{"gene":"TRIM15","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2021,"finding":"TRIM15 functions as an E3 ubiquitin ligase that adds K63-linked polyubiquitin chains to ERK1/2 at defined lysine residues, enhancing ERK interaction with and activation by MEK; the deubiquitinase CYLD opposes this modification through mutually exclusive interactions with ERK1/2.","method":"Co-immunoprecipitation, ubiquitination assays, mutagenesis of ERK lysine residues, in vitro ubiquitination assay, loss-of-function studies","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including in vitro ubiquitination, mutagenesis, and functional rescue in a single study","pmids":["34497368"],"is_preprint":false},{"year":2021,"finding":"TRIM15 interacts with APOA1 through its PRY/SPRY domain and promotes APOA1 polyubiquitination via its RING domain, leading to APOA1 degradation, enhanced lipid anabolism, and lipid droplet accumulation in pancreatic cancer cells.","method":"Mass spectrometry, co-immunoprecipitation, domain mapping, ubiquitination assay, loss-of-function migration/invasion assays","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP and domain mapping with functional readout, single lab","pmids":["34311082"],"is_preprint":false},{"year":2014,"finding":"TRIM15 localizes to focal adhesions through homo-dimerization; B-box2 and PRY domains are essential for focal adhesion localization and inhibition of cell migration; TRIM15 interacts with integrin adhesome proteins including coronin 1B, cortactin, filamin binding LIM protein 1, and VASP.","method":"Fluorescence co-localization, domain mapping, protein-protein interaction screen, loss-of-function migration assays, in vivo tumor growth","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct localization with domain mapping and functional consequence, single lab","pmids":["25450970"],"is_preprint":false},{"year":2014,"finding":"TRIM15 localizes to focal contacts by an interaction between its coiled-coil domain and the LD2 motif of paxillin in a myosin-II-independent manner; TRIM15 is a stable focal adhesion component due to oligomer formation; TRIM15 depletion impairs focal adhesion disassembly and cell migration, and results in enlarged focal adhesions.","method":"FRAP, live imaging, co-immunoprecipitation, domain mapping, siRNA knockdown with focal adhesion disassembly rate measurement","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 — FRAP, direct localization, domain mutagenesis, and functional phenotype in single study with orthogonal methods","pmids":["25015296"],"is_preprint":false},{"year":2021,"finding":"TRIM15 acts as a TNF-α-induced late-response E3 ligase that inhibits NF-κB activation by interacting with TAK1 and reducing its K63-linked ubiquitination; this function depends on the PRY/SPRY domain. TRIM15 also interacts with TRIM8 and inhibits TRIM8-mediated cytosolic translocation that normally promotes NF-κB activity.","method":"Co-immunoprecipitation, ubiquitination assay, domain mapping (PRY/SPRY mutant), NF-κB reporter assay, siRNA knockdown","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with domain mutant and functional reporter, single lab","pmids":["34871740"],"is_preprint":false},{"year":2022,"finding":"TRIM15 directly targets Keap1 for ubiquitination and proteasomal degradation via its E3 ligase activity, preventing Keap1-mediated degradation of Nrf2 and activating the antioxidant response in NSCLC cells.","method":"Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assay in vitro, gain- and loss-of-function experiments","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and in vitro ubiquitination with functional readout, single lab","pmids":["35534896"],"is_preprint":false},{"year":2023,"finding":"TRIM15 mediates K63-linked polyubiquitination of LASP1, promoting its nuclear translocation; nuclear LASP1 increases AKT phosphorylation and Snail expression, contributing to TKI resistance. TRIM15 expression is upregulated after TKI treatment via the AKT/FOXO1 axis, forming a feedback loop.","method":"Co-immunoprecipitation, ubiquitination assay, nuclear fractionation, loss-of-function and gain-of-function experiments, immunofluorescence","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — K63 ubiquitination with localization assay and functional consequence, single lab","pmids":["36670097"],"is_preprint":false},{"year":2025,"finding":"TRIM15 binds YAP and mediates K48-linked ubiquitination of YAP at K254, disrupting the YAP-angiomotin interaction and promoting YAP nuclear translocation, thereby facilitating chondrocyte senescence and osteoarthritis progression.","method":"Co-immunoprecipitation, ubiquitination assay with specific lysine mutagenesis (K254), conditional knockout mouse model (Col2a1-CreER; Trim15flox/flox), in vivo OA models, AAV-mediated shRNA","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 — site-specific mutagenesis, conditional KO mouse model, multiple in vivo models, orthogonal methods","pmids":["40138455"],"is_preprint":false},{"year":2025,"finding":"TRIM15 interacts with Axin1 through its coiled-coil domain to disrupt Axin1 polymerization, thereby inhibiting assembly of the β-catenin destruction complex and promoting Wnt/β-catenin signaling in colorectal cancer. TRIM15 is itself a Wnt target gene, forming a positive feedback loop.","method":"Co-immunoprecipitation, domain mapping (coiled-coil domain), polymerization assays, conditional Trim15 knockout mice in AOM/DSS and ApcMin/+ models, gain- and loss-of-function experiments","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 — domain mapping, polymerization assay, two in vivo genetic mouse models, multiple orthogonal methods","pmids":["41461634"],"is_preprint":false},{"year":2025,"finding":"TRIM15 induces K63-linked ubiquitination of AKT specifically at the pleckstrin homology (PH) domain via its RING domain, activating AKT signaling; TRIM15 transcription is activated by HIF-1α binding to hypoxia response elements in the TRIM15 promoter.","method":"Co-immunoprecipitation, ubiquitination assay (site-specific, RING domain mutant), ubiquitin proteomic analysis, promoter-binding assay (HIF-1α ChIP/reporter), gain- and loss-of-function experiments","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — domain-specific ubiquitination with site mapping and promoter binding, single lab","pmids":["40026037"],"is_preprint":false},{"year":2024,"finding":"TRIM15 ubiquitinates IGF2BP2, enhancing its phase separation function and stabilizing TLR4 mRNA, thereby upregulating TLR4 expression and promoting pancreatic cancer progression.","method":"Transcriptomics, proteomics, co-immunoprecipitation, ubiquitination assay, mRNA stability assay, orthotopic mouse transplantation model","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 — multi-omics with Co-IP and ubiquitination assay and in vivo model, single lab","pmids":["38657551"],"is_preprint":false},{"year":2025,"finding":"TRIM15 promotes ubiquitin-proteasome-mediated degradation of YY2, dysregulating lipid metabolism (via FOXRED1) and modulating ferroptosis sensitivity (via SLC3A2/GPX4 through mTOR/c-MYC) in esophageal adenocarcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, gain- and loss-of-function, transcriptional reporter assay for FOXRED1","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2-3 — ubiquitination with downstream pathway validation, single lab","pmids":["41237333"],"is_preprint":false},{"year":2026,"finding":"TRIM15 stabilizes VDAC3 via K6-linked ubiquitination (non-degradative), suppressing autophagy and mitophagy while elevating ROS levels; VDAC3 knockdown reverses these effects.","method":"Co-immunoprecipitation, ubiquitination assay (K6-linked), siRNA knockdown, autophagy/mitophagy flux assays, ROS measurement, xenograft model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — linkage-specific ubiquitination with functional autophagy readout and in vivo model, single lab","pmids":["41617671"],"is_preprint":false}],"current_model":"TRIM15 is a RING domain E3 ubiquitin ligase that localizes to focal adhesions via its coiled-coil/B-box2/PRY domains and modulates cell migration; it catalyzes K63-linked polyubiquitination of ERK1/2 (activating MAPK signaling), AKT (activating PI3K signaling), and LASP1 (promoting nuclear translocation), as well as K48-linked ubiquitination of substrates including Keap1, APOA1, and YAP for proteasomal degradation, and K6-linked stabilizing ubiquitination of VDAC3, thereby functioning as a context-dependent regulator of proliferation, migration, senescence, autophagy, and stress-response pathways across multiple cancer types."},"narrative":{"teleology":[{"year":2014,"claim":"Establishing that TRIM15 is a stable focal adhesion component resolved its subcellular site of action: it localizes to focal contacts via coiled-coil interaction with paxillin's LD2 motif and oligomerization, and its depletion impairs focal adhesion disassembly and cell migration.","evidence":"FRAP, live imaging, Co-IP with domain mapping, siRNA knockdown with focal adhesion disassembly measurements, and fluorescence co-localization with adhesome proteins (coronin 1B, cortactin, VASP) in cultured cells","pmids":["25015296","25450970"],"confidence":"High","gaps":["Whether TRIM15 E3 ligase activity is required for its focal adhesion function was not tested","Identity of ubiquitination substrates at focal adhesions unknown","In vivo relevance of focal adhesion phenotype not established"]},{"year":2021,"claim":"Identification of ERK1/2 as a direct substrate for TRIM15-catalyzed K63-linked polyubiquitination established TRIM15 as a bona fide E3 ligase that activates MAPK signaling by enhancing ERK-MEK interaction, with CYLD acting as the opposing deubiquitinase.","evidence":"In vitro ubiquitination assay, site-specific lysine mutagenesis, Co-IP, and functional rescue experiments","pmids":["34497368"],"confidence":"High","gaps":["Whether K63-linked ubiquitination of ERK occurs at focal adhesions specifically","Physiological contexts beyond cancer cell proliferation not explored"]},{"year":2021,"claim":"TRIM15 was shown to negatively regulate NF-κB by interacting with TAK1 via its PRY/SPRY domain and reducing TAK1 K63-linked ubiquitination, and separately by sequestering TRIM8, revealing TRIM15 as a TNF-α-induced negative feedback regulator of inflammation.","evidence":"Co-IP, ubiquitination assay, domain mapping with PRY/SPRY mutant, NF-κB luciferase reporter, siRNA knockdown","pmids":["34871740"],"confidence":"Medium","gaps":["Whether TRIM15 directly ubiquitinates TAK1 or acts indirectly was not resolved","In vivo inflammatory phenotype not tested","No independent replication"]},{"year":2021,"claim":"Discovery that TRIM15 ubiquitinates APOA1 via its RING/PRY-SPRY domains leading to APOA1 degradation and lipid droplet accumulation expanded the substrate repertoire to metabolic regulators in pancreatic cancer.","evidence":"Mass spectrometry, reciprocal Co-IP, domain mapping, ubiquitination assay, migration/invasion assays in pancreatic cancer cells","pmids":["34311082"],"confidence":"Medium","gaps":["Ubiquitin chain linkage type on APOA1 not determined","In vivo metabolic consequences not validated","No independent replication"]},{"year":2022,"claim":"Demonstrating that TRIM15 targets Keap1 for proteasomal degradation, thereby stabilizing Nrf2 and activating antioxidant gene expression, linked TRIM15 E3 ligase activity to oxidative stress defense.","evidence":"Co-IP, in vitro ubiquitination assay, gain- and loss-of-function in NSCLC cells with Nrf2 target gene readout","pmids":["35534896"],"confidence":"Medium","gaps":["Ubiquitin chain linkage type on Keap1 not specified","In vivo antioxidant phenotype not tested","No independent replication"]},{"year":2023,"claim":"TRIM15 was found to K63-ubiquitinate LASP1 to promote its nuclear translocation and activate AKT/Snail signaling, with TRIM15 itself upregulated via AKT/FOXO1, establishing a positive feedback loop driving TKI resistance.","evidence":"Co-IP, K63-specific ubiquitination assay, nuclear fractionation, gain/loss-of-function in TKI-treated cancer cells","pmids":["36670097"],"confidence":"Medium","gaps":["Specific ubiquitination sites on LASP1 not mapped","Feedback loop not validated in vivo","No independent replication"]},{"year":2024,"claim":"TRIM15 ubiquitination of IGF2BP2 was shown to enhance its phase separation capacity, stabilizing TLR4 mRNA and promoting pancreatic cancer, linking TRIM15 to RNA metabolism via liquid-liquid phase separation.","evidence":"Multi-omics, Co-IP, ubiquitination assay, mRNA stability assay, orthotopic mouse transplantation model","pmids":["38657551"],"confidence":"Medium","gaps":["Ubiquitin chain type on IGF2BP2 not specified","Direct structural basis for phase separation enhancement unknown","No independent replication"]},{"year":2025,"claim":"Three studies collectively broadened TRIM15's substrate repertoire and in vivo significance: K48-linked ubiquitination of YAP at K254 disrupts YAP-angiomotin interaction and drives chondrocyte senescence/osteoarthritis (validated in conditional KO mice); TRIM15 disrupts Axin1 polymerization via coiled-coil interaction to activate Wnt/β-catenin signaling in colorectal cancer (validated in two genetic mouse models); and TRIM15 K63-ubiquitinates AKT at its PH domain under HIF-1α transcriptional control.","evidence":"Site-specific mutagenesis, conditional Trim15 KO mice (Col2a1-CreER; Trim15flox/flox), AOM/DSS and ApcMin/+ mouse models, polymerization assays, domain-specific ubiquitination with ChIP for HIF-1α","pmids":["40138455","41461634","40026037"],"confidence":"High","gaps":["Whether Axin1 is also a direct ubiquitination substrate is unclear","Relationship between focal adhesion localization and Wnt/YAP/AKT signaling functions not resolved","Tissue-specific hierarchy among TRIM15 substrates unknown"]},{"year":2025,"claim":"TRIM15 was shown to target YY2 for proteasomal degradation, linking it to ferroptosis sensitivity through dysregulated lipid metabolism (FOXRED1) and SLC3A2/GPX4 pathway modulation in esophageal adenocarcinoma.","evidence":"Co-IP, ubiquitination assay, gain/loss-of-function, transcriptional reporter for FOXRED1","pmids":["41237333"],"confidence":"Medium","gaps":["Ubiquitin chain type on YY2 not specified","In vivo ferroptosis relevance not validated","No independent replication"]},{"year":2026,"claim":"Discovery of K6-linked (non-degradative) ubiquitination of VDAC3 by TRIM15 that suppresses autophagy and mitophagy while elevating ROS demonstrated that TRIM15 employs atypical ubiquitin chain types for stabilizing functions.","evidence":"K6-linkage-specific ubiquitination assay, siRNA knockdown of VDAC3, autophagy/mitophagy flux assays, ROS measurement, xenograft model","pmids":["41617671"],"confidence":"Medium","gaps":["Structural basis for K6 linkage specificity unknown","Relationship to TRIM15's other mitochondrial or metabolic functions unexplored","No independent replication"]},{"year":null,"claim":"A unified model explaining how TRIM15 selects among K6, K48, and K63 ubiquitin chain linkages for different substrates, and how its focal adhesion localization relates to its diverse signaling functions, remains to be established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of TRIM15 RING domain explaining linkage selectivity","No systematic in vivo phenotyping of Trim15 knockout across tissues","Substrate prioritization under physiological versus pathological conditions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,5,6,7,9,10,11,12]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,5,7,9]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,5,7,9,10,11,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,6,8,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[5]}],"complexes":[],"partners":["ERK1","ERK2","PAXILLIN","LASP1","YAP1","AXIN1","AKT1","KEAP1"],"other_free_text":[]},"mechanistic_narrative":"TRIM15 is a RING-domain E3 ubiquitin ligase that functions as a context-dependent signaling regulator by catalyzing linkage-specific polyubiquitination of diverse substrates across multiple cellular pathways. It localizes to focal adhesions through coiled-coil-mediated interaction with paxillin and B-box2/PRY domain-dependent oligomerization, where it promotes focal adhesion disassembly and regulates cell migration [PMID:25015296, PMID:25450970]. TRIM15 activates MAPK signaling via K63-linked ubiquitination of ERK1/2 [PMID:34497368], activates PI3K/AKT signaling via K63-linked ubiquitination of AKT [PMID:40026037], promotes Wnt/β-catenin signaling by disrupting Axin1 polymerization [PMID:41461634], and modulates the Keap1-Nrf2 antioxidant axis and NF-κB signaling through targeted ubiquitin-dependent degradation or inhibition of key pathway components [PMID:35534896, PMID:34871740]. It also ubiquitinates YAP via K48-linked chains to promote chondrocyte senescence and osteoarthritis progression, as demonstrated by conditional knockout mouse models [PMID:40138455], and stabilizes VDAC3 via K6-linked ubiquitination to suppress autophagy and mitophagy [PMID:41617671]."},"prefetch_data":{"uniprot":{"accession":"Q9C019","full_name":"E3 ubiquitin-protein ligase TRIM15","aliases":["RING finger protein 93","Zinc finger protein 178","Zinc finger protein B7"],"length_aa":465,"mass_kda":52.1,"function":"E3 ubiquitin ligase that plays a role in several processes including innate antiviral immnity, cell migration and chemotaxis (PubMed:23077300, PubMed:34142270). Acts as a 'Lys-63'-specific ubiquitin ligase for MAPK1/ERK2 and MAPK3/ERK1, promoting their activation by facilitating their interaction with MAP2K1 and MAP2K2 (PubMed:34497368). Also plays a role in cell migration and chemotaxis by acting as a stable focal adhesion component upon recruitment by multi-adapter protein paxillin/PXN (PubMed:25015296). Functions in the RIGI-mediated interferon induction pathway upstream or at the level of MAVS (PubMed:23077300). Inhibits NF-kappa-B activation by turnover of 'Lys-63'-linked ubiquitination of MAP3K7/TAK1. Mechanistically, prevents TRIM8 cytoplasmic translocation and thus inhibits TRIM8-mediated 'Lys-63'-linked polyubiquitination of MAP3K7/TAK1 in the cytoplasm (PubMed:34871740). Also plays an important regulatory effect on the activation of hepatic stellate cells (HSCs)","subcellular_location":"Cytoplasm; Nucleus; Cell junction, focal adhesion","url":"https://www.uniprot.org/uniprotkb/Q9C019/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM15","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRIM15","total_profiled":1310},"omim":[{"mim_id":"126200","title":"MULTIPLE SCLEROSIS, SUSCEPTIBILITY TO; MS","url":"https://www.omim.org/entry/126200"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Centriolar satellite","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"intestine","ntpm":16.0},{"tissue":"kidney","ntpm":6.7},{"tissue":"liver","ntpm":16.2}],"url":"https://www.proteinatlas.org/search/TRIM15"},"hgnc":{"alias_symbol":["ZNFB7","RNF93"],"prev_symbol":["ZNF178"]},"alphafold":{"accession":"Q9C019","domains":[{"cath_id":"-","chopping":"16-41","consensus_level":"medium","plddt":80.2765,"start":16,"end":41},{"cath_id":"2.60.120.920","chopping":"298-465","consensus_level":"high","plddt":90.5623,"start":298,"end":465},{"cath_id":"1.20.5","chopping":"91-175","consensus_level":"medium","plddt":93.1884,"start":91,"end":175},{"cath_id":"1.10.287","chopping":"183-241_248-291","consensus_level":"medium","plddt":86.8315,"start":183,"end":291}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C019","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C019-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C019-F1-predicted_aligned_error_v6.png","plddt_mean":83.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM15","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM15"},"sequence":{"accession":"Q9C019","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9C019.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9C019/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C019"}},"corpus_meta":[{"pmid":"34497368","id":"PMC_34497368","title":"TRIM15 and CYLD regulate ERK activation via lysine-63-linked polyubiquitination.","date":"2021","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/34497368","citation_count":73,"is_preprint":false},{"pmid":"34311082","id":"PMC_34311082","title":"TRIM15 promotes the invasion and metastasis of pancreatic cancer cells by mediating APOA1 ubiquitination and degradation.","date":"2021","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/34311082","citation_count":45,"is_preprint":false},{"pmid":"25450970","id":"PMC_25450970","title":"Role of the focal adhesion protein TRIM15 in colon cancer development.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25450970","citation_count":43,"is_preprint":false},{"pmid":"35534896","id":"PMC_35534896","title":"E3 ligase TRIM15 facilitates non-small cell lung cancer progression through mediating Keap1-Nrf2 signaling pathway.","date":"2022","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/35534896","citation_count":37,"is_preprint":false},{"pmid":"25015296","id":"PMC_25015296","title":"TRIM15 is a focal adhesion protein that regulates focal adhesion disassembly.","date":"2014","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/25015296","citation_count":25,"is_preprint":false},{"pmid":"30412518","id":"PMC_30412518","title":"TRIM15 Exerts Anti-Tumor Effects Through Suppressing Cancer Cell Invasion in Gastric Adenocarcinoma.","date":"2018","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/30412518","citation_count":23,"is_preprint":false},{"pmid":"34871740","id":"PMC_34871740","title":"TNF-α-induced E3 ligase, TRIM15 inhibits TNF-α-regulated NF-κB pathway by promoting turnover of K63 linked ubiquitination of TAK1.","date":"2021","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/34871740","citation_count":19,"is_preprint":false},{"pmid":"36670097","id":"PMC_36670097","title":"TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIs.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36670097","citation_count":16,"is_preprint":false},{"pmid":"33515345","id":"PMC_33515345","title":"Knockdown of TRIM15 inhibits the proliferation, migration and invasion of esophageal squamous cell carcinoma cells through inactivation of the Wnt/β-catenin signaling pathway.","date":"2021","source":"Journal of bioenergetics and biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/33515345","citation_count":14,"is_preprint":false},{"pmid":"40138455","id":"PMC_40138455","title":"TRIM15 drives chondrocyte senescence and osteoarthritis progression.","date":"2025","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40138455","citation_count":9,"is_preprint":false},{"pmid":"38657551","id":"PMC_38657551","title":"Ubiquitin ligase TRIM15 promotes the progression of pancreatic cancer via the upregulation of the IGF2BP2-TLR4 axis.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38657551","citation_count":7,"is_preprint":false},{"pmid":"34142270","id":"PMC_34142270","title":"Knockdown of TRIM15 inhibits the activation of hepatic stellate cells.","date":"2021","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/34142270","citation_count":5,"is_preprint":false},{"pmid":"41461634","id":"PMC_41461634","title":"Targeting TRIM15-mediated Axin1 depolymerization suppresses Wnt signaling and inhibits colorectal cancer growth.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41461634","citation_count":1,"is_preprint":false},{"pmid":"40026037","id":"PMC_40026037","title":"Hypoxia-mediated high expression of TRIM15 promotes malignant progression of high-grade serous ovarian cancer through activation of AKT signaling pathway by K63 ubiquitination.","date":"2025","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40026037","citation_count":1,"is_preprint":false},{"pmid":"41237333","id":"PMC_41237333","title":"Obesity-Associated TRIM15 Promotes the Proliferation of Esophageal Adenocarcinoma Through the YY2/FOXRED1 Axis.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41237333","citation_count":1,"is_preprint":false},{"pmid":"41617671","id":"PMC_41617671","title":"Trim15 stabilizes VDAC3 via ubiquitination to suppress autophagy and enhance chemosensitivity in hypopharyngeal squamous cell carcinoma.","date":"2026","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/41617671","citation_count":0,"is_preprint":false},{"pmid":"41296246","id":"PMC_41296246","title":"Exploring the TRIM15 protein interaction network as a drug target using machine learning in pancreatic cancer.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41296246","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9572,"output_tokens":3127,"usd":0.03781},"stage2":{"model":"claude-opus-4-6","input_tokens":6518,"output_tokens":3159,"usd":0.167348},"total_usd":0.205158,"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\": 2021,\n      \"finding\": \"TRIM15 functions as an E3 ubiquitin ligase that adds K63-linked polyubiquitin chains to ERK1/2 at defined lysine residues, enhancing ERK interaction with and activation by MEK; the deubiquitinase CYLD opposes this modification through mutually exclusive interactions with ERK1/2.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, mutagenesis of ERK lysine residues, in vitro ubiquitination assay, loss-of-function studies\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including in vitro ubiquitination, mutagenesis, and functional rescue in a single study\",\n      \"pmids\": [\"34497368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM15 interacts with APOA1 through its PRY/SPRY domain and promotes APOA1 polyubiquitination via its RING domain, leading to APOA1 degradation, enhanced lipid anabolism, and lipid droplet accumulation in pancreatic cancer cells.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, domain mapping, ubiquitination assay, loss-of-function migration/invasion assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and domain mapping with functional readout, single lab\",\n      \"pmids\": [\"34311082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIM15 localizes to focal adhesions through homo-dimerization; B-box2 and PRY domains are essential for focal adhesion localization and inhibition of cell migration; TRIM15 interacts with integrin adhesome proteins including coronin 1B, cortactin, filamin binding LIM protein 1, and VASP.\",\n      \"method\": \"Fluorescence co-localization, domain mapping, protein-protein interaction screen, loss-of-function migration assays, in vivo tumor growth\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct localization with domain mapping and functional consequence, single lab\",\n      \"pmids\": [\"25450970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIM15 localizes to focal contacts by an interaction between its coiled-coil domain and the LD2 motif of paxillin in a myosin-II-independent manner; TRIM15 is a stable focal adhesion component due to oligomer formation; TRIM15 depletion impairs focal adhesion disassembly and cell migration, and results in enlarged focal adhesions.\",\n      \"method\": \"FRAP, live imaging, co-immunoprecipitation, domain mapping, siRNA knockdown with focal adhesion disassembly rate measurement\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — FRAP, direct localization, domain mutagenesis, and functional phenotype in single study with orthogonal methods\",\n      \"pmids\": [\"25015296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM15 acts as a TNF-α-induced late-response E3 ligase that inhibits NF-κB activation by interacting with TAK1 and reducing its K63-linked ubiquitination; this function depends on the PRY/SPRY domain. TRIM15 also interacts with TRIM8 and inhibits TRIM8-mediated cytosolic translocation that normally promotes NF-κB activity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, domain mapping (PRY/SPRY mutant), NF-κB reporter assay, siRNA knockdown\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with domain mutant and functional reporter, single lab\",\n      \"pmids\": [\"34871740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM15 directly targets Keap1 for ubiquitination and proteasomal degradation via its E3 ligase activity, preventing Keap1-mediated degradation of Nrf2 and activating the antioxidant response in NSCLC cells.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assay in vitro, gain- and loss-of-function experiments\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and in vitro ubiquitination with functional readout, single lab\",\n      \"pmids\": [\"35534896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM15 mediates K63-linked polyubiquitination of LASP1, promoting its nuclear translocation; nuclear LASP1 increases AKT phosphorylation and Snail expression, contributing to TKI resistance. TRIM15 expression is upregulated after TKI treatment via the AKT/FOXO1 axis, forming a feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, nuclear fractionation, loss-of-function and gain-of-function experiments, immunofluorescence\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — K63 ubiquitination with localization assay and functional consequence, single lab\",\n      \"pmids\": [\"36670097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM15 binds YAP and mediates K48-linked ubiquitination of YAP at K254, disrupting the YAP-angiomotin interaction and promoting YAP nuclear translocation, thereby facilitating chondrocyte senescence and osteoarthritis progression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with specific lysine mutagenesis (K254), conditional knockout mouse model (Col2a1-CreER; Trim15flox/flox), in vivo OA models, AAV-mediated shRNA\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — site-specific mutagenesis, conditional KO mouse model, multiple in vivo models, orthogonal methods\",\n      \"pmids\": [\"40138455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM15 interacts with Axin1 through its coiled-coil domain to disrupt Axin1 polymerization, thereby inhibiting assembly of the β-catenin destruction complex and promoting Wnt/β-catenin signaling in colorectal cancer. TRIM15 is itself a Wnt target gene, forming a positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping (coiled-coil domain), polymerization assays, conditional Trim15 knockout mice in AOM/DSS and ApcMin/+ models, gain- and loss-of-function experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — domain mapping, polymerization assay, two in vivo genetic mouse models, multiple orthogonal methods\",\n      \"pmids\": [\"41461634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM15 induces K63-linked ubiquitination of AKT specifically at the pleckstrin homology (PH) domain via its RING domain, activating AKT signaling; TRIM15 transcription is activated by HIF-1α binding to hypoxia response elements in the TRIM15 promoter.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (site-specific, RING domain mutant), ubiquitin proteomic analysis, promoter-binding assay (HIF-1α ChIP/reporter), gain- and loss-of-function experiments\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain-specific ubiquitination with site mapping and promoter binding, single lab\",\n      \"pmids\": [\"40026037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM15 ubiquitinates IGF2BP2, enhancing its phase separation function and stabilizing TLR4 mRNA, thereby upregulating TLR4 expression and promoting pancreatic cancer progression.\",\n      \"method\": \"Transcriptomics, proteomics, co-immunoprecipitation, ubiquitination assay, mRNA stability assay, orthotopic mouse transplantation model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics with Co-IP and ubiquitination assay and in vivo model, single lab\",\n      \"pmids\": [\"38657551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM15 promotes ubiquitin-proteasome-mediated degradation of YY2, dysregulating lipid metabolism (via FOXRED1) and modulating ferroptosis sensitivity (via SLC3A2/GPX4 through mTOR/c-MYC) in esophageal adenocarcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, gain- and loss-of-function, transcriptional reporter assay for FOXRED1\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ubiquitination with downstream pathway validation, single lab\",\n      \"pmids\": [\"41237333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM15 stabilizes VDAC3 via K6-linked ubiquitination (non-degradative), suppressing autophagy and mitophagy while elevating ROS levels; VDAC3 knockdown reverses these effects.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K6-linked), siRNA knockdown, autophagy/mitophagy flux assays, ROS measurement, xenograft model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — linkage-specific ubiquitination with functional autophagy readout and in vivo model, single lab\",\n      \"pmids\": [\"41617671\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM15 is a RING domain E3 ubiquitin ligase that localizes to focal adhesions via its coiled-coil/B-box2/PRY domains and modulates cell migration; it catalyzes K63-linked polyubiquitination of ERK1/2 (activating MAPK signaling), AKT (activating PI3K signaling), and LASP1 (promoting nuclear translocation), as well as K48-linked ubiquitination of substrates including Keap1, APOA1, and YAP for proteasomal degradation, and K6-linked stabilizing ubiquitination of VDAC3, thereby functioning as a context-dependent regulator of proliferation, migration, senescence, autophagy, and stress-response pathways across multiple cancer types.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TRIM15 is a RING-domain E3 ubiquitin ligase that functions as a context-dependent signaling regulator by catalyzing linkage-specific polyubiquitination of diverse substrates across multiple cellular pathways. It localizes to focal adhesions through coiled-coil-mediated interaction with paxillin and B-box2/PRY domain-dependent oligomerization, where it promotes focal adhesion disassembly and regulates cell migration [PMID:25015296, PMID:25450970]. TRIM15 activates MAPK signaling via K63-linked ubiquitination of ERK1/2 [PMID:34497368], activates PI3K/AKT signaling via K63-linked ubiquitination of AKT [PMID:40026037], promotes Wnt/β-catenin signaling by disrupting Axin1 polymerization [PMID:41461634], and modulates the Keap1-Nrf2 antioxidant axis and NF-κB signaling through targeted ubiquitin-dependent degradation or inhibition of key pathway components [PMID:35534896, PMID:34871740]. It also ubiquitinates YAP via K48-linked chains to promote chondrocyte senescence and osteoarthritis progression, as demonstrated by conditional knockout mouse models [PMID:40138455], and stabilizes VDAC3 via K6-linked ubiquitination to suppress autophagy and mitophagy [PMID:41617671].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing that TRIM15 is a stable focal adhesion component resolved its subcellular site of action: it localizes to focal contacts via coiled-coil interaction with paxillin's LD2 motif and oligomerization, and its depletion impairs focal adhesion disassembly and cell migration.\",\n      \"evidence\": \"FRAP, live imaging, Co-IP with domain mapping, siRNA knockdown with focal adhesion disassembly measurements, and fluorescence co-localization with adhesome proteins (coronin 1B, cortactin, VASP) in cultured cells\",\n      \"pmids\": [\"25015296\", \"25450970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether TRIM15 E3 ligase activity is required for its focal adhesion function was not tested\",\n        \"Identity of ubiquitination substrates at focal adhesions unknown\",\n        \"In vivo relevance of focal adhesion phenotype not established\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of ERK1/2 as a direct substrate for TRIM15-catalyzed K63-linked polyubiquitination established TRIM15 as a bona fide E3 ligase that activates MAPK signaling by enhancing ERK-MEK interaction, with CYLD acting as the opposing deubiquitinase.\",\n      \"evidence\": \"In vitro ubiquitination assay, site-specific lysine mutagenesis, Co-IP, and functional rescue experiments\",\n      \"pmids\": [\"34497368\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether K63-linked ubiquitination of ERK occurs at focal adhesions specifically\",\n        \"Physiological contexts beyond cancer cell proliferation not explored\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"TRIM15 was shown to negatively regulate NF-κB by interacting with TAK1 via its PRY/SPRY domain and reducing TAK1 K63-linked ubiquitination, and separately by sequestering TRIM8, revealing TRIM15 as a TNF-α-induced negative feedback regulator of inflammation.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, domain mapping with PRY/SPRY mutant, NF-κB luciferase reporter, siRNA knockdown\",\n      \"pmids\": [\"34871740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether TRIM15 directly ubiquitinates TAK1 or acts indirectly was not resolved\",\n        \"In vivo inflammatory phenotype not tested\",\n        \"No independent replication\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that TRIM15 ubiquitinates APOA1 via its RING/PRY-SPRY domains leading to APOA1 degradation and lipid droplet accumulation expanded the substrate repertoire to metabolic regulators in pancreatic cancer.\",\n      \"evidence\": \"Mass spectrometry, reciprocal Co-IP, domain mapping, ubiquitination assay, migration/invasion assays in pancreatic cancer cells\",\n      \"pmids\": [\"34311082\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ubiquitin chain linkage type on APOA1 not determined\",\n        \"In vivo metabolic consequences not validated\",\n        \"No independent replication\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that TRIM15 targets Keap1 for proteasomal degradation, thereby stabilizing Nrf2 and activating antioxidant gene expression, linked TRIM15 E3 ligase activity to oxidative stress defense.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination assay, gain- and loss-of-function in NSCLC cells with Nrf2 target gene readout\",\n      \"pmids\": [\"35534896\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ubiquitin chain linkage type on Keap1 not specified\",\n        \"In vivo antioxidant phenotype not tested\",\n        \"No independent replication\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"TRIM15 was found to K63-ubiquitinate LASP1 to promote its nuclear translocation and activate AKT/Snail signaling, with TRIM15 itself upregulated via AKT/FOXO1, establishing a positive feedback loop driving TKI resistance.\",\n      \"evidence\": \"Co-IP, K63-specific ubiquitination assay, nuclear fractionation, gain/loss-of-function in TKI-treated cancer cells\",\n      \"pmids\": [\"36670097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific ubiquitination sites on LASP1 not mapped\",\n        \"Feedback loop not validated in vivo\",\n        \"No independent replication\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"TRIM15 ubiquitination of IGF2BP2 was shown to enhance its phase separation capacity, stabilizing TLR4 mRNA and promoting pancreatic cancer, linking TRIM15 to RNA metabolism via liquid-liquid phase separation.\",\n      \"evidence\": \"Multi-omics, Co-IP, ubiquitination assay, mRNA stability assay, orthotopic mouse transplantation model\",\n      \"pmids\": [\"38657551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ubiquitin chain type on IGF2BP2 not specified\",\n        \"Direct structural basis for phase separation enhancement unknown\",\n        \"No independent replication\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Three studies collectively broadened TRIM15's substrate repertoire and in vivo significance: K48-linked ubiquitination of YAP at K254 disrupts YAP-angiomotin interaction and drives chondrocyte senescence/osteoarthritis (validated in conditional KO mice); TRIM15 disrupts Axin1 polymerization via coiled-coil interaction to activate Wnt/β-catenin signaling in colorectal cancer (validated in two genetic mouse models); and TRIM15 K63-ubiquitinates AKT at its PH domain under HIF-1α transcriptional control.\",\n      \"evidence\": \"Site-specific mutagenesis, conditional Trim15 KO mice (Col2a1-CreER; Trim15flox/flox), AOM/DSS and ApcMin/+ mouse models, polymerization assays, domain-specific ubiquitination with ChIP for HIF-1α\",\n      \"pmids\": [\"40138455\", \"41461634\", \"40026037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Axin1 is also a direct ubiquitination substrate is unclear\",\n        \"Relationship between focal adhesion localization and Wnt/YAP/AKT signaling functions not resolved\",\n        \"Tissue-specific hierarchy among TRIM15 substrates unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"TRIM15 was shown to target YY2 for proteasomal degradation, linking it to ferroptosis sensitivity through dysregulated lipid metabolism (FOXRED1) and SLC3A2/GPX4 pathway modulation in esophageal adenocarcinoma.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, gain/loss-of-function, transcriptional reporter for FOXRED1\",\n      \"pmids\": [\"41237333\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ubiquitin chain type on YY2 not specified\",\n        \"In vivo ferroptosis relevance not validated\",\n        \"No independent replication\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Discovery of K6-linked (non-degradative) ubiquitination of VDAC3 by TRIM15 that suppresses autophagy and mitophagy while elevating ROS demonstrated that TRIM15 employs atypical ubiquitin chain types for stabilizing functions.\",\n      \"evidence\": \"K6-linkage-specific ubiquitination assay, siRNA knockdown of VDAC3, autophagy/mitophagy flux assays, ROS measurement, xenograft model\",\n      \"pmids\": [\"41617671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis for K6 linkage specificity unknown\",\n        \"Relationship to TRIM15's other mitochondrial or metabolic functions unexplored\",\n        \"No independent replication\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified model explaining how TRIM15 selects among K6, K48, and K63 ubiquitin chain linkages for different substrates, and how its focal adhesion localization relates to its diverse signaling functions, remains to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of TRIM15 RING domain explaining linkage selectivity\",\n        \"No systematic in vivo phenotyping of Trim15 knockout across tissues\",\n        \"Substrate prioritization under physiological versus pathological conditions unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 5, 6, 7, 9, 10, 11, 12]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 5, 7, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0, 4, 6, 8, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 5, 7, 9, 10, 11, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 6, 8, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ERK1\",\n      \"ERK2\",\n      \"paxillin\",\n      \"LASP1\",\n      \"YAP1\",\n      \"AXIN1\",\n      \"AKT1\",\n      \"KEAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}