}],"current_model":"ELP2 is the WD40-repeat scaffold subunit of the Elongator complex, whose two seven-bladed β-propeller domains mediate binding to Elp1 and Elp3 (forming the catalytic core), support complex-dependent histone H3 acetylation, enable cytoskeletal association via microtubule binding, and are required for tRNA wobble-base modification that ensures proper translation; beyond Elongator, ELP2/STIP also functions as a nuclear scaffold assembling USP7–Mdm2 and USP7–p53 complexes and modulates STAT3 and ERK1/2 signaling through interactions with STAT3 and PP1γ."},"narrative":{"teleology":[{"year":2000,"claim":"Identifying ELP2 as a subunit of the Elongator complex established it as a WD40-repeat protein required for RNA Pol II-associated transcription elongation, with genetic epistasis proving all ELP subunits act in a single functional unit.","evidence":"Yeast Elongator complex purification, ELP2 deletion phenotyping, and genetic epistasis analysis with multiple ELP deletions","pmids":["10777588"],"confidence":"High","gaps":["No structural information on how Elp2 contacts other Elongator subunits","Elongator's catalytic activities beyond transcription elongation were unknown","Metazoan relevance not established"]},{"year":2007,"claim":"Demonstrating that the mammalian ELP2 ortholog (STIP) localizes to the nucleus, forms polymeric structures, and is essential for early embryonic viability across species established a conserved nuclear function beyond yeast transcription elongation.","evidence":"Deletion mutant mapping in mammalian cells, RNAi knockdown in C. elegans causing embryonic lethality, cross-species transgenic rescue with Drosophila and human genes","pmids":["17289020"],"confidence":"Medium","gaps":["The molecular function of the rod-like polymers was not determined","Relationship to Elongator complex activity in metazoans was not addressed"]},{"year":2011,"claim":"Showing that ELP2/STIP mediates STAT3-dependent Hsp70 induction revealed an Elongator-independent signaling role, linking ELP2 to stress-responsive gene activation in mammalian epithelial cells.","evidence":"siRNA knockdown, Hsp70 promoter-luciferase reporter, EMSA for STAT3 binding in cystic fibrosis epithelial cells","pmids":["22069317"],"confidence":"Medium","gaps":["Whether ELP2–STAT3 interaction is direct or mediated through the Elongator complex was not resolved","Relevance to non-epithelial cell types not tested"]},{"year":2015,"claim":"The crystal structure of Elp2 revealed a dual seven-bladed β-propeller architecture and showed that WD40 fold integrity is required for binding Elp1 and Elp3, for microtubule association, and for Elongator-dependent histone H3 acetylation, establishing Elp2 as the structural hub of the complex.","evidence":"X-ray crystallography of yeast Elp2, structure-guided mutagenesis, Co-IP/pulldown for Elp1/Elp3, microtubule co-sedimentation, in vivo histone H3 acetylation assays","pmids":["25960406"],"confidence":"High","gaps":["Structural basis of microtubule binding at atomic resolution was not defined","How histone acetylation and tRNA modification activities are coordinated through Elp2 was unresolved"]},{"year":2015,"claim":"Identification of ELP2/STIP as a nuclear scaffold assembling USP7–Mdm2 and USP7–p53 ternary complexes revealed a mechanism by which ELP2 modulates p53 pathway protein stability independent of Elongator.","evidence":"Reciprocal Co-IP, immunofluorescence co-localization, overexpression and knockdown effects on Mdm2 and p53 protein levels","pmids":["26460617"],"confidence":"Medium","gaps":["Whether ELP2 binds USP7 directly or through intermediary proteins was not conclusively mapped","Physiological significance for tumorigenesis not tested in vivo"]},{"year":2016,"claim":"Demonstration that ELP2/STIP interacts with PP1γ and suppresses its phosphatase activity, leading to ERK1/2 hyper-activation, identified a phosphatase-regulatory mechanism for ELP2-mediated MAPK signaling.","evidence":"Co-IP, siRNA knockdown, phosphatase inhibitor rescue with Calyculin A, Western blot for p-ERK1/2","pmids":["27758712"],"confidence":"Low","gaps":["Single-lab finding with limited mechanistic depth; not independently confirmed","Direct binding between ELP2 and PP1γ not demonstrated with purified proteins","Relationship to Elongator complex function not addressed"]},{"year":2021,"claim":"Mouse knock-in models of patient ELP2 mutations established that biallelic ELP2 loss-of-function causes impaired tRNA modification, perturbed protein homeostasis, defective neurogenesis, and white matter degeneration, defining a human neurodevelopmental disease mechanism.","evidence":"Mouse knock-in models, tRNA modification assays, brain MRI/tractography, neurogenesis and protein homeostasis analyses","pmids":["33976153"],"confidence":"High","gaps":["Whether non-neuronal tissues are affected in patients was not systematically examined","Relative contributions of tRNA modification defects versus histone acetylation defects to pathology remain unresolved"]},{"year":2023,"claim":"Showing that ELP2 associates with STAT3 and NLRP3 to promote inflammasome activation and pyroptosis extended ELP2's signaling role to innate immune regulation, though the mechanistic basis remains preliminary.","evidence":"Co-IP, overexpression and siRNA knockdown, Western blot for NLRP3/GSDMD/GSDME in osteoblast-lineage cells treated with TNF-α","pmids":["37830762"],"confidence":"Low","gaps":["Reliance on computational docking without direct binding validation with purified proteins","Single-lab study in one cell type; generalizability unknown","Relationship between Elongator tRNA modification function and inflammasome activation not addressed"]},{"year":null,"claim":"How ELP2's Elongator-dependent functions (tRNA modification, histone acetylation) and Elongator-independent scaffolding functions (USP7–p53/Mdm2, STAT3, PP1γ) are coordinated or compartmentalized in cells remains unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No study has examined whether distinct ELP2 pools exist for Elongator versus non-Elongator functions","No high-resolution structure of ELP2 in complex with USP7, STAT3, or PP1γ","Tissue-specific contributions of ELP2's dual roles to neurodevelopmental disease pathology are undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,6]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,5]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4]}],"complexes":["Elongator complex"],"partners":["ELP1","ELP3","USP7","MDM2","TP53","STAT3","PPP1CC"],"other_free_text":[]},"mechanistic_narrative":"ELP2 is the WD40-repeat scaffold subunit of the Elongator complex, serving as a structural bridge between the Elp1 and Elp3 catalytic subunits to support tRNA wobble-base modification, histone H3 acetylation, and cytoskeletal association through microtubule binding [PMID:10777588, PMID:25960406]. Its two seven-bladed β-propeller domains are essential for Elongator integrity, and structure-guided mutations that disrupt WD40 fold integrity abolish subunit interactions and complex activity [PMID:25960406]. Biallelic ELP2 mutations cause a neurodevelopmental syndrome characterized by microcephaly, white matter loss, and neurodegeneration, driven by impaired tRNA modification and perturbed protein homeostasis [PMID:33976153]. Outside Elongator, ELP2 (also called STIP) functions as a nuclear scaffold that assembles USP7–Mdm2 and USP7–p53 ternary complexes to regulate protein stability and interacts with STAT3 to modulate Hsp70 expression [PMID:26460617, PMID:22069317]."},"prefetch_data":{"uniprot":{"accession":"Q6IA86","full_name":"Elongator complex protein 2","aliases":["SHINC-2","STAT3-interacting protein 1","StIP1"],"length_aa":826,"mass_kda":92.5,"function":"Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine) (PubMed:29332244). The elongator complex catalyzes the formation of carboxymethyluridine in the wobble base at position 34 in tRNAs (PubMed:29332244)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6IA86/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ELP2","classification":"Common Essential","n_dependent_lines":859,"n_total_lines":1208,"dependency_fraction":0.7110927152317881},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"FKBP5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ELP2","total_profiled":1310},"omim":[{"mim_id":"617270","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 58; MRT58","url":"https://www.omim.org/entry/617270"},{"mim_id":"616054","title":"ELONGATOR ACETYLTRANSFERASE COMPLEX, SUBUNIT 2; ELP2","url":"https://www.omim.org/entry/616054"},{"mim_id":"612722","title":"ELONGATOR ACETYLTRANSFERASE COMPLEX, SUBUNIT 3; ELP3","url":"https://www.omim.org/entry/612722"},{"mim_id":"603722","title":"ELONGATOR COMPLEX PROTEIN 1; ELP1","url":"https://www.omim.org/entry/603722"},{"mim_id":"184757","title":"NUCLEAR RECEPTOR SUBFAMILY 5, GROUP A, MEMBER 1; NR5A1","url":"https://www.omim.org/entry/184757"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ELP2"},"hgnc":{"alias_symbol":["FLJ10879","StIP"],"prev_symbol":["STATIP1"]},"alphafold":{"accession":"Q6IA86","domains":[{"cath_id":"2.130.10.10","chopping":"18-157","consensus_level":"medium","plddt":92.9946,"start":18,"end":157},{"cath_id":"2.130.10.10","chopping":"392-511_536-792_801-823","consensus_level":"medium","plddt":90.7364,"start":392,"end":823},{"cath_id":"2.40.128","chopping":"293-373","consensus_level":"medium","plddt":91.9863,"start":293,"end":373}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6IA86","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6IA86-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6IA86-F1-predicted_aligned_error_v6.png","plddt_mean":89.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ELP2","jax_strain_url":"https://www.jax.org/strain/search?query=ELP2"},"sequence":{"accession":"Q6IA86","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6IA86.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6IA86/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6IA86"}},"corpus_meta":[{"pmid":"25847581","id":"PMC_25847581","title":"ELP2 is a novel gene implicated in neurodevelopmental disabilities.","date":"2015","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/25847581","citation_count":66,"is_preprint":false},{"pmid":"10777588","id":"PMC_10777588","title":"The Elp2 subunit of elongator and elongating RNA polymerase II holoenzyme is a WD40 repeat protein.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10777588","citation_count":57,"is_preprint":false},{"pmid":"22069317","id":"PMC_22069317","title":"4-Phenylbutyrate stimulates Hsp70 expression through the Elp2 component of elongator and STAT-3 in cystic fibrosis epithelial cells.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22069317","citation_count":45,"is_preprint":false},{"pmid":"33976153","id":"PMC_33976153","title":"Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype.","date":"2021","source":"Nature 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physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30847950","citation_count":13,"is_preprint":false},{"pmid":"29723529","id":"PMC_29723529","title":"Suppression of Elp2 prevents renal fibrosis and inflammation induced by unilateral ureter obstruction (UUO) via inactivating Stat3-regulated TGF-β1 and NF-κB pathways.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29723529","citation_count":12,"is_preprint":false},{"pmid":"37830762","id":"PMC_37830762","title":"ELP2-NLRP3-GSDMD/GSDME-mediated pyroptosis is induced by TNF-α in MC3T3-E1 cells during osteogenic differentiation.","date":"2023","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37830762","citation_count":12,"is_preprint":false},{"pmid":"26460617","id":"PMC_26460617","title":"STIP is a critical nuclear scaffolding protein linking USP7 to p53-Mdm2 pathway regulation.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26460617","citation_count":10,"is_preprint":false},{"pmid":"17289020","id":"PMC_17289020","title":"Characterization of STIP, a multi-domain nuclear protein, highly conserved in metazoans, and essential for embryogenesis in Caenorhabditis elegans.","date":"2007","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/17289020","citation_count":10,"is_preprint":false},{"pmid":"18652829","id":"PMC_18652829","title":"Involvement of non-conserved residues important for PGE2 binding to the constrained EP3 eLP2 using NMR and site-directed mutagenesis.","date":"2008","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/18652829","citation_count":9,"is_preprint":false},{"pmid":"33813722","id":"PMC_33813722","title":"HACE1, GLRX5, and ELP2 gene variant cause spastic paraplegies.","date":"2021","source":"Acta neurologica Belgica","url":"https://pubmed.ncbi.nlm.nih.gov/33813722","citation_count":7,"is_preprint":false},{"pmid":"25417721","id":"PMC_25417721","title":"Inhibition of STAT3-interacting protein 1 (STATIP1) promotes STAT3 transcriptional up-regulation and imatinib mesylate resistance in the chronic myeloid leukemia.","date":"2014","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25417721","citation_count":7,"is_preprint":false},{"pmid":"26354852","id":"PMC_26354852","title":"STIP overexpression confers oncogenic potential to human non-small cell lung cancer cells by regulating cell cycle and apoptosis.","date":"2015","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26354852","citation_count":7,"is_preprint":false},{"pmid":"36149055","id":"PMC_36149055","title":"Pivotal role of STIP in ovule pattern formation and female germline development in Arabidopsis thaliana.","date":"2022","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/36149055","citation_count":5,"is_preprint":false},{"pmid":"33510603","id":"PMC_33510603","title":"A Novel ELP2 Compound Heterozygous Mutation in a Boy with Severe Intellectual Disability, Spastic Diplegia, Stereotypic Behavior and Review of the Current Literature.","date":"2020","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/33510603","citation_count":5,"is_preprint":false},{"pmid":"32493705","id":"PMC_32493705","title":"Novel Variants of ELP2 and PIAS1 in the Interferon Gamma Signaling Pathway Are Associated with Non-Small Cell Lung Cancer Survival.","date":"2020","source":"Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32493705","citation_count":5,"is_preprint":false},{"pmid":"34653680","id":"PMC_34653680","title":"ELP2 compound heterozygous variants associated with cortico-cerebellar atrophy, nodular heterotopia and epilepsy: Phenotype expansion and review of the literature.","date":"2021","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34653680","citation_count":4,"is_preprint":false},{"pmid":"33393008","id":"PMC_33393008","title":"Clinical and molecular findings in a Turkish family with an ultra-rare condition, ELP2-related neurodevelopmental disorder.","date":"2021","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/33393008","citation_count":4,"is_preprint":false},{"pmid":"24206355","id":"PMC_24206355","title":"Acinetobacter baylyi long-term stationary-phase protein StiP is a protease required for normal cell morphology and resistance to tellurite.","date":"2013","source":"Canadian journal of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/24206355","citation_count":4,"is_preprint":false},{"pmid":"27758712","id":"PMC_27758712","title":"STIP Regulates ERK1/2 Signaling Pathway Involved in Interaction with PP1γ in Lymphoblastic Leukemia.","date":"2016","source":"Current molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27758712","citation_count":1,"is_preprint":false},{"pmid":"41371317","id":"PMC_41371317","title":"Salmonella Typhimurium StiP-mediated upregulation of membrane protein Alx drives complement evasion via CFI-dependent C3b degradation.","date":"2025","source":"Microbial pathogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/41371317","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12240,"output_tokens":2044,"usd":0.03369},"stage2":{"model":"claude-opus-4-6","input_tokens":5339,"output_tokens":2545,"usd":0.13548},"total_usd":0.16917,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"ELP2 encodes the 90-kDa WD40-repeat subunit of the yeast Elongator complex and elongating RNA polymerase II holoenzyme; deletion of ELP2 causes temperature and salt sensitivity, and genetic double/triple ELP deletions phenocopy single deletions, providing epistasis evidence that ELP subunits function together in one complex.\",\n      \"method\": \"Yeast genetics, protein biochemistry (Elongator complex purification), genetic epistasis with multiple ELP gene deletions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original discovery with biochemical complex purification plus genetic epistasis, foundational paper with >50 citations\",\n      \"pmids\": [\"10777588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of Elp2 reveals two seven-bladed WD40 β-propellers; structure-guided mutagenesis shows WD40 fold integrity is required for Elp2 binding to Elp1 and Elp3 subunits. Elp2 also binds microtubules in vitro and in vivo through conserved alkaline residues, and Elp2 mutations impair histone H3 acetylation activity of Elongator in vivo.\",\n      \"method\": \"X-ray crystallography, structure-guided mutagenesis, Co-IP/pulldown for Elp1/Elp3 binding, microtubule co-sedimentation assay, histone acetylation assay\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis plus multiple orthogonal biochemical assays in one study\",\n      \"pmids\": [\"25960406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Biallelic ELP2 mutations reduce Elongator complex activity and impair tRNA modification, leading to perturbed protein homeostasis, impaired neurogenesis, myelin loss, and neurodegeneration; mouse models recapitulate microcephaly and white matter tract loss.\",\n      \"method\": \"Mouse knock-in models of patient variants, tRNA modification assays, brain MRI/tractography, neurogenesis assays, protein homeostasis analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (animal model, tRNA modification biochemistry, imaging) in a single rigorous study\",\n      \"pmids\": [\"33976153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ELP2 (Elp2/StIP1) mediates 4-phenylbutyrate-induced Hsp70 expression in cystic fibrosis epithelial cells via STAT3 activation; Elp2 depletion reduces Hsp70 protein levels and blocks 4PBA-stimulated Hsp70 promoter activity, while Elp2 overexpression increases Hsp70 promoter activity.\",\n      \"method\": \"siRNA knockdown, luciferase reporter assay, Western blot, EMSA (nuclear STAT3-binding to Hsp70 promoter)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (siRNA, reporter assay, EMSA) but single lab\",\n      \"pmids\": [\"22069317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"STIP (ELP2) acts as a nuclear scaffold linking USP7 to the p53-Mdm2 pathway; STIP co-immunoprecipitates with USP7 and colocalizes in the nucleoplasm, and mediates assembly of separate ternary complexes STIP-USP7-Mdm2 and STIP-USP7-p53, facilitating USP7-dependent stabilization of both Mdm2 and p53.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by immunofluorescence, overexpression and knockdown studies, Western blot for protein stability\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reciprocal Co-IP with functional follow-up (overexpression/KD effects on Mdm2/p53 levels), single lab\",\n      \"pmids\": [\"26460617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"STIP (ELP2 ortholog) localizes to the nucleus and forms large rod-like polymers in mammalian cells; deletion mutant mapping identified regions required for nuclear import and polymer assembly; RNAi knockdown in C. elegans causes embryonic lethality at ~16-cell stage, rescued by Drosophila and human transgenes, demonstrating conserved essential nuclear function.\",\n      \"method\": \"Reporter constructs, deletion mutant analysis, RNAi knockdown in C. elegans, transgenic rescue with Drosophila/human genes, Western blot\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic rescue across species and deletion mapping, but single lab\",\n      \"pmids\": [\"17289020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"STIP (ELP2) interacts with PP1γ (protein phosphatase 1 gamma) and suppresses its phosphatase activity, leading to hyper-activation of ERK1/2 signaling; STIP knockdown reduces p-ERK1/2 levels in a phosphatase-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, phosphatase inhibitor (Calyculin A) rescue experiments, Western blot\",\n      \"journal\": \"Current molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and functional rescue but single lab, single study with limited mechanistic depth\",\n      \"pmids\": [\"27758712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ELP2 associates with STAT3 and NLRP3 as shown by co-immunoprecipitation; forced ELP2 expression promotes NLRP3 inflammasome activation, caspase-dependent pyroptosis (via GSDMD/GSDME), and osteoblast differentiation inhibition in response to TNF-α.\",\n      \"method\": \"Co-immunoprecipitation, protein docking model, siRNA knockdown, overexpression, Western blot for NLRP3/GSDMD/GSDME\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with functional follow-up but single lab, relies partly on computational docking\",\n      \"pmids\": [\"37830762\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ELP2 is the WD40-repeat scaffold subunit of the Elongator complex, whose two seven-bladed β-propeller domains mediate binding to Elp1 and Elp3 (forming the catalytic core), support complex-dependent histone H3 acetylation, enable cytoskeletal association via microtubule binding, and are required for tRNA wobble-base modification that ensures proper translation; beyond Elongator, ELP2/STIP also functions as a nuclear scaffold assembling USP7–Mdm2 and USP7–p53 complexes and modulates STAT3 and ERK1/2 signaling through interactions with STAT3 and PP1γ.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ELP2 is the WD40-repeat scaffold subunit of the Elongator complex, serving as a structural bridge between the Elp1 and Elp3 catalytic subunits to support tRNA wobble-base modification, histone H3 acetylation, and cytoskeletal association through microtubule binding [PMID:10777588, PMID:25960406]. Its two seven-bladed β-propeller domains are essential for Elongator integrity, and structure-guided mutations that disrupt WD40 fold integrity abolish subunit interactions and complex activity [PMID:25960406]. Biallelic ELP2 mutations cause a neurodevelopmental syndrome characterized by microcephaly, white matter loss, and neurodegeneration, driven by impaired tRNA modification and perturbed protein homeostasis [PMID:33976153]. Outside Elongator, ELP2 (also called STIP) functions as a nuclear scaffold that assembles USP7–Mdm2 and USP7–p53 ternary complexes to regulate protein stability and interacts with STAT3 to modulate Hsp70 expression [PMID:26460617, PMID:22069317].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying ELP2 as a subunit of the Elongator complex established it as a WD40-repeat protein required for RNA Pol II-associated transcription elongation, with genetic epistasis proving all ELP subunits act in a single functional unit.\",\n      \"evidence\": \"Yeast Elongator complex purification, ELP2 deletion phenotyping, and genetic epistasis analysis with multiple ELP deletions\",\n      \"pmids\": [\"10777588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural information on how Elp2 contacts other Elongator subunits\",\n        \"Elongator's catalytic activities beyond transcription elongation were unknown\",\n        \"Metazoan relevance not established\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that the mammalian ELP2 ortholog (STIP) localizes to the nucleus, forms polymeric structures, and is essential for early embryonic viability across species established a conserved nuclear function beyond yeast transcription elongation.\",\n      \"evidence\": \"Deletion mutant mapping in mammalian cells, RNAi knockdown in C. elegans causing embryonic lethality, cross-species transgenic rescue with Drosophila and human genes\",\n      \"pmids\": [\"17289020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The molecular function of the rod-like polymers was not determined\",\n        \"Relationship to Elongator complex activity in metazoans was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showing that ELP2/STIP mediates STAT3-dependent Hsp70 induction revealed an Elongator-independent signaling role, linking ELP2 to stress-responsive gene activation in mammalian epithelial cells.\",\n      \"evidence\": \"siRNA knockdown, Hsp70 promoter-luciferase reporter, EMSA for STAT3 binding in cystic fibrosis epithelial cells\",\n      \"pmids\": [\"22069317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ELP2–STAT3 interaction is direct or mediated through the Elongator complex was not resolved\",\n        \"Relevance to non-epithelial cell types not tested\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The crystal structure of Elp2 revealed a dual seven-bladed β-propeller architecture and showed that WD40 fold integrity is required for binding Elp1 and Elp3, for microtubule association, and for Elongator-dependent histone H3 acetylation, establishing Elp2 as the structural hub of the complex.\",\n      \"evidence\": \"X-ray crystallography of yeast Elp2, structure-guided mutagenesis, Co-IP/pulldown for Elp1/Elp3, microtubule co-sedimentation, in vivo histone H3 acetylation assays\",\n      \"pmids\": [\"25960406\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of microtubule binding at atomic resolution was not defined\",\n        \"How histone acetylation and tRNA modification activities are coordinated through Elp2 was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of ELP2/STIP as a nuclear scaffold assembling USP7–Mdm2 and USP7–p53 ternary complexes revealed a mechanism by which ELP2 modulates p53 pathway protein stability independent of Elongator.\",\n      \"evidence\": \"Reciprocal Co-IP, immunofluorescence co-localization, overexpression and knockdown effects on Mdm2 and p53 protein levels\",\n      \"pmids\": [\"26460617\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ELP2 binds USP7 directly or through intermediary proteins was not conclusively mapped\",\n        \"Physiological significance for tumorigenesis not tested in vivo\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstration that ELP2/STIP interacts with PP1γ and suppresses its phosphatase activity, leading to ERK1/2 hyper-activation, identified a phosphatase-regulatory mechanism for ELP2-mediated MAPK signaling.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, phosphatase inhibitor rescue with Calyculin A, Western blot for p-ERK1/2\",\n      \"pmids\": [\"27758712\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single-lab finding with limited mechanistic depth; not independently confirmed\",\n        \"Direct binding between ELP2 and PP1γ not demonstrated with purified proteins\",\n        \"Relationship to Elongator complex function not addressed\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mouse knock-in models of patient ELP2 mutations established that biallelic ELP2 loss-of-function causes impaired tRNA modification, perturbed protein homeostasis, defective neurogenesis, and white matter degeneration, defining a human neurodevelopmental disease mechanism.\",\n      \"evidence\": \"Mouse knock-in models, tRNA modification assays, brain MRI/tractography, neurogenesis and protein homeostasis analyses\",\n      \"pmids\": [\"33976153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether non-neuronal tissues are affected in patients was not systematically examined\",\n        \"Relative contributions of tRNA modification defects versus histone acetylation defects to pathology remain unresolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that ELP2 associates with STAT3 and NLRP3 to promote inflammasome activation and pyroptosis extended ELP2's signaling role to innate immune regulation, though the mechanistic basis remains preliminary.\",\n      \"evidence\": \"Co-IP, overexpression and siRNA knockdown, Western blot for NLRP3/GSDMD/GSDME in osteoblast-lineage cells treated with TNF-α\",\n      \"pmids\": [\"37830762\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Reliance on computational docking without direct binding validation with purified proteins\",\n        \"Single-lab study in one cell type; generalizability unknown\",\n        \"Relationship between Elongator tRNA modification function and inflammasome activation not addressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ELP2's Elongator-dependent functions (tRNA modification, histone acetylation) and Elongator-independent scaffolding functions (USP7–p53/Mdm2, STAT3, PP1γ) are coordinated or compartmentalized in cells remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No study has examined whether distinct ELP2 pools exist for Elongator versus non-Elongator functions\",\n        \"No high-resolution structure of ELP2 in complex with USP7, STAT3, or PP1γ\",\n        \"Tissue-specific contributions of ELP2's dual roles to neurodevelopmental disease pathology are undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [\n      \"Elongator complex\"\n    ],\n    \"partners\": [\n      \"ELP1\",\n      \"ELP3\",\n      \"USP7\",\n      \"MDM2\",\n      \"TP53\",\n      \"STAT3\",\n      \"PPP1CC\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}