{"gene":"TRIM39","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2008,"finding":"TRIM39 directly binds MOAP-1 and stabilizes it by inhibiting its poly-ubiquitination and proteasomal degradation, thereby elevating MOAP-1 levels in mitochondria and promoting cytochrome c release and apoptosis in response to etoposide.","method":"Co-immunoprecipitation, ubiquitination assays, half-life measurements, mitochondrial fractionation, cytochrome c release assay with recombinant Bax, siRNA knockdown","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding, ubiquitination assays, functional rescue, replicated in subsequent studies","pmids":["19100260"],"is_preprint":false},{"year":2012,"finding":"TRIM39 (a RING domain E3 ubiquitin ligase) directly inhibits APC/C(Cdh1)-mediated ubiquitylation, thereby preventing proteasomal degradation of MOAP-1; Cdh1 knockdown phenocopies TRIM39 overexpression by stabilizing MOAP-1 and enhancing etoposide-induced Bax activation and apoptosis.","method":"In vitro APC/C ubiquitylation assay, siRNA knockdown of Cdh1, immunoprecipitation, cell-based apoptosis assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of APC/C inhibition, genetic epistasis via Cdh1 knockdown, multiple orthogonal methods","pmids":["22529100"],"is_preprint":false},{"year":2012,"finding":"TRIM39 directly binds and ubiquitylates p53 in vitro and in vivo, promoting p53 degradation; Trim39 loss increases p53 protein levels, causing cell growth retardation in p53-positive cells and enhanced apoptosis.","method":"In vitro ubiquitylation assay, co-immunoprecipitation, siRNA knockdown, cell growth and apoptosis assays in multiple cell lines","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitylation reconstitution plus in vivo validation, single lab but two orthogonal methods","pmids":["23213260"],"is_preprint":false},{"year":2012,"finding":"TRIM39 interacts with p21 and prevents Cdt2 (CRL4-Cdt2 E3 ligase) from binding to p21, thereby blocking p21 ubiquitylation and proteasomal degradation; TRIM39 ablation destabilizes p21, accelerates G1/S transition, abolishes DNA damage-induced p21 accumulation, and abrogates the G2 checkpoint, leading to mitotic entry and apoptosis.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, cell cycle analysis, DNA damage response assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assays, cell cycle phenotype with epistasis through p21, single lab with multiple orthogonal methods","pmids":["23213251"],"is_preprint":false},{"year":2015,"finding":"TRIM39 interacts with Cactin (identified by yeast two-hybrid screening) and stabilizes Cactin protein; TRIM39 stabilization of Cactin negatively regulates NFκB-mediated signaling, and TRIM39 knockdown activates NFκB signaling.","method":"Yeast two-hybrid screening, co-immunoprecipitation, protein stability assays, NFκB reporter assays, siRNA knockdown","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus reporter assay, single lab","pmids":["26363554"],"is_preprint":false},{"year":2022,"finding":"Trim39 acts as a SUMO-targeted E3 ubiquitin ligase (STUbL) for NFATc3: it binds and ubiquitinates NFATc3 in vitro and in cells, reducing NFATc3 protein level and transcriptional activity; mutation of SUMOylation sites in NFATc3 or SUMO-interacting motifs (SIMs) in Trim39 reduces their interaction and Trim39-mediated ubiquitination; Trim39 preferentially ubiquitinates SUMOylated forms of NFATc3; Trim17 inhibits this process by reducing Trim39 E3 ligase activity and the NFATc3/Trim39 interaction; silencing Trim39 enhances neuronal apoptosis via increased NFATc3 activity.","method":"In vitro ubiquitination assay, co-immunoprecipitation, site-directed mutagenesis of SUMOylation sites and SIMs, siRNA knockdown, transcriptional activity assays, neuronal apoptosis assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of ubiquitination, mutagenesis of functional motifs, and cellular functional validation in a single study","pmids":["35449213"],"is_preprint":false},{"year":2024,"finding":"TRIM39 directly interacts with PRDX3 and induces its K48-linked poly-ubiquitination and proteasomal degradation at lysines K73 and K149, leading to ROS accumulation, increased inflammatory cytokine generation, and aggravated renal fibrosis.","method":"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K73/K149 sites), siRNA knockdown in HK-2 cells, UUO mouse model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated by Co-IP, ubiquitination site mapping by mutagenesis, in vitro and in vivo functional validation, single lab","pmids":["38195664"],"is_preprint":false},{"year":2025,"finding":"TRIM39 interacts with p62 and facilitates its ubiquitination, leading to decreased p62 protein stability; reduced p62 releases KEAP1, which subsequently inhibits the NRF2-HO-1 pathway, promoting hepatocellular carcinoma cell proliferation.","method":"Co-immunoprecipitation, ubiquitination assays, overexpression rescue experiments, in vitro and in vivo proliferation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus p62 overexpression epistasis rescue, single lab","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; this mechanism is associated with alleviation of aortic dissection progression through maintenance of aortic smooth muscle cell contractile phenotype.","method":"Co-immunoprecipitation, TRIM39 overexpression in cell and mouse AD models, Western blot for SUMOylated ESR1, bioinformatics substrate prediction","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP validation of SUMOylation, in vivo and in vitro functional assays, single lab","pmids":["40921118"],"is_preprint":false},{"year":2025,"finding":"TRIM39 deubiquitinates RNF168 (upregulates it by preventing its degradation), and the TRIM39-RNF168 axis suppresses autophagy-coupled ferroptosis in triple-negative breast cancer cells; knockdown of TRIM39 or RNF168 activates autophagy-dependent ferroptosis and suppresses TNBC progression in vivo.","method":"siRNA knockdown, in vitro and in vivo functional assays, Western blot, TNBC xenograft model","journal":"NPJ breast cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional knockdown phenotype described but detailed mechanistic dissection of deubiquitination activity not fully detailed in abstract; single lab, single study","pmids":["41034232"],"is_preprint":false},{"year":2000,"finding":"TRIM39 (originally named RNF23/tfp) was cloned and found to encode a RING-B box-coiled coil (RBCC)-B30.2 domain protein; Northern blot showed testis-enriched but ubiquitous expression; the gene was mapped to the class I region of the human MHC.","method":"cDNA cloning, Northern blot analysis, chromosomal mapping","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular cloning and domain characterization, chromosomal mapping; foundational structural characterization paper","pmids":["11006080"],"is_preprint":false}],"current_model":"TRIM39 is a RING domain E3 ubiquitin ligase and SUMO-targeted ubiquitin ligase (STUbL) that regulates apoptosis, cell cycle progression, and inflammation through multiple substrates: it stabilizes MOAP-1 (by inhibiting APC/C-Cdh1-mediated ubiquitylation) and p21 (by blocking CRL4-Cdt2 binding), directly ubiquitylates and degrades p53 and NFATc3 (the latter in a SUMO-dependent manner), ubiquitylates PRDX3 and p62 for proteasomal degradation, stabilizes Cactin to negatively regulate NFκB signaling, and mediates SUMOylation of ESR1 to enhance its stability."},"narrative":{"mechanistic_narrative":"TRIM39 is a RING-B box-coiled-coil (RBCC)-B30.2 domain protein and RING-type E3 ubiquitin ligase that governs apoptosis, cell cycle progression, and inflammatory signaling by controlling the stability of diverse substrates [PMID:11006080, PMID:23213260]. It acts both as a positive regulator that stabilizes pro-apoptotic and checkpoint factors and as a degradative ligase. TRIM39 stabilizes MOAP-1 by directly inhibiting APC/C(Cdh1)-mediated ubiquitylation, raising mitochondrial MOAP-1 to promote Bax activation, cytochrome c release, and etoposide-induced apoptosis [PMID:19100260, PMID:22529100], and it stabilizes the CDK inhibitor p21 by blocking CRL4-Cdt2 access, thereby enforcing the G1/S and G2 DNA-damage checkpoints [PMID:23213251]. Conversely, TRIM39 directly ubiquitylates and degrades p53, restraining its growth-suppressive and apoptotic output [PMID:23213260]. It also operates as a SUMO-targeted ubiquitin ligase (STUbL), engaging SUMOylated NFATc3 through its SUMO-interacting motifs to drive its ubiquitin-dependent degradation and limit neuronal apoptosis [PMID:35449213]. Through additional substrates it shapes redox and inflammatory responses, degrading PRDX3 (K48-linked, at K73/K149) to elevate ROS and renal fibrosis [PMID:38195664], facilitating p62 ubiquitylation to modulate the KEAP1-NRF2-HO-1 axis in hepatocellular carcinoma [PMID:41422284], and stabilizing Cactin to negatively regulate NFκB signaling [PMID:26363554].","teleology":[{"year":2000,"claim":"Established the molecular identity of TRIM39, defining it as an RBCC-B30.2 (TRIM-family) protein and placing it in the MHC class I region before any enzymatic function was known.","evidence":"cDNA cloning, Northern blot, and chromosomal mapping (RNF23/tfp)","pmids":["11006080"],"confidence":"Medium","gaps":["No enzymatic activity or substrate assigned at this stage","Functional significance of testis-enriched expression not addressed"]},{"year":2008,"claim":"Assigned TRIM39 its first functional role, showing it stabilizes the pro-apoptotic factor MOAP-1 to promote mitochondrial apoptosis, framing it as a positive apoptotic regulator.","evidence":"Co-IP, ubiquitination/half-life assays, mitochondrial fractionation, cytochrome c release with recombinant Bax, siRNA in cells","pmids":["19100260"],"confidence":"High","gaps":["Did not identify which ligase TRIM39 antagonizes to stabilize MOAP-1","RING ligase activity not directly reconstituted here"]},{"year":2012,"claim":"Resolved the mechanism of MOAP-1 stabilization by showing TRIM39 directly inhibits APC/C(Cdh1), linking apoptotic control to cell-cycle machinery.","evidence":"In vitro APC/C ubiquitylation assay, Cdh1 knockdown epistasis, apoptosis assays","pmids":["22529100"],"confidence":"High","gaps":["Structural basis of APC/C inhibition unresolved","Whether TRIM39 broadly regulates other APC/C substrates not tested"]},{"year":2012,"claim":"Expanded TRIM39 into a checkpoint regulator: it stabilizes p21 by blocking CRL4-Cdt2 binding, enforcing G1/S and G2 arrest after DNA damage.","evidence":"Reciprocal Co-IP, ubiquitination assays, cell cycle and DNA-damage analysis with p21 epistasis","pmids":["23213251"],"confidence":"High","gaps":["Whether TRIM39 catalyzes ubiquitin chains on p21 or acts purely as a competitive shield not fully separated","Trigger that engages TRIM39 at p21 upon damage unknown"]},{"year":2012,"claim":"Demonstrated a degradative function distinct from its stabilizing roles by showing TRIM39 directly ubiquitylates and degrades p53, establishing it as a bidirectional regulator of cell fate.","evidence":"In vitro ubiquitylation reconstitution, Co-IP, siRNA, growth/apoptosis assays across cell lines","pmids":["23213260"],"confidence":"High","gaps":["How TRIM39 chooses to stabilize versus degrade substrates not explained","Physiological context distinguishing p53 versus p21 regulation unclear"]},{"year":2015,"claim":"Connected TRIM39 to innate immune signaling by identifying Cactin as a stabilized partner that dampens NFκB activation.","evidence":"Yeast two-hybrid, Co-IP, stability assays, NFκB reporter, siRNA","pmids":["26363554"],"confidence":"Medium","gaps":["Mechanism of Cactin stabilization not dissected","Direct ubiquitin chain involvement not established"]},{"year":2022,"claim":"Defined TRIM39 as a SUMO-targeted ubiquitin ligase (STUbL), showing SIM-dependent recognition and ubiquitylation of SUMOylated NFATc3 and antagonism by Trim17.","evidence":"In vitro ubiquitination, SIM/SUMO-site mutagenesis, Co-IP, transcriptional and neuronal apoptosis assays","pmids":["35449213"],"confidence":"High","gaps":["Whether STUbL activity extends to other SUMOylated substrates not surveyed","In vivo neuronal relevance beyond cell models not established"]},{"year":2024,"claim":"Linked TRIM39 to redox and fibrotic disease by mapping K48-linked ubiquitylation of PRDX3 at K73/K149 driving ROS and renal fibrosis.","evidence":"Co-IP, ubiquitination assays, K-site mutagenesis, HK-2 cells, UUO mouse model","pmids":["38195664"],"confidence":"Medium","gaps":["Single-lab finding without independent replication","Upstream signals activating TRIM39 in fibrosis unknown"]},{"year":2025,"claim":"Extended TRIM39 substrate range to p62, coupling its ligase activity to the KEAP1-NRF2-HO-1 axis in hepatocellular carcinoma proliferation.","evidence":"Co-IP, ubiquitination assays, p62 overexpression rescue, in vitro/in vivo proliferation","pmids":["41422284"],"confidence":"Medium","gaps":["Ubiquitin chain linkage on p62 not specified","Single-study mechanism awaiting independent confirmation"]},{"year":2025,"claim":"Showed TRIM39 can promote SUMOylation of ESR1 to stabilize it and sustain smooth muscle contractile phenotype in aortic dissection, indicating a SUMO-conjugation-promoting activity in addition to STUbL function.","evidence":"Co-IP, SUMO Western blot, TRIM39 overexpression in cell and mouse AD models, substrate prediction","pmids":["40921118"],"confidence":"Medium","gaps":["Direct catalytic role of TRIM39 in ESR1 SUMOylation versus indirect effect not separated","Reconciliation with degradative STUbL activity unclear"]},{"year":2025,"claim":"Proposed a TRIM39-RNF168 axis suppressing autophagy-coupled ferroptosis in triple-negative breast cancer.","evidence":"siRNA knockdown, Western blot, in vitro assays, TNBC xenograft","pmids":["41034232"],"confidence":"Low","gaps":["Claimed deubiquitination activity not biochemically reconstituted in abstract","Single lab, single study","Mechanism by which a RING ligase removes ubiquitin from RNF168 unexplained"]},{"year":null,"claim":"How TRIM39 selects between stabilizing and degrading substrates, and the upstream signals that direct its ligase versus SUMO-related activities, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying determinant of substrate fate identified","Regulation of TRIM39 activity by post-translational modification or partners not mapped","No structural model of substrate engagement"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[2,5,6,10]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,5,6,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,3,4]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,2,5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,5,6,7]}],"complexes":[],"partners":["MOAP1","TP53","CDKN1A","NFATC3","CACTIN","PRDX3","SQSTM1","ESR1"],"other_free_text":[]}},"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":"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":"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":"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":44,"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":26,"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":"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":13,"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":"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":2,"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":9906,"output_tokens":2853,"usd":0.036256,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10180,"output_tokens":3718,"usd":0.071925,"stage2_stop_reason":"end_turn"},"total_usd":0.108181,"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\": 2008,\n      \"finding\": \"TRIM39 directly binds MOAP-1 and stabilizes it by inhibiting its poly-ubiquitination and proteasomal degradation, thereby elevating MOAP-1 levels in mitochondria and promoting cytochrome c release and apoptosis in response to etoposide.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, half-life measurements, mitochondrial fractionation, cytochrome c release assay with recombinant Bax, siRNA knockdown\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding, ubiquitination assays, functional rescue, replicated in subsequent studies\",\n      \"pmids\": [\"19100260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM39 (a RING domain E3 ubiquitin ligase) directly inhibits APC/C(Cdh1)-mediated ubiquitylation, thereby preventing proteasomal degradation of MOAP-1; Cdh1 knockdown phenocopies TRIM39 overexpression by stabilizing MOAP-1 and enhancing etoposide-induced Bax activation and apoptosis.\",\n      \"method\": \"In vitro APC/C ubiquitylation assay, siRNA knockdown of Cdh1, immunoprecipitation, cell-based apoptosis assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of APC/C inhibition, genetic epistasis via Cdh1 knockdown, multiple orthogonal methods\",\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, promoting p53 degradation; Trim39 loss increases p53 protein levels, causing cell growth retardation in p53-positive cells and enhanced apoptosis.\",\n      \"method\": \"In vitro ubiquitylation assay, co-immunoprecipitation, siRNA knockdown, cell growth and apoptosis assays in multiple cell lines\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitylation reconstitution plus in vivo validation, single lab but two orthogonal methods\",\n      \"pmids\": [\"23213260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM39 interacts with p21 and prevents Cdt2 (CRL4-Cdt2 E3 ligase) from binding to p21, thereby blocking p21 ubiquitylation and proteasomal degradation; TRIM39 ablation destabilizes p21, accelerates G1/S transition, abolishes DNA damage-induced p21 accumulation, and abrogates the G2 checkpoint, leading to mitotic entry and apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, cell cycle analysis, DNA damage response assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assays, cell cycle phenotype with epistasis through p21, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23213251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM39 interacts with Cactin (identified by yeast two-hybrid screening) and stabilizes Cactin protein; TRIM39 stabilization of Cactin negatively regulates NFκB-mediated signaling, and TRIM39 knockdown activates NFκB signaling.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, protein stability assays, NFκB reporter assays, siRNA knockdown\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus reporter assay, single lab\",\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 NFATc3: it binds and ubiquitinates NFATc3 in vitro and in cells, reducing NFATc3 protein level and transcriptional activity; mutation of SUMOylation sites in NFATc3 or SUMO-interacting motifs (SIMs) in Trim39 reduces their interaction and Trim39-mediated ubiquitination; Trim39 preferentially ubiquitinates SUMOylated forms of NFATc3; Trim17 inhibits this process by reducing Trim39 E3 ligase activity and the NFATc3/Trim39 interaction; silencing Trim39 enhances neuronal apoptosis via increased NFATc3 activity.\",\n      \"method\": \"In vitro ubiquitination assay, co-immunoprecipitation, site-directed mutagenesis of SUMOylation sites and SIMs, siRNA knockdown, transcriptional activity assays, neuronal apoptosis assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of ubiquitination, mutagenesis of functional motifs, and cellular functional validation in a single study\",\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 and proteasomal degradation at lysines K73 and K149, leading to ROS accumulation, increased inflammatory cytokine generation, and aggravated renal fibrosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K73/K149 sites), siRNA knockdown in HK-2 cells, UUO mouse model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated by Co-IP, ubiquitination site mapping by mutagenesis, in vitro and in vivo functional validation, single lab\",\n      \"pmids\": [\"38195664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM39 interacts with p62 and facilitates its ubiquitination, leading to decreased p62 protein stability; reduced p62 releases KEAP1, which subsequently inhibits the NRF2-HO-1 pathway, promoting hepatocellular carcinoma cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, overexpression rescue experiments, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus p62 overexpression epistasis rescue, single lab\",\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; this mechanism is associated with alleviation of aortic dissection progression through maintenance of aortic smooth muscle cell contractile phenotype.\",\n      \"method\": \"Co-immunoprecipitation, TRIM39 overexpression in cell and mouse AD models, Western blot for SUMOylated ESR1, bioinformatics substrate prediction\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP validation of SUMOylation, in vivo and in vitro functional assays, single lab\",\n      \"pmids\": [\"40921118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM39 deubiquitinates RNF168 (upregulates it by preventing its degradation), and the TRIM39-RNF168 axis suppresses autophagy-coupled ferroptosis in triple-negative breast cancer cells; knockdown of TRIM39 or RNF168 activates autophagy-dependent ferroptosis and suppresses TNBC progression in vivo.\",\n      \"method\": \"siRNA knockdown, in vitro and in vivo functional assays, Western blot, TNBC xenograft model\",\n      \"journal\": \"NPJ breast cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional knockdown phenotype described but detailed mechanistic dissection of deubiquitination activity not fully detailed in abstract; single lab, single study\",\n      \"pmids\": [\"41034232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"TRIM39 (originally named RNF23/tfp) was cloned and found to encode a RING-B box-coiled coil (RBCC)-B30.2 domain protein; Northern blot showed testis-enriched but ubiquitous expression; the gene was mapped to the class I region of the human MHC.\",\n      \"method\": \"cDNA cloning, Northern blot analysis, chromosomal mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular cloning and domain characterization, chromosomal mapping; foundational structural characterization paper\",\n      \"pmids\": [\"11006080\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM39 is a RING domain E3 ubiquitin ligase and SUMO-targeted ubiquitin ligase (STUbL) that regulates apoptosis, cell cycle progression, and inflammation through multiple substrates: it stabilizes MOAP-1 (by inhibiting APC/C-Cdh1-mediated ubiquitylation) and p21 (by blocking CRL4-Cdt2 binding), directly ubiquitylates and degrades p53 and NFATc3 (the latter in a SUMO-dependent manner), ubiquitylates PRDX3 and p62 for proteasomal degradation, stabilizes Cactin to negatively regulate NFκB signaling, and mediates SUMOylation of ESR1 to enhance its stability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM39 is a RING-B box-coiled-coil (RBCC)-B30.2 domain protein and RING-type E3 ubiquitin ligase that governs apoptosis, cell cycle progression, and inflammatory signaling by controlling the stability of diverse substrates [#10, #2]. It acts both as a positive regulator that stabilizes pro-apoptotic and checkpoint factors and as a degradative ligase. TRIM39 stabilizes MOAP-1 by directly inhibiting APC/C(Cdh1)-mediated ubiquitylation, raising mitochondrial MOAP-1 to promote Bax activation, cytochrome c release, and etoposide-induced apoptosis [#0, #1], and it stabilizes the CDK inhibitor p21 by blocking CRL4-Cdt2 access, thereby enforcing the G1/S and G2 DNA-damage checkpoints [#3]. Conversely, TRIM39 directly ubiquitylates and degrades p53, restraining its growth-suppressive and apoptotic output [#2]. It also operates as a SUMO-targeted ubiquitin ligase (STUbL), engaging SUMOylated NFATc3 through its SUMO-interacting motifs to drive its ubiquitin-dependent degradation and limit neuronal apoptosis [#5]. Through additional substrates it shapes redox and inflammatory responses, degrading PRDX3 (K48-linked, at K73/K149) to elevate ROS and renal fibrosis [#6], facilitating p62 ubiquitylation to modulate the KEAP1-NRF2-HO-1 axis in hepatocellular carcinoma [#7], and stabilizing Cactin to negatively regulate NF\\u03baB signaling [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the molecular identity of TRIM39, defining it as an RBCC-B30.2 (TRIM-family) protein and placing it in the MHC class I region before any enzymatic function was known.\",\n      \"evidence\": \"cDNA cloning, Northern blot, and chromosomal mapping (RNF23/tfp)\",\n      \"pmids\": [\"11006080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic activity or substrate assigned at this stage\", \"Functional significance of testis-enriched expression not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Assigned TRIM39 its first functional role, showing it stabilizes the pro-apoptotic factor MOAP-1 to promote mitochondrial apoptosis, framing it as a positive apoptotic regulator.\",\n      \"evidence\": \"Co-IP, ubiquitination/half-life assays, mitochondrial fractionation, cytochrome c release with recombinant Bax, siRNA in cells\",\n      \"pmids\": [\"19100260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify which ligase TRIM39 antagonizes to stabilize MOAP-1\", \"RING ligase activity not directly reconstituted here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved the mechanism of MOAP-1 stabilization by showing TRIM39 directly inhibits APC/C(Cdh1), linking apoptotic control to cell-cycle machinery.\",\n      \"evidence\": \"In vitro APC/C ubiquitylation assay, Cdh1 knockdown epistasis, apoptosis assays\",\n      \"pmids\": [\"22529100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of APC/C inhibition unresolved\", \"Whether TRIM39 broadly regulates other APC/C substrates not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Expanded TRIM39 into a checkpoint regulator: it stabilizes p21 by blocking CRL4-Cdt2 binding, enforcing G1/S and G2 arrest after DNA damage.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assays, cell cycle and DNA-damage analysis with p21 epistasis\",\n      \"pmids\": [\"23213251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRIM39 catalyzes ubiquitin chains on p21 or acts purely as a competitive shield not fully separated\", \"Trigger that engages TRIM39 at p21 upon damage unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated a degradative function distinct from its stabilizing roles by showing TRIM39 directly ubiquitylates and degrades p53, establishing it as a bidirectional regulator of cell fate.\",\n      \"evidence\": \"In vitro ubiquitylation reconstitution, Co-IP, siRNA, growth/apoptosis assays across cell lines\",\n      \"pmids\": [\"23213260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRIM39 chooses to stabilize versus degrade substrates not explained\", \"Physiological context distinguishing p53 versus p21 regulation unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected TRIM39 to innate immune signaling by identifying Cactin as a stabilized partner that dampens NF\\u03baB activation.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, stability assays, NF\\u03baB reporter, siRNA\",\n      \"pmids\": [\"26363554\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Cactin stabilization not dissected\", \"Direct ubiquitin chain involvement not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined TRIM39 as a SUMO-targeted ubiquitin ligase (STUbL), showing SIM-dependent recognition and ubiquitylation of SUMOylated NFATc3 and antagonism by Trim17.\",\n      \"evidence\": \"In vitro ubiquitination, SIM/SUMO-site mutagenesis, Co-IP, transcriptional and neuronal apoptosis assays\",\n      \"pmids\": [\"35449213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STUbL activity extends to other SUMOylated substrates not surveyed\", \"In vivo neuronal relevance beyond cell models not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked TRIM39 to redox and fibrotic disease by mapping K48-linked ubiquitylation of PRDX3 at K73/K149 driving ROS and renal fibrosis.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, K-site mutagenesis, HK-2 cells, UUO mouse model\",\n      \"pmids\": [\"38195664\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without independent replication\", \"Upstream signals activating TRIM39 in fibrosis unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended TRIM39 substrate range to p62, coupling its ligase activity to the KEAP1-NRF2-HO-1 axis in hepatocellular carcinoma proliferation.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, p62 overexpression rescue, in vitro/in vivo proliferation\",\n      \"pmids\": [\"41422284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin chain linkage on p62 not specified\", \"Single-study mechanism awaiting independent confirmation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed TRIM39 can promote SUMOylation of ESR1 to stabilize it and sustain smooth muscle contractile phenotype in aortic dissection, indicating a SUMO-conjugation-promoting activity in addition to STUbL function.\",\n      \"evidence\": \"Co-IP, SUMO Western blot, TRIM39 overexpression in cell and mouse AD models, substrate prediction\",\n      \"pmids\": [\"40921118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct catalytic role of TRIM39 in ESR1 SUMOylation versus indirect effect not separated\", \"Reconciliation with degradative STUbL activity unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed a TRIM39-RNF168 axis suppressing autophagy-coupled ferroptosis in triple-negative breast cancer.\",\n      \"evidence\": \"siRNA knockdown, Western blot, in vitro assays, TNBC xenograft\",\n      \"pmids\": [\"41034232\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Claimed deubiquitination activity not biochemically reconstituted in abstract\", \"Single lab, single study\", \"Mechanism by which a RING ligase removes ubiquitin from RNF168 unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRIM39 selects between stabilizing and degrading substrates, and the upstream signals that direct its ligase versus SUMO-related activities, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying determinant of substrate fate identified\", \"Regulation of TRIM39 activity by post-translational modification or partners not mapped\", \"No structural model of substrate engagement\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [2, 5, 6, 10]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 5, 6, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 5, 6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MOAP1\", \"TP53\", \"CDKN1A\", \"NFATC3\", \"CACTIN\", \"PRDX3\", \"SQSTM1\", \"ESR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}