{"gene":"TRIM15","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2021,"finding":"TRIM15 acts as a K63-linked polyubiquitin E3 ligase for ERK1/2, modifying defined lysine residues. This K63-linked ubiquitination enhances ERK interaction with and activation by MEK. CYLD serves as the opposing deubiquitinase of ERK1/2, and TRIM15 and CYLD regulate ERK ubiquitination through mutually exclusive interactions.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, mutagenesis of ubiquitin acceptor lysines, ERK-MEK interaction assays, TRIM15/CYLD knockdown with ERK activation readouts","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including in vitro ubiquitination, mutagenesis of substrate lysines, and functional epistasis; published in high-impact journal","pmids":["34497368"],"is_preprint":false},{"year":2021,"finding":"TRIM15 interacts with APOA1 through its PRY/SPRY domain and promotes APOA1 polyubiquitination and degradation via its RING domain, leading to enhanced lipid anabolism and lipid droplet accumulation in pancreatic cancer cells.","method":"Mass spectrometry, co-immunoprecipitation, domain mapping, ubiquitination assay, lipid droplet staining, knockdown experiments","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus domain mapping and ubiquitination assay, single lab, multiple orthogonal methods","pmids":["34311082"],"is_preprint":false},{"year":2014,"finding":"TRIM15 localizes to focal adhesions via 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 protein1, and VASP.","method":"Fluorescence microscopy localization, domain deletion mapping, protein-protein interaction screen (co-immunoprecipitation), cell migration assay, knockdown","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct localization with domain mapping and functional consequence (migration), multiple methods, single lab","pmids":["25450970"],"is_preprint":false},{"year":2014,"finding":"TRIM15 localizes to focal contacts via an interaction between its coiled-coil domain and the LD2 motif of paxillin, independently of myosin-II. TRIM15 forms oligomers conferring restricted mobility (stable focal adhesion component), and its depletion impairs focal adhesion disassembly and cell migration, resulting in enlarged focal adhesions.","method":"Co-immunoprecipitation, domain mapping (coiled-coil domain to LD2 of paxillin), live imaging, FRAP, siRNA knockdown with focal adhesion turnover and migration readouts","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with domain mapping, FRAP demonstrating restricted mobility, functional KD phenotype; replicated independently of PMID:25450970","pmids":["25015296"],"is_preprint":false},{"year":2021,"finding":"TRIM15 is a TNF-α-induced late-response gene that inhibits the TNF-α-induced NF-κB pathway by interacting with TAK1 and promoting turnover of K63-linked ubiquitin chains on TAK1, in a PRY/SPRY domain-dependent manner. TRIM15 also interacts with TRIM8 and inhibits TRIM8 cytosolic translocation, thereby antagonizing TRIM8-modulated NF-κB activation.","method":"Co-immunoprecipitation, ubiquitination assay, domain mutants (PRY/SPRY), NF-κB reporter assays, knockdown/overexpression in multiple cell lines","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus domain mutants, single lab, multiple cell lines tested","pmids":["34871740"],"is_preprint":false},{"year":2022,"finding":"TRIM15 directly targets Keap1 for ubiquitination and degradation via its E3 ligase activity, preventing Keap1-mediated degradation of Nrf2 and leading to activation of the antioxidant response and promotion of NSCLC progression.","method":"Co-immunoprecipitation, immunofluorescence co-localization, in vitro ubiquitination assay, gain/loss-of-function experiments, in vivo xenograft models","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus functional rescue experiments, single lab","pmids":["35534896"],"is_preprint":false},{"year":2023,"finding":"TRIM15 mediates K63-linked polyubiquitination of LASP1, inducing its nuclear translocation, which increases AKT phosphorylation and Snail expression. TRIM15 expression is upregulated by AKT/FOXO1 signaling, forming a positive feedback loop that promotes TKI resistance in HCC.","method":"Co-immunoprecipitation, ubiquitination assay, nuclear/cytoplasmic fractionation, pathway inhibition, knockdown/overexpression experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, fractionation with functional consequence, single lab","pmids":["36670097"],"is_preprint":false},{"year":2025,"finding":"TRIM15 binds YAP and mediates K48-linked ubiquitination of YAP at K254, which disrupts the interaction between YAP and angiomotin, leading to enhanced YAP nuclear translocation. This TRIM15-YAP axis promotes chondrocyte senescence and osteoarthritis progression. Conditional Trim15 deletion in mouse chondrocytes impairs skeletal growth and embryonic chondrocyte senescence.","method":"Co-immunoprecipitation, ubiquitination assay with lysine site mutagenesis (K254), conditional knockout mouse model, in vivo OA models (surgery-induced and aging), AAV-shRNA knockdown, nuclear translocation imaging","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site-specific mutagenesis of ubiquitination site, conditional knockout in vivo models, multiple orthogonal methods, mechanistic rescue experiments","pmids":["40138455"],"is_preprint":false},{"year":2024,"finding":"TRIM15 ubiquitinates IGF2BP2 to enhance its phase separation function and stabilize TLR4 mRNA, thereby upregulating TLR4 and promoting pancreatic cancer progression.","method":"Transcriptomics, proteomics, co-immunoprecipitation, ubiquitination assay, orthotopic mouse transplantation model, knockdown/overexpression","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo model, single lab, multiple methods","pmids":["38657551"],"is_preprint":false},{"year":2025,"finding":"TRIM15 induces K63-linked ubiquitination of AKT at its pleckstrin homology (PH) domain via the RING domain, activating AKT signaling. HIF-1α promotes TRIM15 transcription by binding hypoxia response elements in the TRIM15 promoter.","method":"Co-immunoprecipitation, ubiquitination assay, RING domain mutant, domain mapping (PH domain of AKT), ChIP/promoter reporter for HIF-1α binding, in vivo xenograft models","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding, ubiquitination with domain mapping, RING mutant validation, single lab","pmids":["40026037"],"is_preprint":false},{"year":2025,"finding":"TRIM15 interacts with Axin1 through its coiled-coil domain and disrupts Axin1 polymerization, thereby preventing assembly of the β-catenin destruction complex and promoting Wnt/β-catenin signaling activation and colorectal cancer growth. TRIM15 is itself a Wnt target gene, forming a positive feedback loop. Conditional Trim15 genetic ablation in mice inhibits tumor formation in AOM/DSS-induced and ApcMin/+ CRC models.","method":"Co-immunoprecipitation, domain mapping (coiled-coil), Axin1 polymerization assay, Wnt reporter assay, conditional knockout mouse models (AOM/DSS and ApcMin/+), tumor growth assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — domain mapping, polymerization disruption assay, in vivo conditional knockout in two CRC models, multiple orthogonal methods","pmids":["41461634"],"is_preprint":false},{"year":2025,"finding":"TRIM15 promotes degradation of the transcription factor YY2 through the ubiquitin-proteasome system, leading to dysregulation of lipid metabolism (reduced FOXRED1 expression) and enhanced proliferation of esophageal adenocarcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor rescue, knockdown/overexpression, gene expression analysis","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination plus proteasome-dependent degradation rescue, single lab","pmids":["41237333"],"is_preprint":false},{"year":2026,"finding":"TRIM15 (Trim15) stabilizes VDAC3 via K6-linked ubiquitination (non-degradative), suppressing autophagy and mitophagy and elevating reactive oxygen species levels in hypopharyngeal squamous cell carcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assay (K6-linked), VDAC3 knockdown, autophagy/mitophagy assays, ROS measurement, xenograft models","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus linkage-specific ubiquitination assay, functional autophagy readouts, single lab","pmids":["41617671"],"is_preprint":false},{"year":2026,"finding":"TRIM15 interacts with Paxillin and mediates its ubiquitination via Lys11- and Lys29-linked polyubiquitin chains. TRIM15 also enhances the interaction between Paxillin and FAK, promoting Paxillin phosphorylation and ovarian cancer cell migration and proliferation.","method":"Mass spectrometry substrate identification, co-immunoprecipitation, ubiquitination assay (K11- and K29-linkage), phosphorylation assay, siRNA knockdown, colony formation and Transwell migration assays","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS substrate ID followed by Co-IP, linkage-specific ubiquitination assay, and phosphorylation readout, single lab","pmids":["42192404"],"is_preprint":false}],"current_model":"TRIM15 is a RING-domain E3 ubiquitin ligase that localizes to focal adhesions via its coiled-coil domain (interacting with paxillin LD2) and regulates focal adhesion turnover and cell migration; it catalyzes K63-linked polyubiquitination of ERK1/2 (promoting MEK-dependent ERK activation) and AKT (activating AKT signaling), K48-linked ubiquitination of YAP (disrupting angiomotin binding and driving nuclear YAP), K63-linked ubiquitination of LASP1 (nuclear translocation), degradative ubiquitination of Keap1 (activating Nrf2), APOA1, and YY2, non-degradative K6-linked ubiquitination of VDAC3 (suppressing autophagy), and linkage-specific ubiquitination of Paxillin (K11/K29) and IGF2BP2; it also disrupts Axin1 polymerization via its coiled-coil domain to promote Wnt/β-catenin signaling, and inhibits NF-κB by promoting K63-ubiquitin turnover on TAK1 through its PRY/SPRY domain, collectively placing TRIM15 as a multi-substrate ubiquitin ligase at the intersection of adhesion, proliferation, and inflammatory signaling pathways."},"narrative":{"mechanistic_narrative":"TRIM15 is a RING-domain E3 ubiquitin ligase that functions as a multi-substrate node coupling cell adhesion to proliferative and inflammatory signaling, predominantly acting through non-canonical and degradative polyubiquitination of diverse targets [PMID:34497368, PMID:25015296, PMID:41461634]. At the structural level, TRIM15 localizes to focal adhesions: it oligomerizes and binds the LD2 motif of paxillin through its coiled-coil domain, behaving as a stable, restricted-mobility adhesome component whose depletion impairs focal adhesion disassembly and cell migration [PMID:25015296]. Its catalytic output is strikingly linkage-diverse — it assembles K63-linked chains on ERK1/2 to promote MEK-dependent ERK activation (opposed by the deubiquitinase CYLD) [PMID:34497368] and on AKT at its PH domain to drive AKT signaling [PMID:40026037], builds non-degradative K6-linked chains on VDAC3 to stabilize it and suppress autophagy/mitophagy [PMID:41617671], generates K48-linked chains on YAP at K254 to displace angiomotin and enhance YAP nuclear translocation [PMID:40138455], and directs proteasomal degradation of Keap1 (activating Nrf2) [PMID:35534896], APOA1 [PMID:34311082], and the transcription factor YY2 [PMID:41237333]. Beyond enzymatic substrates, TRIM15 disrupts Axin1 polymerization via its coiled-coil domain to block β-catenin destruction-complex assembly and activate Wnt signaling [PMID:41461634], and inhibits TNF-α-induced NF-κB signaling by promoting turnover of K63-ubiquitin chains on TAK1 through its PRY/SPRY domain [PMID:34871740]. Across these axes TRIM15 is embedded in feed-forward loops — induced by AKT/FOXO1, HIF-1α, and Wnt signaling — that reinforce its pro-proliferative roles in multiple cancers and in chondrocyte senescence, where conditional Trim15 deletion impairs skeletal growth and tumor formation in vivo [PMID:36670097, PMID:40138455, PMID:40026037, PMID:41461634].","teleology":[{"year":2014,"claim":"Established TRIM15's subcellular home and its first functional role by showing it is a stable focal adhesion component that controls adhesion turnover and migration, defining the structural platform on which its later signaling activities operate.","evidence":"Fluorescence/live imaging, FRAP, domain mapping of coiled-coil to paxillin LD2 and of B-box2/PRY for localization, adhesome interaction screen, and knockdown migration assays in two independent studies","pmids":["25015296","25450970"],"confidence":"High","gaps":["Whether focal-adhesion localization requires its E3 ligase activity was not addressed","No ubiquitination substrate at adhesions identified in these studies","Mechanism linking adhesion residence to downstream signaling unresolved"]},{"year":2021,"claim":"Defined TRIM15 as a catalytically active E3 ligase using non-degradative K63 chains on ERK1/2 to enhance MEK-dependent activation, the first demonstration that TRIM15 ubiquitination can be activating rather than degradative.","evidence":"Co-IP, in vitro ubiquitination, acceptor-lysine mutagenesis, ERK-MEK interaction assays, and TRIM15/CYLD epistasis","pmids":["34497368"],"confidence":"High","gaps":["Did not address whether ERK ubiquitination occurs at focal adhesions","Structural basis of the mutually exclusive TRIM15/CYLD interaction not resolved"]},{"year":2021,"claim":"Showed TRIM15 also performs classical degradative ubiquitination (APOA1) and acts as a negative regulator of NF-κB via TAK1 K63-chain turnover, revealing that the same enzyme operates in both degradative and chain-editing modes through distinct domains.","evidence":"Mass spectrometry, reciprocal Co-IP, domain mapping (RING for catalysis, PRY/SPRY for substrate/TAK1 binding), ubiquitination assays, NF-κB reporters in multiple cell lines","pmids":["34311082","34871740"],"confidence":"Medium","gaps":["Single-lab findings without independent replication","Mechanism of how TRIM15 promotes TAK1 K63-chain turnover (recruitment of DUB vs. direct editing) unresolved","APOA1 ubiquitin linkage type not defined"]},{"year":2022,"claim":"Connected TRIM15 to the antioxidant axis by showing it degrades Keap1 to stabilize Nrf2, extending its substrate repertoire to a redox master regulator in lung cancer.","evidence":"Co-IP, immunofluorescence co-localization, in vitro ubiquitination, gain/loss-of-function, and xenograft models","pmids":["35534896"],"confidence":"Medium","gaps":["Keap1 ubiquitin linkage type not specified","Single lab","Direct vs. indirect engagement of Keap1 not fully resolved"]},{"year":2023,"claim":"Identified a positive feedback loop in which AKT/FOXO1 induces TRIM15, which in turn K63-ubiquitinates LASP1 to drive its nuclear translocation and further AKT phosphorylation, linking TRIM15 to TKI resistance.","evidence":"Co-IP, ubiquitination assay, nuclear/cytoplasmic fractionation, pathway inhibition, knockdown/overexpression in HCC","pmids":["36670097"],"confidence":"Medium","gaps":["LASP1 acceptor lysines not mapped","Single lab","Mechanism by which nuclear LASP1 increases AKT phosphorylation unresolved"]},{"year":2024,"claim":"Expanded TRIM15 substrates into RNA-binding regulation by showing it ubiquitinates IGF2BP2 to enhance its phase separation and stabilize TLR4 mRNA, linking the ligase to post-transcriptional control.","evidence":"Transcriptomics/proteomics, Co-IP, ubiquitination assay, orthotopic transplantation in pancreatic cancer","pmids":["38657551"],"confidence":"Medium","gaps":["IGF2BP2 ubiquitin linkage type not defined","Mechanistic link between ubiquitination and phase separation not structurally resolved","Single lab"]},{"year":2025,"claim":"Multiple 2025 studies broadened TRIM15 into Hippo, Wnt, AKT, and lipid-metabolism control, establishing it as a hub whose transcription is driven by HIF-1α and Wnt and validating roles in vivo via conditional knockouts.","evidence":"Site-specific lysine mutagenesis (YAP K254, AKT PH domain), coiled-coil-dependent Axin1 polymerization disruption assays, Wnt reporters, ChIP/promoter reporters, proteasome-rescue, and conditional Trim15 knockout mouse models (chondrocyte, AOM/DSS, ApcMin/+)","pmids":["40138455","40026037","41461634","41237333"],"confidence":"High","gaps":["Whether one cell type uses all of these substrate axes simultaneously is unknown","How substrate selection among the many targets is governed is unresolved","YY2 ubiquitin linkage type not specified"]},{"year":2026,"claim":"Refined TRIM15's linkage-specific repertoire by defining non-degradative K6 ubiquitination of VDAC3 (autophagy suppression) and K11/K29 ubiquitination of Paxillin coupled to enhanced Paxillin-FAK interaction, tying its catalytic chemistry back to its founding adhesion role.","evidence":"MS substrate ID, Co-IP, linkage-specific ubiquitination assays (K6; K11/K29), autophagy/mitophagy/ROS readouts, phosphorylation assays, and xenograft/migration models","pmids":["41617671","42192404"],"confidence":"Medium","gaps":["Single-lab findings","Functional consequence of specific K6/K11/K29 linkages at the molecular level not fully resolved","Acceptor lysines on Paxillin and VDAC3 not all mapped"]},{"year":null,"claim":"How a single E3 ligase achieves substrate- and linkage-specificity across degradative (K48), activating (K63), and non-degradative (K6, K11, K29) ubiquitination of structurally unrelated targets, and how this is coordinated in any one cellular context, remains unresolved.","evidence":"No single study reconciles the diverse substrate/linkage repertoire or defines context-specific substrate selection","pmids":[],"confidence":"Low","gaps":["No structural basis for linkage selectivity reported","No proteome-wide substrate map","Relationship between focal-adhesion residence and cytosolic/nuclear substrate engagement not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,5,7,9,11,12,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,7,9,12,13]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,5,7,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,10]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,7,9,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,5,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6,8,10]}],"complexes":["focal adhesion"],"partners":["PXN","TAK1","YAP1","AKT1","KEAP1","AXIN1","LASP1","VDAC3"],"other_free_text":[]}},"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":76,"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":44,"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":20,"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":18,"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":15,"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":10,"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":8,"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":2,"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":"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":"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},{"pmid":"42192404","id":"PMC_42192404","title":"TRIM15 Mediates ubiquitination of Paxillin to facilitate the progression of ovarian cancer.","date":"2026","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/42192404","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10978,"output_tokens":3705,"usd":0.044255,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11452,"output_tokens":3947,"usd":0.077967,"stage2_stop_reason":"end_turn"},"total_usd":0.122222,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM15 acts as a K63-linked polyubiquitin E3 ligase for ERK1/2, modifying defined lysine residues. This K63-linked ubiquitination enhances ERK interaction with and activation by MEK. CYLD serves as the opposing deubiquitinase of ERK1/2, and TRIM15 and CYLD regulate ERK ubiquitination through mutually exclusive interactions.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, mutagenesis of ubiquitin acceptor lysines, ERK-MEK interaction assays, TRIM15/CYLD knockdown with ERK activation readouts\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including in vitro ubiquitination, mutagenesis of substrate lysines, and functional epistasis; published in high-impact journal\",\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 and degradation via its RING domain, leading to enhanced lipid anabolism and lipid droplet accumulation in pancreatic cancer cells.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, domain mapping, ubiquitination assay, lipid droplet staining, knockdown experiments\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus domain mapping and ubiquitination assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34311082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIM15 localizes to focal adhesions via 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 protein1, and VASP.\",\n      \"method\": \"Fluorescence microscopy localization, domain deletion mapping, protein-protein interaction screen (co-immunoprecipitation), cell migration assay, knockdown\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct localization with domain mapping and functional consequence (migration), multiple methods, single lab\",\n      \"pmids\": [\"25450970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIM15 localizes to focal contacts via an interaction between its coiled-coil domain and the LD2 motif of paxillin, independently of myosin-II. TRIM15 forms oligomers conferring restricted mobility (stable focal adhesion component), and its depletion impairs focal adhesion disassembly and cell migration, resulting in enlarged focal adhesions.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping (coiled-coil domain to LD2 of paxillin), live imaging, FRAP, siRNA knockdown with focal adhesion turnover and migration readouts\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with domain mapping, FRAP demonstrating restricted mobility, functional KD phenotype; replicated independently of PMID:25450970\",\n      \"pmids\": [\"25015296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM15 is a TNF-α-induced late-response gene that inhibits the TNF-α-induced NF-κB pathway by interacting with TAK1 and promoting turnover of K63-linked ubiquitin chains on TAK1, in a PRY/SPRY domain-dependent manner. TRIM15 also interacts with TRIM8 and inhibits TRIM8 cytosolic translocation, thereby antagonizing TRIM8-modulated NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, domain mutants (PRY/SPRY), NF-κB reporter assays, knockdown/overexpression in multiple cell lines\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus domain mutants, single lab, multiple cell lines tested\",\n      \"pmids\": [\"34871740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM15 directly targets Keap1 for ubiquitination and degradation via its E3 ligase activity, preventing Keap1-mediated degradation of Nrf2 and leading to activation of the antioxidant response and promotion of NSCLC progression.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, in vitro ubiquitination assay, gain/loss-of-function experiments, in vivo xenograft models\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus functional rescue experiments, single lab\",\n      \"pmids\": [\"35534896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM15 mediates K63-linked polyubiquitination of LASP1, inducing its nuclear translocation, which increases AKT phosphorylation and Snail expression. TRIM15 expression is upregulated by AKT/FOXO1 signaling, forming a positive feedback loop that promotes TKI resistance in HCC.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, nuclear/cytoplasmic fractionation, pathway inhibition, knockdown/overexpression experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, fractionation with 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, which disrupts the interaction between YAP and angiomotin, leading to enhanced YAP nuclear translocation. This TRIM15-YAP axis promotes chondrocyte senescence and osteoarthritis progression. Conditional Trim15 deletion in mouse chondrocytes impairs skeletal growth and embryonic chondrocyte senescence.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with lysine site mutagenesis (K254), conditional knockout mouse model, in vivo OA models (surgery-induced and aging), AAV-shRNA knockdown, nuclear translocation imaging\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site-specific mutagenesis of ubiquitination site, conditional knockout in vivo models, multiple orthogonal methods, mechanistic rescue experiments\",\n      \"pmids\": [\"40138455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM15 ubiquitinates IGF2BP2 to enhance its phase separation function and stabilize TLR4 mRNA, thereby upregulating TLR4 and promoting pancreatic cancer progression.\",\n      \"method\": \"Transcriptomics, proteomics, co-immunoprecipitation, ubiquitination assay, orthotopic mouse transplantation model, knockdown/overexpression\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo model, single lab, multiple methods\",\n      \"pmids\": [\"38657551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM15 induces K63-linked ubiquitination of AKT at its pleckstrin homology (PH) domain via the RING domain, activating AKT signaling. HIF-1α promotes TRIM15 transcription by binding hypoxia response elements in the TRIM15 promoter.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, RING domain mutant, domain mapping (PH domain of AKT), ChIP/promoter reporter for HIF-1α binding, in vivo xenograft models\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding, ubiquitination with domain mapping, RING mutant validation, single lab\",\n      \"pmids\": [\"40026037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM15 interacts with Axin1 through its coiled-coil domain and disrupts Axin1 polymerization, thereby preventing assembly of the β-catenin destruction complex and promoting Wnt/β-catenin signaling activation and colorectal cancer growth. TRIM15 is itself a Wnt target gene, forming a positive feedback loop. Conditional Trim15 genetic ablation in mice inhibits tumor formation in AOM/DSS-induced and ApcMin/+ CRC models.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping (coiled-coil), Axin1 polymerization assay, Wnt reporter assay, conditional knockout mouse models (AOM/DSS and ApcMin/+), tumor growth assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — domain mapping, polymerization disruption assay, in vivo conditional knockout in two CRC models, multiple orthogonal methods\",\n      \"pmids\": [\"41461634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM15 promotes degradation of the transcription factor YY2 through the ubiquitin-proteasome system, leading to dysregulation of lipid metabolism (reduced FOXRED1 expression) and enhanced proliferation of esophageal adenocarcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor rescue, knockdown/overexpression, gene expression analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination plus proteasome-dependent degradation rescue, single lab\",\n      \"pmids\": [\"41237333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM15 (Trim15) stabilizes VDAC3 via K6-linked ubiquitination (non-degradative), suppressing autophagy and mitophagy and elevating reactive oxygen species levels in hypopharyngeal squamous cell carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K6-linked), VDAC3 knockdown, autophagy/mitophagy assays, ROS measurement, xenograft models\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus linkage-specific ubiquitination assay, functional autophagy readouts, single lab\",\n      \"pmids\": [\"41617671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM15 interacts with Paxillin and mediates its ubiquitination via Lys11- and Lys29-linked polyubiquitin chains. TRIM15 also enhances the interaction between Paxillin and FAK, promoting Paxillin phosphorylation and ovarian cancer cell migration and proliferation.\",\n      \"method\": \"Mass spectrometry substrate identification, co-immunoprecipitation, ubiquitination assay (K11- and K29-linkage), phosphorylation assay, siRNA knockdown, colony formation and Transwell migration assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS substrate ID followed by Co-IP, linkage-specific ubiquitination assay, and phosphorylation readout, single lab\",\n      \"pmids\": [\"42192404\"],\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 domain (interacting with paxillin LD2) and regulates focal adhesion turnover and cell migration; it catalyzes K63-linked polyubiquitination of ERK1/2 (promoting MEK-dependent ERK activation) and AKT (activating AKT signaling), K48-linked ubiquitination of YAP (disrupting angiomotin binding and driving nuclear YAP), K63-linked ubiquitination of LASP1 (nuclear translocation), degradative ubiquitination of Keap1 (activating Nrf2), APOA1, and YY2, non-degradative K6-linked ubiquitination of VDAC3 (suppressing autophagy), and linkage-specific ubiquitination of Paxillin (K11/K29) and IGF2BP2; it also disrupts Axin1 polymerization via its coiled-coil domain to promote Wnt/β-catenin signaling, and inhibits NF-κB by promoting K63-ubiquitin turnover on TAK1 through its PRY/SPRY domain, collectively placing TRIM15 as a multi-substrate ubiquitin ligase at the intersection of adhesion, proliferation, and inflammatory signaling pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM15 is a RING-domain E3 ubiquitin ligase that functions as a multi-substrate node coupling cell adhesion to proliferative and inflammatory signaling, predominantly acting through non-canonical and degradative polyubiquitination of diverse targets [#0, #3, #10]. At the structural level, TRIM15 localizes to focal adhesions: it oligomerizes and binds the LD2 motif of paxillin through its coiled-coil domain, behaving as a stable, restricted-mobility adhesome component whose depletion impairs focal adhesion disassembly and cell migration [#3]. Its catalytic output is strikingly linkage-diverse — it assembles K63-linked chains on ERK1/2 to promote MEK-dependent ERK activation (opposed by the deubiquitinase CYLD) [#0] and on AKT at its PH domain to drive AKT signaling [#9], builds non-degradative K6-linked chains on VDAC3 to stabilize it and suppress autophagy/mitophagy [#12], generates K48-linked chains on YAP at K254 to displace angiomotin and enhance YAP nuclear translocation [#7], and directs proteasomal degradation of Keap1 (activating Nrf2) [#5], APOA1 [#1], and the transcription factor YY2 [#11]. Beyond enzymatic substrates, TRIM15 disrupts Axin1 polymerization via its coiled-coil domain to block β-catenin destruction-complex assembly and activate Wnt signaling [#10], and inhibits TNF-α-induced NF-κB signaling by promoting turnover of K63-ubiquitin chains on TAK1 through its PRY/SPRY domain [#4]. Across these axes TRIM15 is embedded in feed-forward loops — induced by AKT/FOXO1, HIF-1α, and Wnt signaling — that reinforce its pro-proliferative roles in multiple cancers and in chondrocyte senescence, where conditional Trim15 deletion impairs skeletal growth and tumor formation in vivo [#6, #7, #9, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established TRIM15's subcellular home and its first functional role by showing it is a stable focal adhesion component that controls adhesion turnover and migration, defining the structural platform on which its later signaling activities operate.\",\n      \"evidence\": \"Fluorescence/live imaging, FRAP, domain mapping of coiled-coil to paxillin LD2 and of B-box2/PRY for localization, adhesome interaction screen, and knockdown migration assays in two independent studies\",\n      \"pmids\": [\"25015296\", \"25450970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether focal-adhesion localization requires its E3 ligase activity was not addressed\", \"No ubiquitination substrate at adhesions identified in these studies\", \"Mechanism linking adhesion residence to downstream signaling unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined TRIM15 as a catalytically active E3 ligase using non-degradative K63 chains on ERK1/2 to enhance MEK-dependent activation, the first demonstration that TRIM15 ubiquitination can be activating rather than degradative.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination, acceptor-lysine mutagenesis, ERK-MEK interaction assays, and TRIM15/CYLD epistasis\",\n      \"pmids\": [\"34497368\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether ERK ubiquitination occurs at focal adhesions\", \"Structural basis of the mutually exclusive TRIM15/CYLD interaction not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed TRIM15 also performs classical degradative ubiquitination (APOA1) and acts as a negative regulator of NF-κB via TAK1 K63-chain turnover, revealing that the same enzyme operates in both degradative and chain-editing modes through distinct domains.\",\n      \"evidence\": \"Mass spectrometry, reciprocal Co-IP, domain mapping (RING for catalysis, PRY/SPRY for substrate/TAK1 binding), ubiquitination assays, NF-κB reporters in multiple cell lines\",\n      \"pmids\": [\"34311082\", \"34871740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings without independent replication\", \"Mechanism of how TRIM15 promotes TAK1 K63-chain turnover (recruitment of DUB vs. direct editing) unresolved\", \"APOA1 ubiquitin linkage type not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected TRIM15 to the antioxidant axis by showing it degrades Keap1 to stabilize Nrf2, extending its substrate repertoire to a redox master regulator in lung cancer.\",\n      \"evidence\": \"Co-IP, immunofluorescence co-localization, in vitro ubiquitination, gain/loss-of-function, and xenograft models\",\n      \"pmids\": [\"35534896\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Keap1 ubiquitin linkage type not specified\", \"Single lab\", \"Direct vs. indirect engagement of Keap1 not fully resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a positive feedback loop in which AKT/FOXO1 induces TRIM15, which in turn K63-ubiquitinates LASP1 to drive its nuclear translocation and further AKT phosphorylation, linking TRIM15 to TKI resistance.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, nuclear/cytoplasmic fractionation, pathway inhibition, knockdown/overexpression in HCC\",\n      \"pmids\": [\"36670097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LASP1 acceptor lysines not mapped\", \"Single lab\", \"Mechanism by which nuclear LASP1 increases AKT phosphorylation unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded TRIM15 substrates into RNA-binding regulation by showing it ubiquitinates IGF2BP2 to enhance its phase separation and stabilize TLR4 mRNA, linking the ligase to post-transcriptional control.\",\n      \"evidence\": \"Transcriptomics/proteomics, Co-IP, ubiquitination assay, orthotopic transplantation in pancreatic cancer\",\n      \"pmids\": [\"38657551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IGF2BP2 ubiquitin linkage type not defined\", \"Mechanistic link between ubiquitination and phase separation not structurally resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple 2025 studies broadened TRIM15 into Hippo, Wnt, AKT, and lipid-metabolism control, establishing it as a hub whose transcription is driven by HIF-1α and Wnt and validating roles in vivo via conditional knockouts.\",\n      \"evidence\": \"Site-specific lysine mutagenesis (YAP K254, AKT PH domain), coiled-coil-dependent Axin1 polymerization disruption assays, Wnt reporters, ChIP/promoter reporters, proteasome-rescue, and conditional Trim15 knockout mouse models (chondrocyte, AOM/DSS, ApcMin/+)\",\n      \"pmids\": [\"40138455\", \"40026037\", \"41461634\", \"41237333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether one cell type uses all of these substrate axes simultaneously is unknown\", \"How substrate selection among the many targets is governed is unresolved\", \"YY2 ubiquitin linkage type not specified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Refined TRIM15's linkage-specific repertoire by defining non-degradative K6 ubiquitination of VDAC3 (autophagy suppression) and K11/K29 ubiquitination of Paxillin coupled to enhanced Paxillin-FAK interaction, tying its catalytic chemistry back to its founding adhesion role.\",\n      \"evidence\": \"MS substrate ID, Co-IP, linkage-specific ubiquitination assays (K6; K11/K29), autophagy/mitophagy/ROS readouts, phosphorylation assays, and xenograft/migration models\",\n      \"pmids\": [\"41617671\", \"42192404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings\", \"Functional consequence of specific K6/K11/K29 linkages at the molecular level not fully resolved\", \"Acceptor lysines on Paxillin and VDAC3 not all mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single E3 ligase achieves substrate- and linkage-specificity across degradative (K48), activating (K63), and non-degradative (K6, K11, K29) ubiquitination of structurally unrelated targets, and how this is coordinated in any one cellular context, remains unresolved.\",\n      \"evidence\": \"No single study reconciles the diverse substrate/linkage repertoire or defines context-specific substrate selection\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural basis for linkage selectivity reported\", \"No proteome-wide substrate map\", \"Relationship between focal-adhesion residence and cytosolic/nuclear substrate engagement not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 5, 7, 9, 11, 12, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 7, 9, 12, 13]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 5, 7, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005925\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 7, 9, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 5, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6, 8, 10]}\n    ],\n    \"complexes\": [\"focal adhesion\"],\n    \"partners\": [\"PXN\", \"TAK1\", \"YAP1\", \"AKT1\", \"KEAP1\", \"AXIN1\", \"LASP1\", \"VDAC3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}