{"gene":"TRIP4","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2020,"finding":"The ASC-1 complex (ASCC), containing the ASCC3 helicase, disassembles the leading (stalled) ribosome in collided polysomes in an ATP-dependent reaction. Disassembly requires prior 40S ubiquitination by ZNF598 but does not require GTP-dependent factors such as the Pelo-Hbs1L complex. TRIP4 is a subunit of this ASCC complex.","method":"Mammalian cell-free reconstitution of collided polysome disassembly, biochemical fractionation, dominant-negative and depletion experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with multiple orthogonal biochemical validations in a single rigorous study","pmids":["32579943"],"is_preprint":false},{"year":2023,"finding":"The ASC-1 complex (ASCC), through its ASCC3 helicase subunit, associates with scanning (43S preinitiation complex) ribosomes at 5' UTRs and promotes translation initiation for a specific subset of mRNAs, distinct from its role in collided ribosome disassembly.","method":"TCP-seq (selective translation complex profiling), Ribo-seq, luciferase reporter assays, ASCC3 knockdown","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal genome-wide and reporter methods in single study with clear mechanistic interpretation","pmids":["37092320"],"is_preprint":false},{"year":2018,"finding":"All four ALS-causative RNA/DNA binding proteins (FUS, EWSR1, TAF15, MATR3) are required for association of the ASC-1 transcriptional coactivator complex (containing TRIP4) with the RNAP II/U1 snRNP machinery; an SMA-causative mutation in an ASC-1 component or an ALS-causative FUS mutation disrupts this association.","method":"CRISPR knockout of ALS-causative proteins, mass spectrometry interactome, co-immunoprecipitation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and MS interactome with genetic perturbation across multiple ALS-causative proteins","pmids":["30398641"],"is_preprint":false},{"year":2016,"finding":"TRIP4 (ASC-1) is required for late myogenic differentiation; its depletion in C2C12 cells and patient-derived muscle cells causes a significant reduction in myotube diameter without affecting fusion index or early myogenic differentiation markers, identifying a role in myotube growth.","method":"shRNA knockdown in C2C12 cells, patient-derived muscle cell culture, myotube diameter measurement, Western blot for differentiation markers","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — clean KO/KD with defined cellular phenotype replicated in both patient-derived cells and mouse C2C12 cells","pmids":["27008887"],"is_preprint":false},{"year":2019,"finding":"ASC-1 (TRIP4) depletion in C2C12 cells and patient-derived fibroblasts and muscles causes accelerated proliferation, altered expression of cell cycle proteins, and shortening of the G0/G1 cell cycle phase, leading to cell size reduction, establishing TRIP4 as a novel cell cycle regulator.","method":"FACS cell cycle analysis, Western blot for cell cycle proteins, Trip4 knockdown in C2C12 cells and patient-derived cells","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (FACS, Western blot) in both patient-derived and mouse model cells","pmids":["31794073"],"is_preprint":false},{"year":2008,"finding":"The ASC-1 complex (containing TRIP4/p50 and a p65 subunit) binds a specific response element in the PAI-2 promoter and mediates gastrin-induced PAI-2 transcription via IL-8 paracrine signaling; RNAi knockdown of both subunits inhibits PAI-2 induction.","method":"Yeast one-hybrid screening, promoter mutational analysis, RNAi knockdown, reporter assays","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 — yeast one-hybrid and RNAi with reporter assay, single lab","pmids":["19074642"],"is_preprint":false},{"year":2017,"finding":"TRIP4 promotes melanoma cell growth by modulating COX-2 and iNOS expression, partially by activating NF-κB signaling indirectly and partially by directly anchoring at COX-2 and iNOS promoters in synergy with p300 transcriptional coactivator.","method":"ChIP assay demonstrating TRIP4 promoter binding, siRNA knockdown, co-immunoprecipitation with p300, in vivo xenograft","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and Co-IP with functional knockdown in vitro and in vivo, single lab","pmids":["28899685"],"is_preprint":false},{"year":2021,"finding":"TRIP4 functions as a transcriptional activator that directly binds the promoter region of DDIT4 (positions −196 to −11), activating its transcription and thereby promoting mTOR signaling in glioma; this regulation is influenced by HIF1α.","method":"ChIP assay, promoter deletion/reporter assay, siRNA knockdown, rescue experiments with DDIT4 overexpression, in vivo xenograft","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP with promoter reporter and rescue experiments, single lab","pmids":["34648907"],"is_preprint":false},{"year":2025,"finding":"The E3 ubiquitin ligase RNF25 directly binds TRIP4 and catalyzes its non-degradative ubiquitination at lysine 135, which disrupts TRIP4-p65 interactions, liberating p65 to activate NF-κB signaling and upregulate anti-apoptotic effectors (cIAP2, Bcl-2) in renal cell carcinoma.","method":"Co-immunoprecipitation, site-directed mutagenesis (K135 ubiquitination site), Western blot, loss-of-function and rescue experiments","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with mutagenesis of modification site and functional consequence, single lab","pmids":["40765826"],"is_preprint":false},{"year":2024,"finding":"The C-terminal ASCH domain of human TRIP4 binds ssDNA and dsDNA in a sequence-independent manner through two adjacent positively charged surface patches that contact the 5'-end and 3'-end of DNA respectively; key residues were confirmed by mutagenesis.","method":"Crystal structure determination, biochemical binding assays, site-directed mutagenesis","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with mutagenesis and binding assays in a single study","pmids":["38870938"],"is_preprint":false},{"year":2025,"finding":"TRIP4 binds to a specific region of the GATA2 promoter and directly activates GATA2 transcription in cervical cancer cells; GATA2 overexpression rescues the inhibitory effects of TRIP4 knockdown on cervical cancer cell growth and radiation sensitivity.","method":"ChIP assay, pulldown assay, RNA sequencing of TRIP4 knockdown cells, rescue experiments, Western blot","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and pulldown with RNA-seq identification and functional rescue, single lab","pmids":["40180167"],"is_preprint":false},{"year":2024,"finding":"The ASC-1 complex splits stalled ribosomes (60S RNCs), which then associate with NEMF that recruits the E3 ligase Listerin to ubiquitinate nascent chains; TCF25 imposes K48-specificity on this ubiquitination by binding the Listerin RING domain and orienting the acceptor ubiquitin.","method":"Biochemical reconstitution, AlphaFold3 modeling, functional ubiquitination assays with mutant proteins","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 — reconstitution with structural modeling, but preprint and TRIP4/ASCC role is upstream context for this study","pmids":["bio_10.1101_2024.10.17.618946"],"is_preprint":true}],"current_model":"TRIP4 is the core subunit of the tetrameric ASC-1 (ASCC) complex, which functions mechanistically in: (1) ATP-dependent disassembly of collided (stalled) ribosomes during ribosome-associated quality control, requiring prior ZNF598-mediated 40S ubiquitination; (2) promotion of translation initiation by associating with scanning 43S preinitiation complexes at 5' UTRs of a subset of mRNAs; (3) transcriptional coactivation by binding promoter elements of specific target genes (PAI-2, DDIT4, GATA2, COX-2/iNOS) directly or in complex with p300; (4) regulation of cell cycle progression and myotube growth in skeletal muscle; and (5) modulation of NF-κB signaling through non-degradative ubiquitination at K135 by RNF25, which disrupts its interaction with p65."},"narrative":{"teleology":[{"year":2008,"claim":"Establishing TRIP4 as a promoter-binding transcriptional coactivator: the ASC-1 complex was shown to bind a specific response element in the PAI-2 promoter and mediate gastrin-induced transcription, demonstrating that TRIP4 functions directly at gene promoters rather than solely as a nuclear receptor coactivator.","evidence":"Yeast one-hybrid screening, promoter mutational analysis, RNAi knockdown, and reporter assays in gastric cells","pmids":["19074642"],"confidence":"Medium","gaps":["Single target gene; generalizability of promoter-binding was unknown","Mechanism of TRIP4 recruitment to specific promoter elements not defined","Contribution of individual ASC-1 subunits to DNA binding not resolved"]},{"year":2016,"claim":"Linking TRIP4 to muscle cell differentiation: TRIP4 depletion reduced myotube diameter without affecting fusion or early differentiation, establishing a specific role for TRIP4 in late myogenic differentiation and myotube growth.","evidence":"shRNA knockdown in C2C12 and patient-derived muscle cells with myotube morphometry","pmids":["27008887"],"confidence":"High","gaps":["Transcriptional targets mediating the myotube growth phenotype not identified","Whether the ASCC complex or TRIP4 alone drives this function was unclear"]},{"year":2017,"claim":"Demonstrating TRIP4 occupancy at inflammatory gene promoters: ChIP showed TRIP4 directly anchors at COX-2 and iNOS promoters in synergy with p300, linking TRIP4 transcriptional coactivation to NF-κB-dependent gene expression in melanoma.","evidence":"ChIP assay, Co-IP with p300, siRNA knockdown, and xenograft models in melanoma cells","pmids":["28899685"],"confidence":"Medium","gaps":["Whether TRIP4 contacts DNA directly or is recruited via p300/other factors was unresolved","Structural basis for promoter selectivity unknown"]},{"year":2018,"claim":"Connecting the ASC-1 complex to the RNAP II/U1 snRNP machinery: all four ALS-causative RNA/DNA-binding proteins were required for ASC-1 association with RNAP II, and disease mutations disrupted this interaction, placing TRIP4 at the intersection of transcription and neurodegenerative disease pathways.","evidence":"CRISPR knockout, mass spectrometry interactome, and reciprocal Co-IP in human cells","pmids":["30398641"],"confidence":"High","gaps":["Functional consequence of lost RNAP II association on specific transcripts not determined","Direct versus indirect bridging by ALS proteins not resolved"]},{"year":2019,"claim":"Identifying TRIP4 as a cell cycle regulator: TRIP4 depletion shortened G0/G1, accelerated proliferation, and reduced cell size, revealing a function in cell cycle control distinct from its transcriptional coactivation of specific genes.","evidence":"FACS cell cycle analysis and Western blot for cell cycle proteins in C2C12 and patient-derived cells","pmids":["31794073"],"confidence":"High","gaps":["Direct transcriptional targets responsible for cell cycle phenotype not identified","Whether the effect is ASC-1 complex-dependent or TRIP4-autonomous was unknown"]},{"year":2020,"claim":"Revealing the ribosome quality control function of the ASCC complex: reconstitution showed that the ASCC complex, with TRIP4 as a subunit, disassembles the leading stalled ribosome in collided polysomes in an ATP-dependent, ZNF598-ubiquitination-dependent manner, establishing a mechanistically distinct pathway from canonical ribosome recycling.","evidence":"Mammalian cell-free reconstitution of collided polysome disassembly with biochemical fractionation and dominant-negative experiments","pmids":["32579943"],"confidence":"High","gaps":["Specific role of TRIP4 within the ASCC complex during ribosome splitting not defined","Whether TRIP4's DNA-binding domain contributes to ribosome recognition was untested"]},{"year":2021,"claim":"Expanding the transcriptional target repertoire: TRIP4 was shown to directly bind the DDIT4 promoter and activate its transcription, connecting TRIP4 to mTOR signaling regulation in glioma under HIF1α influence.","evidence":"ChIP assay, promoter deletion reporters, siRNA knockdown with rescue, and xenograft in glioma cells","pmids":["34648907"],"confidence":"Medium","gaps":["Mechanism by which HIF1α influences TRIP4 activity at the DDIT4 promoter not resolved","Single cancer type studied"]},{"year":2024,"claim":"Solving the structural basis for TRIP4 DNA binding: the crystal structure of the ASCH domain revealed sequence-independent ssDNA and dsDNA binding via two positively charged patches contacting the 5′ and 3′ ends of DNA, providing a molecular explanation for TRIP4's ability to occupy diverse promoters.","evidence":"Crystal structure determination, biochemical binding assays, and site-directed mutagenesis","pmids":["38870938"],"confidence":"High","gaps":["How sequence-independent DNA binding achieves promoter specificity in vivo remains unresolved","No structure of TRIP4 in complex with other ASCC subunits or transcriptional machinery"]},{"year":2025,"claim":"Defining post-translational regulation of TRIP4: RNF25-mediated non-degradative ubiquitination at K135 disrupts the TRIP4–p65 interaction, liberating p65 to activate NF-κB target genes, revealing how TRIP4 is regulated to modulate inflammatory signaling.","evidence":"Co-IP, K135 site-directed mutagenesis, and functional rescue experiments in renal cell carcinoma cells","pmids":["40765826"],"confidence":"Medium","gaps":["Whether K135 ubiquitination affects TRIP4's ribosome quality control function untested","Deubiquitinase reversing this modification not identified"]},{"year":2025,"claim":"Adding GATA2 as a direct TRIP4 transcriptional target: TRIP4 binds the GATA2 promoter and activates its transcription in cervical cancer, with GATA2 overexpression rescuing TRIP4 knockdown effects on growth and radiation sensitivity.","evidence":"ChIP, pulldown, RNA-seq of knockdown cells, and rescue experiments","pmids":["40180167"],"confidence":"Medium","gaps":["TRIP4's promoter selectivity mechanism still unresolved despite known DNA-binding structure","Whether GATA2 regulation occurs in non-cancer contexts untested"]},{"year":null,"claim":"The specific molecular role of TRIP4 within the ASCC complex during ribosome splitting — whether it serves as a structural scaffold, contacts the ribosome directly, or modulates ASCC3 helicase activity — remains mechanistically undefined, as does the question of how TRIP4 partitions between its ribosome quality control and transcriptional coactivation functions.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of TRIP4 within the assembled ASCC complex on ribosomes","No separation-of-function mutations distinguishing translational from transcriptional roles","How TRIP4's sequence-independent DNA binding achieves promoter selectivity in vivo is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,6,7,9,10]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,6,7,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,6,7,9,10]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8]}],"complexes":["ASC-1/ASCC complex"],"partners":["ASCC3","P300","P65/RELA","RNF25","ZNF598","FUS","EWSR1"],"other_free_text":[]},"mechanistic_narrative":"TRIP4 is a multifunctional scaffolding protein that operates both as the core subunit of the tetrameric ASC-1 (ASCC) complex in ribosome-associated quality control and translation initiation, and as a sequence-independent DNA-binding transcriptional coactivator at specific gene promoters. Within the ASCC complex, TRIP4 participates in ATP-dependent disassembly of collided (stalled) ribosomes downstream of ZNF598-mediated 40S ubiquitination and in promoting translation initiation at 5′ UTRs of a subset of mRNAs via association with scanning 43S preinitiation complexes [PMID:32579943, PMID:37092320]. The C-terminal ASCH domain of TRIP4 binds single- and double-stranded DNA in a sequence-independent manner through two positively charged surface patches, and TRIP4 directly occupies the promoters of target genes including PAI-2, DDIT4, COX-2, iNOS, and GATA2 to activate their transcription, in some cases synergizing with p300 [PMID:38870938, PMID:19074642, PMID:34648907, PMID:28899685, PMID:40180167]. TRIP4 also modulates NF-κB signaling through its interaction with p65, which is disrupted by RNF25-mediated non-degradative ubiquitination at K135, and regulates cell cycle progression and myotube growth in skeletal muscle [PMID:40765826, PMID:31794073, PMID:27008887]."},"prefetch_data":{"uniprot":{"accession":"Q15650","full_name":"Activating signal cointegrator 1","aliases":["Thyroid receptor-interacting protein 4","TR-interacting protein 4","TRIP-4"],"length_aa":581,"mass_kda":66.1,"function":"Transcription coactivator which associates with nuclear receptors, transcriptional coactivators including EP300, CREBBP and NCOA1, and basal transcription factors like TBP and TFIIA to facilitate nuclear receptors-mediated transcription (PubMed:10454579, PubMed:25219498). May thereby play an important role in establishing distinct coactivator complexes under different cellular conditions (PubMed:10454579, PubMed:25219498). Plays a role in thyroid hormone receptor and estrogen receptor transactivation (PubMed:10454579, PubMed:25219498). Also involved in androgen receptor transactivation (By similarity). Plays a pivotal role in the transactivation of NF-kappa-B, SRF and AP1 (PubMed:12077347). Acts as a mediator of transrepression between nuclear receptor and either AP1 or NF-kappa-B (PubMed:12077347). May play a role in the development of neuromuscular junction (PubMed:26924529). May play a role in late myogenic differentiation (By similarity). Also functions as part of the RQC trigger (RQT) complex that activates the ribosome quality control (RQC) pathway, a pathway that degrades nascent peptide chains during problematic translation (PubMed:32099016, PubMed:32579943, PubMed:36302773)","subcellular_location":"Nucleus; Cytoplasm, cytosol; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q15650/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIP4","classification":"Not Classified","n_dependent_lines":27,"n_total_lines":1208,"dependency_fraction":0.022350993377483443},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"EIF3B","stoichiometry":0.2},{"gene":"EIF3G","stoichiometry":0.2},{"gene":"EIF4A1","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"RBM8A","stoichiometry":0.2},{"gene":"RIOK3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TRIP4","total_profiled":1310},"omim":[{"mim_id":"617066","title":"MUSCULAR DYSTROPHY, CONGENITAL, DAVIGNON-CHAUVEAU TYPE; MDCDC","url":"https://www.omim.org/entry/617066"},{"mim_id":"616866","title":"SPINAL MUSCULAR ATROPHY WITH CONGENITAL BONE FRACTURES 1; SMABF1","url":"https://www.omim.org/entry/616866"},{"mim_id":"614217","title":"ACTIVATING SIGNAL COINTEGRATOR 1 COMPLEX, SUBUNIT 3; ASCC3","url":"https://www.omim.org/entry/614217"},{"mim_id":"614216","title":"ACTIVATING SIGNAL COINTEGRATOR 1 COMPLEX, SUBUNIT 2; ASCC2","url":"https://www.omim.org/entry/614216"},{"mim_id":"614215","title":"ACTIVATING SIGNAL COINTEGRATOR 1 COMPLEX, SUBUNIT 1; ASCC1","url":"https://www.omim.org/entry/614215"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRIP4"},"hgnc":{"alias_symbol":["HsT17391","ZC2HC5","ASC-1"],"prev_symbol":[]},"alphafold":{"accession":"Q15650","domains":[{"cath_id":"-","chopping":"10-77","consensus_level":"high","plddt":82.0932,"start":10,"end":77},{"cath_id":"-","chopping":"167-233","consensus_level":"high","plddt":87.3688,"start":167,"end":233},{"cath_id":"2.30.130.30","chopping":"428-575","consensus_level":"high","plddt":90.9135,"start":428,"end":575}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15650","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15650-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15650-F1-predicted_aligned_error_v6.png","plddt_mean":71.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIP4","jax_strain_url":"https://www.jax.org/strain/search?query=TRIP4"},"sequence":{"accession":"Q15650","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15650.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15650/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15650"}},"corpus_meta":[{"pmid":"16356857","id":"PMC_16356857","title":"A 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The function of glutaraldehyde-polymerized antigen in the induction of reaginic (IgE) antibodies in the rat.","date":"1977","source":"International archives of allergy and applied immunology","url":"https://pubmed.ncbi.nlm.nih.gov/301862","citation_count":9,"is_preprint":false},{"pmid":"34648907","id":"PMC_34648907","title":"TRIP4 transcriptionally activates DDIT4 and subsequent mTOR signaling to promote glioma progression.","date":"2021","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34648907","citation_count":8,"is_preprint":false},{"pmid":"37903619","id":"PMC_37903619","title":"Dual Role of Dysfunctional Asc-1 Transporter in Distinct Human Pathologies, Human Startle Disease, and Developmental Delay.","date":"2023","source":"eNeuro","url":"https://pubmed.ncbi.nlm.nih.gov/37903619","citation_count":8,"is_preprint":false},{"pmid":"40765826","id":"PMC_40765826","title":"BAY11-7082 Targets RNF25 to Reverse TRIP4 Ubiquitination-dependent NF-κB Activation and Apoptosis Resistance in Renal Cell Carcinoma.","date":"2025","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40765826","citation_count":4,"is_preprint":false},{"pmid":"40180167","id":"PMC_40180167","title":"GATA2 promotes cervical cancer progression under the transcriptional activation of TRIP4.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/40180167","citation_count":2,"is_preprint":false},{"pmid":"37718780","id":"PMC_37718780","title":"LINC00668 promoted non-small lung cancer progression by miR-518c-3p/TRIP4 axis.","date":"2023","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/37718780","citation_count":2,"is_preprint":false},{"pmid":"36403747","id":"PMC_36403747","title":"Amino acid transporter Asc-1 (SLC7A10) expression is altered in basal ganglia in experimental Parkinsonism and L-dopa-induced dyskinesia model mice.","date":"2022","source":"Journal of chemical neuroanatomy","url":"https://pubmed.ncbi.nlm.nih.gov/36403747","citation_count":2,"is_preprint":false},{"pmid":"38870938","id":"PMC_38870938","title":"Biochemical and structural characterization of the DNA-binding properties of human TRIP4 ASCH domain reveals insights into its functional role.","date":"2024","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/38870938","citation_count":1,"is_preprint":false},{"pmid":"20074644","id":"PMC_20074644","title":"Over-expression, purification and characterization of an Asc-1 homologue from Gloeobacter violaceus.","date":"2010","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/20074644","citation_count":1,"is_preprint":false},{"pmid":"38143368","id":"PMC_38143368","title":"'A novel TRIP4 Variant Associated with Peripheral Neuropathy: Expanding the Clinical and Genetic Spectrum of ASC1-Related Myopathy'.","date":"2024","source":"Journal of neuromuscular diseases","url":"https://pubmed.ncbi.nlm.nih.gov/38143368","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.17.618946","title":"The ribosome-associated quality control factor TCF25 imposes K48 specificity on Listerin-mediated ubiquitination of nascent chains by binding and specifically orienting the acceptor ubiquitin","date":"2024-10-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.17.618946","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21873,"output_tokens":2846,"usd":0.054155},"stage2":{"model":"claude-opus-4-6","input_tokens":6206,"output_tokens":2852,"usd":0.153495},"total_usd":0.20765,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"The ASC-1 complex (ASCC), containing the ASCC3 helicase, disassembles the leading (stalled) ribosome in collided polysomes in an ATP-dependent reaction. Disassembly requires prior 40S ubiquitination by ZNF598 but does not require GTP-dependent factors such as the Pelo-Hbs1L complex. TRIP4 is a subunit of this ASCC complex.\",\n      \"method\": \"Mammalian cell-free reconstitution of collided polysome disassembly, biochemical fractionation, dominant-negative and depletion experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with multiple orthogonal biochemical validations in a single rigorous study\",\n      \"pmids\": [\"32579943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The ASC-1 complex (ASCC), through its ASCC3 helicase subunit, associates with scanning (43S preinitiation complex) ribosomes at 5' UTRs and promotes translation initiation for a specific subset of mRNAs, distinct from its role in collided ribosome disassembly.\",\n      \"method\": \"TCP-seq (selective translation complex profiling), Ribo-seq, luciferase reporter assays, ASCC3 knockdown\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genome-wide and reporter methods in single study with clear mechanistic interpretation\",\n      \"pmids\": [\"37092320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"All four ALS-causative RNA/DNA binding proteins (FUS, EWSR1, TAF15, MATR3) are required for association of the ASC-1 transcriptional coactivator complex (containing TRIP4) with the RNAP II/U1 snRNP machinery; an SMA-causative mutation in an ASC-1 component or an ALS-causative FUS mutation disrupts this association.\",\n      \"method\": \"CRISPR knockout of ALS-causative proteins, mass spectrometry interactome, co-immunoprecipitation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and MS interactome with genetic perturbation across multiple ALS-causative proteins\",\n      \"pmids\": [\"30398641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIP4 (ASC-1) is required for late myogenic differentiation; its depletion in C2C12 cells and patient-derived muscle cells causes a significant reduction in myotube diameter without affecting fusion index or early myogenic differentiation markers, identifying a role in myotube growth.\",\n      \"method\": \"shRNA knockdown in C2C12 cells, patient-derived muscle cell culture, myotube diameter measurement, Western blot for differentiation markers\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/KD with defined cellular phenotype replicated in both patient-derived cells and mouse C2C12 cells\",\n      \"pmids\": [\"27008887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ASC-1 (TRIP4) depletion in C2C12 cells and patient-derived fibroblasts and muscles causes accelerated proliferation, altered expression of cell cycle proteins, and shortening of the G0/G1 cell cycle phase, leading to cell size reduction, establishing TRIP4 as a novel cell cycle regulator.\",\n      \"method\": \"FACS cell cycle analysis, Western blot for cell cycle proteins, Trip4 knockdown in C2C12 cells and patient-derived cells\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (FACS, Western blot) in both patient-derived and mouse model cells\",\n      \"pmids\": [\"31794073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The ASC-1 complex (containing TRIP4/p50 and a p65 subunit) binds a specific response element in the PAI-2 promoter and mediates gastrin-induced PAI-2 transcription via IL-8 paracrine signaling; RNAi knockdown of both subunits inhibits PAI-2 induction.\",\n      \"method\": \"Yeast one-hybrid screening, promoter mutational analysis, RNAi knockdown, reporter assays\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — yeast one-hybrid and RNAi with reporter assay, single lab\",\n      \"pmids\": [\"19074642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIP4 promotes melanoma cell growth by modulating COX-2 and iNOS expression, partially by activating NF-κB signaling indirectly and partially by directly anchoring at COX-2 and iNOS promoters in synergy with p300 transcriptional coactivator.\",\n      \"method\": \"ChIP assay demonstrating TRIP4 promoter binding, siRNA knockdown, co-immunoprecipitation with p300, in vivo xenograft\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and Co-IP with functional knockdown in vitro and in vivo, single lab\",\n      \"pmids\": [\"28899685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIP4 functions as a transcriptional activator that directly binds the promoter region of DDIT4 (positions −196 to −11), activating its transcription and thereby promoting mTOR signaling in glioma; this regulation is influenced by HIF1α.\",\n      \"method\": \"ChIP assay, promoter deletion/reporter assay, siRNA knockdown, rescue experiments with DDIT4 overexpression, in vivo xenograft\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP with promoter reporter and rescue experiments, single lab\",\n      \"pmids\": [\"34648907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The E3 ubiquitin ligase RNF25 directly binds TRIP4 and catalyzes its non-degradative ubiquitination at lysine 135, which disrupts TRIP4-p65 interactions, liberating p65 to activate NF-κB signaling and upregulate anti-apoptotic effectors (cIAP2, Bcl-2) in renal cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (K135 ubiquitination site), Western blot, loss-of-function and rescue experiments\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with mutagenesis of modification site and functional consequence, single lab\",\n      \"pmids\": [\"40765826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The C-terminal ASCH domain of human TRIP4 binds ssDNA and dsDNA in a sequence-independent manner through two adjacent positively charged surface patches that contact the 5'-end and 3'-end of DNA respectively; key residues were confirmed by mutagenesis.\",\n      \"method\": \"Crystal structure determination, biochemical binding assays, site-directed mutagenesis\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with mutagenesis and binding assays in a single study\",\n      \"pmids\": [\"38870938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIP4 binds to a specific region of the GATA2 promoter and directly activates GATA2 transcription in cervical cancer cells; GATA2 overexpression rescues the inhibitory effects of TRIP4 knockdown on cervical cancer cell growth and radiation sensitivity.\",\n      \"method\": \"ChIP assay, pulldown assay, RNA sequencing of TRIP4 knockdown cells, rescue experiments, Western blot\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and pulldown with RNA-seq identification and functional rescue, single lab\",\n      \"pmids\": [\"40180167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The ASC-1 complex splits stalled ribosomes (60S RNCs), which then associate with NEMF that recruits the E3 ligase Listerin to ubiquitinate nascent chains; TCF25 imposes K48-specificity on this ubiquitination by binding the Listerin RING domain and orienting the acceptor ubiquitin.\",\n      \"method\": \"Biochemical reconstitution, AlphaFold3 modeling, functional ubiquitination assays with mutant proteins\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with structural modeling, but preprint and TRIP4/ASCC role is upstream context for this study\",\n      \"pmids\": [\"bio_10.1101_2024.10.17.618946\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TRIP4 is the core subunit of the tetrameric ASC-1 (ASCC) complex, which functions mechanistically in: (1) ATP-dependent disassembly of collided (stalled) ribosomes during ribosome-associated quality control, requiring prior ZNF598-mediated 40S ubiquitination; (2) promotion of translation initiation by associating with scanning 43S preinitiation complexes at 5' UTRs of a subset of mRNAs; (3) transcriptional coactivation by binding promoter elements of specific target genes (PAI-2, DDIT4, GATA2, COX-2/iNOS) directly or in complex with p300; (4) regulation of cell cycle progression and myotube growth in skeletal muscle; and (5) modulation of NF-κB signaling through non-degradative ubiquitination at K135 by RNF25, which disrupts its interaction with p65.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TRIP4 is a multifunctional scaffolding protein that operates both as the core subunit of the tetrameric ASC-1 (ASCC) complex in ribosome-associated quality control and translation initiation, and as a sequence-independent DNA-binding transcriptional coactivator at specific gene promoters. Within the ASCC complex, TRIP4 participates in ATP-dependent disassembly of collided (stalled) ribosomes downstream of ZNF598-mediated 40S ubiquitination and in promoting translation initiation at 5′ UTRs of a subset of mRNAs via association with scanning 43S preinitiation complexes [PMID:32579943, PMID:37092320]. The C-terminal ASCH domain of TRIP4 binds single- and double-stranded DNA in a sequence-independent manner through two positively charged surface patches, and TRIP4 directly occupies the promoters of target genes including PAI-2, DDIT4, COX-2, iNOS, and GATA2 to activate their transcription, in some cases synergizing with p300 [PMID:38870938, PMID:19074642, PMID:34648907, PMID:28899685, PMID:40180167]. TRIP4 also modulates NF-κB signaling through its interaction with p65, which is disrupted by RNF25-mediated non-degradative ubiquitination at K135, and regulates cell cycle progression and myotube growth in skeletal muscle [PMID:40765826, PMID:31794073, PMID:27008887].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing TRIP4 as a promoter-binding transcriptional coactivator: the ASC-1 complex was shown to bind a specific response element in the PAI-2 promoter and mediate gastrin-induced transcription, demonstrating that TRIP4 functions directly at gene promoters rather than solely as a nuclear receptor coactivator.\",\n      \"evidence\": \"Yeast one-hybrid screening, promoter mutational analysis, RNAi knockdown, and reporter assays in gastric cells\",\n      \"pmids\": [\"19074642\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single target gene; generalizability of promoter-binding was unknown\", \"Mechanism of TRIP4 recruitment to specific promoter elements not defined\", \"Contribution of individual ASC-1 subunits to DNA binding not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linking TRIP4 to muscle cell differentiation: TRIP4 depletion reduced myotube diameter without affecting fusion or early differentiation, establishing a specific role for TRIP4 in late myogenic differentiation and myotube growth.\",\n      \"evidence\": \"shRNA knockdown in C2C12 and patient-derived muscle cells with myotube morphometry\",\n      \"pmids\": [\"27008887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional targets mediating the myotube growth phenotype not identified\", \"Whether the ASCC complex or TRIP4 alone drives this function was unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating TRIP4 occupancy at inflammatory gene promoters: ChIP showed TRIP4 directly anchors at COX-2 and iNOS promoters in synergy with p300, linking TRIP4 transcriptional coactivation to NF-κB-dependent gene expression in melanoma.\",\n      \"evidence\": \"ChIP assay, Co-IP with p300, siRNA knockdown, and xenograft models in melanoma cells\",\n      \"pmids\": [\"28899685\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TRIP4 contacts DNA directly or is recruited via p300/other factors was unresolved\", \"Structural basis for promoter selectivity unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connecting the ASC-1 complex to the RNAP II/U1 snRNP machinery: all four ALS-causative RNA/DNA-binding proteins were required for ASC-1 association with RNAP II, and disease mutations disrupted this interaction, placing TRIP4 at the intersection of transcription and neurodegenerative disease pathways.\",\n      \"evidence\": \"CRISPR knockout, mass spectrometry interactome, and reciprocal Co-IP in human cells\",\n      \"pmids\": [\"30398641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of lost RNAP II association on specific transcripts not determined\", \"Direct versus indirect bridging by ALS proteins not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying TRIP4 as a cell cycle regulator: TRIP4 depletion shortened G0/G1, accelerated proliferation, and reduced cell size, revealing a function in cell cycle control distinct from its transcriptional coactivation of specific genes.\",\n      \"evidence\": \"FACS cell cycle analysis and Western blot for cell cycle proteins in C2C12 and patient-derived cells\",\n      \"pmids\": [\"31794073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets responsible for cell cycle phenotype not identified\", \"Whether the effect is ASC-1 complex-dependent or TRIP4-autonomous was unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealing the ribosome quality control function of the ASCC complex: reconstitution showed that the ASCC complex, with TRIP4 as a subunit, disassembles the leading stalled ribosome in collided polysomes in an ATP-dependent, ZNF598-ubiquitination-dependent manner, establishing a mechanistically distinct pathway from canonical ribosome recycling.\",\n      \"evidence\": \"Mammalian cell-free reconstitution of collided polysome disassembly with biochemical fractionation and dominant-negative experiments\",\n      \"pmids\": [\"32579943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific role of TRIP4 within the ASCC complex during ribosome splitting not defined\", \"Whether TRIP4's DNA-binding domain contributes to ribosome recognition was untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanding the transcriptional target repertoire: TRIP4 was shown to directly bind the DDIT4 promoter and activate its transcription, connecting TRIP4 to mTOR signaling regulation in glioma under HIF1α influence.\",\n      \"evidence\": \"ChIP assay, promoter deletion reporters, siRNA knockdown with rescue, and xenograft in glioma cells\",\n      \"pmids\": [\"34648907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which HIF1α influences TRIP4 activity at the DDIT4 promoter not resolved\", \"Single cancer type studied\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Solving the structural basis for TRIP4 DNA binding: the crystal structure of the ASCH domain revealed sequence-independent ssDNA and dsDNA binding via two positively charged patches contacting the 5′ and 3′ ends of DNA, providing a molecular explanation for TRIP4's ability to occupy diverse promoters.\",\n      \"evidence\": \"Crystal structure determination, biochemical binding assays, and site-directed mutagenesis\",\n      \"pmids\": [\"38870938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How sequence-independent DNA binding achieves promoter specificity in vivo remains unresolved\", \"No structure of TRIP4 in complex with other ASCC subunits or transcriptional machinery\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defining post-translational regulation of TRIP4: RNF25-mediated non-degradative ubiquitination at K135 disrupts the TRIP4–p65 interaction, liberating p65 to activate NF-κB target genes, revealing how TRIP4 is regulated to modulate inflammatory signaling.\",\n      \"evidence\": \"Co-IP, K135 site-directed mutagenesis, and functional rescue experiments in renal cell carcinoma cells\",\n      \"pmids\": [\"40765826\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether K135 ubiquitination affects TRIP4's ribosome quality control function untested\", \"Deubiquitinase reversing this modification not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Adding GATA2 as a direct TRIP4 transcriptional target: TRIP4 binds the GATA2 promoter and activates its transcription in cervical cancer, with GATA2 overexpression rescuing TRIP4 knockdown effects on growth and radiation sensitivity.\",\n      \"evidence\": \"ChIP, pulldown, RNA-seq of knockdown cells, and rescue experiments\",\n      \"pmids\": [\"40180167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TRIP4's promoter selectivity mechanism still unresolved despite known DNA-binding structure\", \"Whether GATA2 regulation occurs in non-cancer contexts untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The specific molecular role of TRIP4 within the ASCC complex during ribosome splitting — whether it serves as a structural scaffold, contacts the ribosome directly, or modulates ASCC3 helicase activity — remains mechanistically undefined, as does the question of how TRIP4 partitions between its ribosome quality control and transcriptional coactivation functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of TRIP4 within the assembled ASCC complex on ribosomes\", \"No separation-of-function mutations distinguishing translational from transcriptional roles\", \"How TRIP4's sequence-independent DNA binding achieves promoter selectivity in vivo is unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 6, 7, 9, 10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 6, 7, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 6, 7, 9, 10]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074160\", \"supporting_discovery_ids\": [5, 6, 7, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\"ASC-1/ASCC complex\"],\n    \"partners\": [\"ASCC3\", \"p300\", \"p65/RELA\", \"RNF25\", \"ZNF598\", \"FUS\", \"EWSR1\"],\n    \"other_free_text\": []\n  }\n}\n```"}