{"gene":"TRIM39","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2008,"finding":"TRIM39 directly binds MOAP-1 (a Bax-activating protein) and inhibits its poly-ubiquitination, thereby stabilizing MOAP-1 and promoting apoptosis. TRIM39 elevates MOAP-1 levels in mitochondria and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax.","method":"Co-immunoprecipitation, ubiquitination assays, mitochondrial fractionation, cytochrome c release assay, siRNA knockdown","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (binding, ubiquitination inhibition, mitochondrial fractionation, functional apoptosis assays) in a single study","pmids":["19100260"],"is_preprint":false},{"year":2012,"finding":"TRIM39 directly inhibits APC/C(Cdh1)-mediated ubiquitylation of MOAP-1, identifying TRIM39 as a novel APC/C regulator. Cdh1 knockdown similarly stabilizes MOAP-1 and enhances etoposide-induced Bax activation and apoptosis.","method":"In vitro ubiquitylation assay, siRNA knockdown of Cdh1 and Trim39, co-immunoprecipitation, cell death assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution of APC/C inhibition plus genetic epistasis (Cdh1 KD rescues MOAP-1 levels), replicated across two independent labs (PMID 19100260 and 22529100)","pmids":["22529100"],"is_preprint":false},{"year":2012,"finding":"TRIM39 directly binds and ubiquitylates p53 in vitro and in vivo, leading to p53 proteasomal degradation. Depletion of TRIM39 increases p53 protein levels and retards cell growth, identifying TRIM39 as an E3 ligase for p53 distinct from MDM2.","method":"In vitro ubiquitylation assay, co-immunoprecipitation, siRNA knockdown, cell growth and apoptosis assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro ubiquitylation with purified components plus in-cell validation across multiple cell lines","pmids":["23213260"],"is_preprint":false},{"year":2012,"finding":"TRIM39 stabilizes p21 by binding p21 and preventing CRL4(Cdt2) E3 ligase from accessing p21 (blocking Cdt2 binding), thereby inhibiting ubiquitylation and proteasomal degradation of p21. This mechanism controls G1/S transition and DNA damage-induced G2 checkpoint.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, cell cycle analysis (flow cytometry), competitive binding assay (TRIM39 blocks Cdt2-p21 interaction)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing mechanism; loss-of-function phenotype (G2 checkpoint abrogation) linked directly to p21 as downstream effector","pmids":["23213251"],"is_preprint":false},{"year":2015,"finding":"TRIM39 stabilizes Cactin protein (identified by yeast two-hybrid screening), and Cactin is upregulated after TNFα stimulation. TRIM39 knockdown activates NFκB signaling, indicating TRIM39 negatively regulates NFκB in collaboration with Cactin.","method":"Yeast two-hybrid screening, co-immunoprecipitation, siRNA knockdown, NFκB reporter assay, Western blot","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2-3 — binding identified by Y2H and confirmed by Co-IP; functional consequence (NFκB activation) upon knockdown, but mechanistic detail of how stabilization occurs is incomplete","pmids":["26363554"],"is_preprint":false},{"year":2022,"finding":"TRIM39 acts as a SUMO-targeted E3 ubiquitin ligase (STUbL) for the transcription factor NFATc3 in neurons. TRIM39 binds and ubiquitinates NFATc3 in vitro and in cells, reducing NFATc3 protein level and transcriptional activity. TRIM39 preferentially ubiquitinates SUMOylated NFATc3; mutation of SUMO-interacting motifs in TRIM39 or SUMOylation sites in NFATc3 reduces their interaction and ubiquitination. TRIM17 inhibits TRIM39-mediated NFATc3 ubiquitination by reducing TRIM39's E3 ligase activity and the NFATc3/TRIM39 interaction.","method":"In vitro ubiquitylation assay with SUMOylated vs. unmodified substrates, co-immunoprecipitation, mutagenesis of SIMs and SUMOylation sites, neuronal knockdown with apoptosis readout","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution with SUMOylated substrates plus mutagenesis of key motifs plus cellular loss-of-function with defined phenotype","pmids":["35449213"],"is_preprint":false},{"year":2024,"finding":"TRIM39 directly interacts with PRDX3 and induces its K48-linked poly-ubiquitination at K73 and K149, leading to proteasomal degradation of PRDX3, ROS accumulation, and inflammatory cytokine generation that aggravates renal fibrosis.","method":"Co-immunoprecipitation, ubiquitination assay (K48 chain-specific), site-directed mutagenesis (K73R, K149R), siRNA knockdown in UUO mouse model and HK-2 cells","journal":"Cell death discovery","confidence":"High","confidence_rationale":"Tier 2 — binding and site-specific ubiquitination confirmed by mutagenesis plus in vivo mouse model validation","pmids":["38195664"],"is_preprint":false},{"year":2025,"finding":"TRIM39 interacts with p62 and facilitates its K48-linked ubiquitination, leading to decreased p62 stability. Reduced p62 releases KEAP1, which subsequently inhibits the NRF2-HO-1 pathway, promoting hepatocellular carcinoma growth.","method":"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown in vitro and in vivo xenograft models, rescue by p62 overexpression","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP and ubiquitination assay with pathway rescue; single lab, single study","pmids":["41422284"],"is_preprint":false},{"year":2025,"finding":"TRIM39 mediates SUMOylation of ESR1 (estrogen receptor alpha), enhancing ESR1 protein stability and strengthening E2-ESR1 signaling, thereby alleviating aortic dissection progression.","method":"Co-immunoprecipitation, bioinformatics prediction (UBIBROWSER, GPS-SUMO), overexpression in AD mouse and cell models, Western blot for ESR1 stability","journal":"Atherosclerosis","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP and functional overexpression data; SUMOylation E3 ligase activity of TRIM39 for ESR1 not reconstituted in vitro","pmids":["40921118"],"is_preprint":false},{"year":2025,"finding":"TRIM39 deubiquitinates RNF168, upregulating RNF168 protein levels in TNBC cells, which suppresses autophagy-coupled ferroptosis and confers ferroptosis resistance.","method":"Knockdown experiments, ubiquitination/deubiquitination assays, in vivo xenograft model","journal":"NPJ breast cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional link established by knockdown and rescue in vivo; deubiquitinase activity is unexpected for a RING E3 ligase and warrants further confirmation","pmids":["41034232"],"is_preprint":false},{"year":2000,"finding":"TRIM39 (originally named testis-abundant finger protein/tfp) was cloned and characterized as an RBCC-B30.2 (RING-B-box-coiled coil) domain protein encoded in the MHC class I region, highly expressed in testis.","method":"Molecular cloning, Northern blot, genomic mapping","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — initial cloning and domain characterization; foundational identification paper","pmids":["11006080"],"is_preprint":false}],"current_model":"TRIM39 is a RING-domain E3 ubiquitin ligase that regulates apoptosis and cell cycle progression through multiple substrates: it stabilizes MOAP-1 (by blocking APC/C(Cdh1)-mediated ubiquitylation) and p21 (by blocking CRL4(Cdt2) access), directly ubiquitylates and degrades p53 and NFATc3 (the latter as a SUMO-targeted E3 STUbL), ubiquitylates PRDX3 (K48-linked, at K73/K149) and p62 to promote their proteasomal degradation, and stabilizes Cactin to negatively regulate NFκB signaling."},"narrative":{"teleology":[{"year":2000,"claim":"Identification of TRIM39 as an RBCC/B30.2-domain protein encoded in the MHC class I region established the gene's domain architecture and predicted E3 ligase function, but left substrates and biological roles unknown.","evidence":"Molecular cloning, Northern blot, and genomic mapping from human testis cDNA","pmids":["11006080"],"confidence":"Medium","gaps":["No substrates or enzymatic activity demonstrated","Expression beyond testis not systematically characterized"]},{"year":2008,"claim":"The first functional role was established when TRIM39 was shown to bind and stabilize the Bax-activating protein MOAP-1 by inhibiting its poly-ubiquitination, linking TRIM39 to mitochondrial apoptosis.","evidence":"Co-immunoprecipitation, ubiquitination assays, mitochondrial fractionation, and cytochrome c release assay in mammalian cells","pmids":["19100260"],"confidence":"High","gaps":["The E3 ligase responsible for MOAP-1 ubiquitylation that TRIM39 counteracts was not identified","Whether TRIM39's RING domain catalytic activity was required was untested"]},{"year":2012,"claim":"Three major substrates were defined in rapid succession: TRIM39 inhibits APC/C(Cdh1)-mediated MOAP-1 ubiquitylation, directly ubiquitylates p53 for proteasomal degradation independently of MDM2, and stabilizes p21 by blocking CRL4(Cdt2) access—establishing TRIM39 as a multifunctional node connecting apoptosis and cell cycle control.","evidence":"In vitro reconstituted ubiquitylation assays, epistasis experiments (Cdh1 knockdown), competitive binding assays (TRIM39 blocks Cdt2–p21 interaction), cell cycle analysis by flow cytometry across multiple cell lines","pmids":["22529100","23213260","23213251"],"confidence":"High","gaps":["How TRIM39 simultaneously stabilizes some substrates (MOAP-1, p21) while degrading others (p53) was mechanistically unexplained","Structural basis for substrate selectivity unknown","In vivo validation in animal models was lacking"]},{"year":2015,"claim":"TRIM39 was connected to innate immune signaling when it was found to stabilize Cactin and negatively regulate NF-κB, broadening its functional scope beyond cell cycle and apoptosis.","evidence":"Yeast two-hybrid screen, co-immunoprecipitation, NF-κB reporter assay upon TRIM39 knockdown","pmids":["26363554"],"confidence":"Medium","gaps":["Mechanism by which TRIM39 stabilizes Cactin (direct deubiquitylation vs. shielding) not resolved","Whether Cactin is a direct ubiquitylation substrate or a binding partner was unclear"]},{"year":2022,"claim":"TRIM39 was demonstrated to function as a SUMO-targeted ubiquitin ligase (STUbL) for NFATc3 in neurons, revealing that substrate SUMOylation is a prerequisite for TRIM39-mediated ubiquitylation and providing a selectivity mechanism.","evidence":"In vitro ubiquitylation with SUMOylated vs. unmodified NFATc3, mutagenesis of SUMO-interacting motifs in TRIM39 and SUMOylation sites in NFATc3, neuronal apoptosis readout","pmids":["35449213"],"confidence":"High","gaps":["Whether STUbL activity applies to other TRIM39 substrates beyond NFATc3 is untested","The relative contribution of SIM-dependent vs. SIM-independent ubiquitylation in physiological contexts is undefined"]},{"year":2024,"claim":"Site-specific K48-linked ubiquitylation of PRDX3 at K73 and K149 by TRIM39 was mapped, linking TRIM39 to mitochondrial redox control and renal fibrosis through ROS accumulation and inflammatory cytokine generation.","evidence":"Co-immunoprecipitation, K48 chain-specific ubiquitination assay, K73R/K149R mutagenesis, UUO mouse model and HK-2 cells","pmids":["38195664"],"confidence":"High","gaps":["Whether TRIM39 localizes to mitochondria to access PRDX3 or acts on cytosolic pools is unclear","Upstream signals regulating TRIM39 activity in renal injury not identified"]},{"year":2025,"claim":"TRIM39 was shown to K48-ubiquitylate p62/SQSTM1, releasing KEAP1 to suppress the NRF2-HO-1 antioxidant axis, and separately reported to deubiquitylate RNF168 to confer ferroptosis resistance—expanding its substrate range but raising questions about dual E3/DUB activity.","evidence":"Co-IP and ubiquitination assays with p62 plus xenograft rescue; knockdown/deubiquitination assays with RNF168 in TNBC cells and xenograft models","pmids":["41422284","41034232"],"confidence":"Medium","gaps":["Reported deubiquitinase activity toward RNF168 is mechanistically unexpected for a RING E3 ligase and requires biochemical reconstitution with purified components","p62 ubiquitylation sites not mapped","Whether p62 degradation and RNF168 stabilization occur in the same cellular context is unknown"]},{"year":null,"claim":"Key unresolved questions include the structural basis for TRIM39's substrate selectivity across its diverse targets, whether its reported deubiquitinase activity is direct or indirect, and the physiological signals that switch TRIM39 between stabilizing and degradative modes.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No crystal or cryo-EM structure of TRIM39 or its substrate complexes","No systematic identification of TRIM39 regulators or post-translational modifications controlling its activity","In vivo knockout phenotype in mammals not reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3,5,6,7]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[2,5,6,7]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,3,5]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,5,6,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]}],"complexes":[],"partners":["MOAP1","TP53","CDKN1A","NFATC3","CACTIN","PRDX3","SQSTM1","CDH1"],"other_free_text":[]},"mechanistic_narrative":"TRIM39 is a RING-domain E3 ubiquitin ligase that controls apoptosis, cell cycle progression, and inflammatory signaling by selectively ubiquitylating or stabilizing multiple substrates. It directly ubiquitylates and promotes proteasomal degradation of p53, NFATc3 (functioning as a SUMO-targeted ubiquitin ligase/STUbL), PRDX3 (K48-linked ubiquitination at K73/K149), and p62 (K48-linked), while stabilizing MOAP-1 by blocking APC/C(Cdh1)-mediated ubiquitylation and stabilizing p21 by preventing CRL4(Cdt2) access [PMID:22529100, PMID:23213260, PMID:23213251, PMID:35449213, PMID:38195664, PMID:41422284]. Through these activities, TRIM39 promotes Bax-dependent apoptosis via MOAP-1, enforces G1/S and DNA damage-induced G2 checkpoints via p21, modulates NF-κB signaling through Cactin stabilization, and influences oxidative stress responses through PRDX3 degradation and p62-dependent NRF2 pathway suppression [PMID:19100260, PMID:23213251, PMID:26363554, PMID:38195664, PMID:41422284]."},"prefetch_data":{"uniprot":{"accession":"Q9HCM9","full_name":"E3 ubiquitin-protein ligase TRIM39","aliases":["RING finger protein 23","RING-type E3 ubiquitin transferase TRIM39","Testis-abundant finger protein","Tripartite motif-containing protein 39"],"length_aa":518,"mass_kda":59.7,"function":"E3 ubiquitin-protein ligase (PubMed:22529100). May facilitate apoptosis by inhibiting APC/C-Cdh1-mediated poly-ubiquitination and subsequent proteasome-mediated degradation of the pro-apoptotic protein MOAP1 (PubMed:19100260, PubMed:22529100). Regulates the G1/S transition of the cell cycle and DNA damage-induced G2 arrest by stabilizing CDKN1A/p21 (PubMed:23213251). Positively regulates CDKN1A/p21 stability by competing with DTL for CDKN1A/p21 binding, therefore disrupting DCX(DTL) E3 ubiquitin ligase complex-mediated CDKN1A/p21 ubiquitination and degradation (PubMed:23213251) Regulates the G1/S transition of the cell cycle and DNA damage-induced G2 arrest by stabilizing CDKN1A/p21 (PubMed:23213251). Positively regulates CDKN1A/p21 stability by competing with DTL for CDKN1A/p21 binding, therefore disrupting DCX(DTL) E3 ubiquitin ligase complex-mediated CDKN1A/p21 ubiquitination and degradation (PubMed:23213251). Negatively regulates the canonical NF-kappa-B signaling pathway via stabilization of CACTIN in an ubiquitination-independent manner (PubMed:26363554)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9HCM9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM39","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRIM39","total_profiled":1310},"omim":[{"mim_id":"618536","title":"CACTIN, SPLICEOSOME C COMPLEX SUBUNIT; CACTIN","url":"https://www.omim.org/entry/618536"},{"mim_id":"612524","title":"RIBONUCLEASE P/MRP SUBUNIT p21; RPP21","url":"https://www.omim.org/entry/612524"},{"mim_id":"605700","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 39; TRIM39","url":"https://www.omim.org/entry/605700"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRIM39"},"hgnc":{"alias_symbol":[],"prev_symbol":["RNF23"]},"alphafold":{"accession":"Q9HCM9","domains":[{"cath_id":"2.60.120.920","chopping":"322-511","consensus_level":"high","plddt":88.7345,"start":322,"end":511}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCM9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCM9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCM9-F1-predicted_aligned_error_v6.png","plddt_mean":84.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM39","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM39"},"sequence":{"accession":"Q9HCM9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HCM9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HCM9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCM9"}},"corpus_meta":[{"pmid":"26363554","id":"PMC_26363554","title":"TRIM39 negatively regulates the NFκB-mediated signaling pathway through stabilization of Cactin.","date":"2015","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/26363554","citation_count":54,"is_preprint":false},{"pmid":"26784918","id":"PMC_26784918","title":"Fish TRIM39 regulates cell cycle progression and exerts its antiviral function against iridovirus and nodavirus.","date":"2016","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26784918","citation_count":54,"is_preprint":false},{"pmid":"22529100","id":"PMC_22529100","title":"The Trim39 ubiquitin ligase inhibits APC/CCdh1-mediated degradation of the Bax activator MOAP-1.","date":"2012","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22529100","citation_count":54,"is_preprint":false},{"pmid":"19100260","id":"PMC_19100260","title":"TRIM39 is a MOAP-1-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process.","date":"2008","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/19100260","citation_count":48,"is_preprint":false},{"pmid":"23213251","id":"PMC_23213251","title":"TRIM39 regulates cell cycle progression and DNA damage responses via stabilizing p21.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23213251","citation_count":43,"is_preprint":false},{"pmid":"23213260","id":"PMC_23213260","title":"Ubiquitylation of p53 by the APC/C inhibitor Trim39.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23213260","citation_count":40,"is_preprint":false},{"pmid":"20875797","id":"PMC_20875797","title":"TRIM39 and RNF39 are associated with Behçet's disease independently of HLA-B∗51 and -A∗26.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20875797","citation_count":32,"is_preprint":false},{"pmid":"33311639","id":"PMC_33311639","title":"Nasopharyngeal carcinoma MHC region deep sequencing identifies HLA and novel non-HLA TRIM31 and TRIM39 loci.","date":"2020","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/33311639","citation_count":24,"is_preprint":false},{"pmid":"11006080","id":"PMC_11006080","title":"Molecular cloning of testis-abundant finger Protein/Ring finger protein 23 (RNF23), a novel RING-B box-coiled coil-B30.2 protein on the class I region of the human MHC.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11006080","citation_count":22,"is_preprint":false},{"pmid":"35449213","id":"PMC_35449213","title":"Trim39 regulates neuronal apoptosis by acting as a SUMO-targeted E3 ubiquitin-ligase for the transcription factor NFATc3.","date":"2022","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/35449213","citation_count":12,"is_preprint":false},{"pmid":"38195664","id":"PMC_38195664","title":"The E3 ubiquitin ligase TRIM39 modulates renal fibrosis induced by unilateral ureteral obstruction through regulating proteasomal degradation of PRDX3.","date":"2024","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/38195664","citation_count":11,"is_preprint":false},{"pmid":"35465405","id":"PMC_35465405","title":"Sequence Variant in the TRIM39-RPP21 Gene Readthrough is Shared Across a Cohort of Arabian Foals Diagnosed with Juvenile Idiopathic Epilepsy.","date":"2022","source":"Journal of genetic mutation disorders","url":"https://pubmed.ncbi.nlm.nih.gov/35465405","citation_count":5,"is_preprint":false},{"pmid":"35514248","id":"PMC_35514248","title":"Nile tilapia TRIM39 recruits I3K413 and I3KL45 as adaptors and is involved in the NF-κB pathway.","date":"2022","source":"Journal of fish biology","url":"https://pubmed.ncbi.nlm.nih.gov/35514248","citation_count":4,"is_preprint":false},{"pmid":"31623255","id":"PMC_31623255","title":"TRIM39-RPP21 Variants (∆19InsCCC) Are Not Associated with Juvenile Idiopathic Epilepsy in Egyptian Arabian Horses.","date":"2019","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/31623255","citation_count":4,"is_preprint":false},{"pmid":"41034232","id":"PMC_41034232","title":"TRIM39-mediated deubiquitination upregulates RNF168 to evade autophagy-ferroptosis in triple-negative breast cancer.","date":"2025","source":"NPJ breast cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41034232","citation_count":1,"is_preprint":false},{"pmid":"40921118","id":"PMC_40921118","title":"TRIM39 reinforces E2-ESR1 signaling through SUMOylation of ESR1 to hinder the progression of aortic dissection.","date":"2025","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/40921118","citation_count":1,"is_preprint":false},{"pmid":"41422284","id":"PMC_41422284","title":"TRIM39 aggravates hepatocellular carcinoma growth through targeting the p62-KEAP1-NRF2 axis.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41422284","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9150,"output_tokens":2802,"usd":0.03474},"stage2":{"model":"claude-opus-4-6","input_tokens":6151,"output_tokens":2408,"usd":0.136433},"total_usd":0.171173,"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\": 2008,\n      \"finding\": \"TRIM39 directly binds MOAP-1 (a Bax-activating protein) and inhibits its poly-ubiquitination, thereby stabilizing MOAP-1 and promoting apoptosis. TRIM39 elevates MOAP-1 levels in mitochondria and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, mitochondrial fractionation, cytochrome c release assay, siRNA knockdown\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (binding, ubiquitination inhibition, mitochondrial fractionation, functional apoptosis assays) in a single study\",\n      \"pmids\": [\"19100260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM39 directly inhibits APC/C(Cdh1)-mediated ubiquitylation of MOAP-1, identifying TRIM39 as a novel APC/C regulator. Cdh1 knockdown similarly stabilizes MOAP-1 and enhances etoposide-induced Bax activation and apoptosis.\",\n      \"method\": \"In vitro ubiquitylation assay, siRNA knockdown of Cdh1 and Trim39, co-immunoprecipitation, cell death assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution of APC/C inhibition plus genetic epistasis (Cdh1 KD rescues MOAP-1 levels), replicated across two independent labs (PMID 19100260 and 22529100)\",\n      \"pmids\": [\"22529100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM39 directly binds and ubiquitylates p53 in vitro and in vivo, leading to p53 proteasomal degradation. Depletion of TRIM39 increases p53 protein levels and retards cell growth, identifying TRIM39 as an E3 ligase for p53 distinct from MDM2.\",\n      \"method\": \"In vitro ubiquitylation assay, co-immunoprecipitation, siRNA knockdown, cell growth and apoptosis assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro ubiquitylation with purified components plus in-cell validation across multiple cell lines\",\n      \"pmids\": [\"23213260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM39 stabilizes p21 by binding p21 and preventing CRL4(Cdt2) E3 ligase from accessing p21 (blocking Cdt2 binding), thereby inhibiting ubiquitylation and proteasomal degradation of p21. This mechanism controls G1/S transition and DNA damage-induced G2 checkpoint.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, cell cycle analysis (flow cytometry), competitive binding assay (TRIM39 blocks Cdt2-p21 interaction)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing mechanism; loss-of-function phenotype (G2 checkpoint abrogation) linked directly to p21 as downstream effector\",\n      \"pmids\": [\"23213251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM39 stabilizes Cactin protein (identified by yeast two-hybrid screening), and Cactin is upregulated after TNFα stimulation. TRIM39 knockdown activates NFκB signaling, indicating TRIM39 negatively regulates NFκB in collaboration with Cactin.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, siRNA knockdown, NFκB reporter assay, Western blot\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — binding identified by Y2H and confirmed by Co-IP; functional consequence (NFκB activation) upon knockdown, but mechanistic detail of how stabilization occurs is incomplete\",\n      \"pmids\": [\"26363554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM39 acts as a SUMO-targeted E3 ubiquitin ligase (STUbL) for the transcription factor NFATc3 in neurons. TRIM39 binds and ubiquitinates NFATc3 in vitro and in cells, reducing NFATc3 protein level and transcriptional activity. TRIM39 preferentially ubiquitinates SUMOylated NFATc3; mutation of SUMO-interacting motifs in TRIM39 or SUMOylation sites in NFATc3 reduces their interaction and ubiquitination. TRIM17 inhibits TRIM39-mediated NFATc3 ubiquitination by reducing TRIM39's E3 ligase activity and the NFATc3/TRIM39 interaction.\",\n      \"method\": \"In vitro ubiquitylation assay with SUMOylated vs. unmodified substrates, co-immunoprecipitation, mutagenesis of SIMs and SUMOylation sites, neuronal knockdown with apoptosis readout\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution with SUMOylated substrates plus mutagenesis of key motifs plus cellular loss-of-function with defined phenotype\",\n      \"pmids\": [\"35449213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM39 directly interacts with PRDX3 and induces its K48-linked poly-ubiquitination at K73 and K149, leading to proteasomal degradation of PRDX3, ROS accumulation, and inflammatory cytokine generation that aggravates renal fibrosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48 chain-specific), site-directed mutagenesis (K73R, K149R), siRNA knockdown in UUO mouse model and HK-2 cells\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — binding and site-specific ubiquitination confirmed by mutagenesis plus in vivo mouse model validation\",\n      \"pmids\": [\"38195664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM39 interacts with p62 and facilitates its K48-linked ubiquitination, leading to decreased p62 stability. Reduced p62 releases KEAP1, which subsequently inhibits the NRF2-HO-1 pathway, promoting hepatocellular carcinoma growth.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown in vitro and in vivo xenograft models, rescue by p62 overexpression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP and ubiquitination assay with pathway rescue; single lab, single study\",\n      \"pmids\": [\"41422284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM39 mediates SUMOylation of ESR1 (estrogen receptor alpha), enhancing ESR1 protein stability and strengthening E2-ESR1 signaling, thereby alleviating aortic dissection progression.\",\n      \"method\": \"Co-immunoprecipitation, bioinformatics prediction (UBIBROWSER, GPS-SUMO), overexpression in AD mouse and cell models, Western blot for ESR1 stability\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP and functional overexpression data; SUMOylation E3 ligase activity of TRIM39 for ESR1 not reconstituted in vitro\",\n      \"pmids\": [\"40921118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM39 deubiquitinates RNF168, upregulating RNF168 protein levels in TNBC cells, which suppresses autophagy-coupled ferroptosis and confers ferroptosis resistance.\",\n      \"method\": \"Knockdown experiments, ubiquitination/deubiquitination assays, in vivo xenograft model\",\n      \"journal\": \"NPJ breast cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional link established by knockdown and rescue in vivo; deubiquitinase activity is unexpected for a RING E3 ligase and warrants further confirmation\",\n      \"pmids\": [\"41034232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TRIM39 (originally named testis-abundant finger protein/tfp) was cloned and characterized as an RBCC-B30.2 (RING-B-box-coiled coil) domain protein encoded in the MHC class I region, highly expressed in testis.\",\n      \"method\": \"Molecular cloning, Northern blot, genomic mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — initial cloning and domain characterization; foundational identification paper\",\n      \"pmids\": [\"11006080\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM39 is a RING-domain E3 ubiquitin ligase that regulates apoptosis and cell cycle progression through multiple substrates: it stabilizes MOAP-1 (by blocking APC/C(Cdh1)-mediated ubiquitylation) and p21 (by blocking CRL4(Cdt2) access), directly ubiquitylates and degrades p53 and NFATc3 (the latter as a SUMO-targeted E3 STUbL), ubiquitylates PRDX3 (K48-linked, at K73/K149) and p62 to promote their proteasomal degradation, and stabilizes Cactin to negatively regulate NFκB signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TRIM39 is a RING-domain E3 ubiquitin ligase that controls apoptosis, cell cycle progression, and inflammatory signaling by selectively ubiquitylating or stabilizing multiple substrates. It directly ubiquitylates and promotes proteasomal degradation of p53, NFATc3 (functioning as a SUMO-targeted ubiquitin ligase/STUbL), PRDX3 (K48-linked ubiquitination at K73/K149), and p62 (K48-linked), while stabilizing MOAP-1 by blocking APC/C(Cdh1)-mediated ubiquitylation and stabilizing p21 by preventing CRL4(Cdt2) access [PMID:22529100, PMID:23213260, PMID:23213251, PMID:35449213, PMID:38195664, PMID:41422284]. Through these activities, TRIM39 promotes Bax-dependent apoptosis via MOAP-1, enforces G1/S and DNA damage-induced G2 checkpoints via p21, modulates NF-κB signaling through Cactin stabilization, and influences oxidative stress responses through PRDX3 degradation and p62-dependent NRF2 pathway suppression [PMID:19100260, PMID:23213251, PMID:26363554, PMID:38195664, PMID:41422284].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of TRIM39 as an RBCC/B30.2-domain protein encoded in the MHC class I region established the gene's domain architecture and predicted E3 ligase function, but left substrates and biological roles unknown.\",\n      \"evidence\": \"Molecular cloning, Northern blot, and genomic mapping from human testis cDNA\",\n      \"pmids\": [\"11006080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrates or enzymatic activity demonstrated\", \"Expression beyond testis not systematically characterized\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The first functional role was established when TRIM39 was shown to bind and stabilize the Bax-activating protein MOAP-1 by inhibiting its poly-ubiquitination, linking TRIM39 to mitochondrial apoptosis.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assays, mitochondrial fractionation, and cytochrome c release assay in mammalian cells\",\n      \"pmids\": [\"19100260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The E3 ligase responsible for MOAP-1 ubiquitylation that TRIM39 counteracts was not identified\", \"Whether TRIM39's RING domain catalytic activity was required was untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Three major substrates were defined in rapid succession: TRIM39 inhibits APC/C(Cdh1)-mediated MOAP-1 ubiquitylation, directly ubiquitylates p53 for proteasomal degradation independently of MDM2, and stabilizes p21 by blocking CRL4(Cdt2) access—establishing TRIM39 as a multifunctional node connecting apoptosis and cell cycle control.\",\n      \"evidence\": \"In vitro reconstituted ubiquitylation assays, epistasis experiments (Cdh1 knockdown), competitive binding assays (TRIM39 blocks Cdt2–p21 interaction), cell cycle analysis by flow cytometry across multiple cell lines\",\n      \"pmids\": [\"22529100\", \"23213260\", \"23213251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRIM39 simultaneously stabilizes some substrates (MOAP-1, p21) while degrading others (p53) was mechanistically unexplained\", \"Structural basis for substrate selectivity unknown\", \"In vivo validation in animal models was lacking\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"TRIM39 was connected to innate immune signaling when it was found to stabilize Cactin and negatively regulate NF-κB, broadening its functional scope beyond cell cycle and apoptosis.\",\n      \"evidence\": \"Yeast two-hybrid screen, co-immunoprecipitation, NF-κB reporter assay upon TRIM39 knockdown\",\n      \"pmids\": [\"26363554\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which TRIM39 stabilizes Cactin (direct deubiquitylation vs. shielding) not resolved\", \"Whether Cactin is a direct ubiquitylation substrate or a binding partner was unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"TRIM39 was demonstrated to function as a SUMO-targeted ubiquitin ligase (STUbL) for NFATc3 in neurons, revealing that substrate SUMOylation is a prerequisite for TRIM39-mediated ubiquitylation and providing a selectivity mechanism.\",\n      \"evidence\": \"In vitro ubiquitylation with SUMOylated vs. unmodified NFATc3, mutagenesis of SUMO-interacting motifs in TRIM39 and SUMOylation sites in NFATc3, neuronal apoptosis readout\",\n      \"pmids\": [\"35449213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STUbL activity applies to other TRIM39 substrates beyond NFATc3 is untested\", \"The relative contribution of SIM-dependent vs. SIM-independent ubiquitylation in physiological contexts is undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Site-specific K48-linked ubiquitylation of PRDX3 at K73 and K149 by TRIM39 was mapped, linking TRIM39 to mitochondrial redox control and renal fibrosis through ROS accumulation and inflammatory cytokine generation.\",\n      \"evidence\": \"Co-immunoprecipitation, K48 chain-specific ubiquitination assay, K73R/K149R mutagenesis, UUO mouse model and HK-2 cells\",\n      \"pmids\": [\"38195664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRIM39 localizes to mitochondria to access PRDX3 or acts on cytosolic pools is unclear\", \"Upstream signals regulating TRIM39 activity in renal injury not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"TRIM39 was shown to K48-ubiquitylate p62/SQSTM1, releasing KEAP1 to suppress the NRF2-HO-1 antioxidant axis, and separately reported to deubiquitylate RNF168 to confer ferroptosis resistance—expanding its substrate range but raising questions about dual E3/DUB activity.\",\n      \"evidence\": \"Co-IP and ubiquitination assays with p62 plus xenograft rescue; knockdown/deubiquitination assays with RNF168 in TNBC cells and xenograft models\",\n      \"pmids\": [\"41422284\", \"41034232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reported deubiquitinase activity toward RNF168 is mechanistically unexpected for a RING E3 ligase and requires biochemical reconstitution with purified components\", \"p62 ubiquitylation sites not mapped\", \"Whether p62 degradation and RNF168 stabilization occur in the same cellular context is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for TRIM39's substrate selectivity across its diverse targets, whether its reported deubiquitinase activity is direct or indirect, and the physiological signals that switch TRIM39 between stabilizing and degradative modes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No crystal or cryo-EM structure of TRIM39 or its substrate complexes\", \"No systematic identification of TRIM39 regulators or post-translational modifications controlling its activity\", \"In vivo knockout phenotype in mammals not reported\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3, 5, 6, 7]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [2, 5, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 5, 6, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MOAP1\", \"TP53\", \"CDKN1A\", \"NFATC3\", \"CACTIN\", \"PRDX3\", \"SQSTM1\", \"CDH1\"],\n    \"other_free_text\": []\n  }\n}\n```"}