{"gene":"TRIM13","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2007,"finding":"RFP2 (TRIM13) is an ER-resident E3 ubiquitin ligase: it exhibits auto-polyubiquitination activity in vivo and in vitro dependent on an intact RING domain; RING-deficient mutants fail to drive polyubiquitination in vitro and are stabilized in vivo. RFP2 co-immunopurifies with VCP/p97 (an ERAD component) and regulates degradation of the ERAD substrate CD3-delta but not an N-end rule substrate. A C-terminal transmembrane domain is required for ER localization.","method":"In vitro ubiquitination assay, in vivo ubiquitination assay, RING domain mutagenesis, immunopurification + tandem mass spectrometry, co-localization with ER markers, CD3-delta degradation assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro and in vivo ubiquitination assays with mutagenesis, mass spectrometry identification of interacting partners, functional substrate degradation assay, all in one rigorous study","pmids":["17314412"],"is_preprint":false},{"year":2010,"finding":"TRIM13 (RFP2) ubiquitinates Cav1.2 L-type calcium channels in the absence of the Cavβ subunit, targeting them to the ERAD complex (via derlin-1 and p97) and proteasomal degradation. Cavβ co-expression interferes with TRIM13-mediated ubiquitination, thereby preventing ER-associated degradation and promoting channel surface expression.","method":"Co-immunoprecipitation of channel with ERAD components (derlin-1, p97), ubiquitination assay, proteasome inhibitor (MG132) rescue experiment, overexpression/knockdown of RFP2","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal Co-IP, ubiquitination assay, proteasome rescue, multiple orthogonal methods in one study with clear mechanistic chain","pmids":["21186355"],"is_preprint":false},{"year":2011,"finding":"TRIM13 induces autophagy when ectopically expressed in HEK-293 cells; the coiled-coil (CC) domain is required for autophagy induction. TRIM13 is stabilized during ER stress, interacts with p62/SQSTM1, and co-localizes with the autophagosome marker DFCP1. TRIM13 regulates initiation of autophagy during ER stress and decreases clonogenic ability of cells.","method":"Ectopic expression, domain deletion mapping (CC domain mutants), co-immunoprecipitation with p62/SQSTM1, co-localization with DFCP1 by fluorescence microscopy, clonogenic assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — domain mapping with multiple deletion constructs, Co-IP, co-localization imaging, functional clonogenic readout; single lab","pmids":["22178386"],"is_preprint":false},{"year":2013,"finding":"TRIM13 induces K63-linked polyubiquitination of caspase-8, resulting in caspase-8 stabilization and activation during ER stress. TRIM13-induced autophagy is essential for caspase-8 translocation to autophagosomes and lysosomal fusion, linking TRIM13-mediated ubiquitination to ER stress-induced cell death.","method":"Ubiquitination assay (K63-linkage specific), caspase-8 activation assay, autophagosome translocation assay (co-localization), lysosome fusion assay, TRIM13 overexpression and knockdown","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — linkage-specific ubiquitination assay, translocation co-localization, functional cell death readout; single lab","pmids":["24021263"],"is_preprint":false},{"year":2014,"finding":"TRIM13 interacts with MDA5 and negatively regulates MDA5-mediated type I IFN production, acting upstream of IRF3. Trim13-/- mice and MEFs challenged with EMCV (sensed by MDA5) produce increased IFN-β. TRIM13 also interacts with RIG-I, and Trim13-/- MEFs show diminished IFN-β responses to RIG-I-activating Sendai virus, suggesting TRIM13 may positively regulate RIG-I signaling.","method":"Co-immunoprecipitation (TRIM13 with MDA5 and RIG-I), TRIM13 knockout mouse generation, IFN-β ELISA in MEFs and in vivo, viral challenge (EMCV, Sendai virus), poly(I:C) stimulation","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic knockout mouse model, multiple viral and ligand systems, consistent in vitro and in vivo results","pmids":["25008915"],"is_preprint":false},{"year":2014,"finding":"TRIM13 interacts with NEMO (NF-κB essential modulator), modulates NEMO ubiquitination and turnover, and thereby suppresses TNF-induced NF-κB activation. E3 ligase activity (RING domain) and ER localization are required for NF-κB suppression; TRIM13-regulated autophagy is not required for this function.","method":"Co-immunoprecipitation (TRIM13 with NEMO), ubiquitination assay, TRIM13 knockdown/overexpression, NF-κB reporter assay, RING domain mutant and ER-localization mutant analysis","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, domain mutants, functional NF-κB readout; single lab","pmids":["25152375"],"is_preprint":false},{"year":2017,"finding":"TRIM13 potentiates TLR2-mediated NF-κB activation by interacting with TRAF6 and catalyzing K29-linked polyubiquitination of TRAF6. RING domain mutants (C10/13A or RING deletion) abolish TRAF6 ubiquitination and NF-κB activation, confirming dependence on E3 ligase activity. TRIM13 is upregulated in macrophages upon TLR2 ligand stimulation.","method":"Co-immunoprecipitation (TRIM13 with TRAF6), K29-linkage-specific ubiquitination assay, RING domain active-site mutagenesis (C10/13A), NF-κB reporter assay, TRIM13 knockdown","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination assay, catalytic site mutagenesis, functional NF-κB readout; single lab","pmids":["28087809"],"is_preprint":false},{"year":2018,"finding":"TRIM13 ubiquitinates the nuclear receptor Nur77 at Lys539, leading to its proteasomal degradation; optimal ubiquitination requires the E2 enzyme UbcH5. TRIM13–Nur77 interaction was confirmed by co-immunoprecipitation. CK2α phosphorylates Nur77 at Ser154 to promote TRIM13-mediated ubiquitination and degradation, and this CK2α–TRIM13 axis controls TNFα-mediated IL-6 production.","method":"Co-immunoprecipitation (TRIM13 with Nur77), ubiquitination assay with E2 enzyme panel, site-directed mutagenesis (Lys539), CK2 pharmacological inhibition and CK2α overexpression/inactive mutant, IL-6 cytokine measurement","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay with mutagenesis, kinase inhibitor and mutant orthogonal validation; single lab","pmids":["30224829"],"is_preprint":false},{"year":2020,"finding":"TRIM13 promotes ubiquitination and degradation of CHOP in renal mesangial cells, thereby suppressing collagen synthesis. TRIM13 promoter methylation is increased in diabetic nephropathy, correlating with reduced TRIM13 expression and elevated CHOP. Restoring TRIM13 expression attenuated DN-induced collagen synthesis and improved renal function in vitro and in vivo.","method":"Ubiquitination assay (TRIM13 ubiquitinates CHOP), TRIM13 overexpression in mesangial cells and diabetic mouse model, promoter methylation analysis, collagen synthesis assay","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ubiquitination assay, in vitro and in vivo functional rescue, methylation analysis; single lab","pmids":["31901873"],"is_preprint":false},{"year":2022,"finding":"TRIM13 interacts with STING via its transmembrane domain and catalyzes Lys6-linked polyubiquitination of STING, leading to decelerated ER exit and accelerated ER-initiated degradation of STING. TRIM13 deficiency enhances pathogenic-DNA-triggered inflammatory cytokine production and causes age-related autoinflammation; STING deficiency reverses enhanced innate responses in TRIM13-knockout mice.","method":"Co-immunoprecipitation (TRIM13 TM domain with STING), K6-linkage-specific ubiquitination assay, TRIM13 knockout mice, STING double-knockout epistasis, STING ER exit/degradation assay, cytokine measurement","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — domain-specific interaction mapping, linkage-specific ubiquitination, double-knockout epistasis, multiple orthogonal methods with in vivo validation","pmids":["35080984"],"is_preprint":false},{"year":2024,"finding":"TRIM13 ubiquitinates and degrades LXRα/β, downregulating ABCA1/G1 expression and inhibiting cholesterol efflux in macrophages and smooth muscle cells. TRIM13 also ubiquitinates and degrades SOCS1/3, leading to STAT1 activation, CD36 upregulation, and foam cell formation. Genetic deletion of TRIM13 rescues cholesterol efflux and protects against diet-induced atherosclerosis in ApoE-/- mice.","method":"Ubiquitination assay (TRIM13 ubiquitinates LXRα/β and SOCS1/3), TRIM13 knockout mouse model, cholesterol efflux assay, foam cell assay, Western blot for ABCA1/G1/CD36/STAT1, human coronary artery tissue analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple substrate ubiquitination assays, KO mouse model, functional cholesterol efflux assay, human tissue correlation, multiple orthogonal methods","pmids":["38537695"],"is_preprint":false},{"year":2023,"finding":"TRIM13 interacts with p62/SQSTM1 and mediates its ubiquitination and degradation via the RING finger domain in lung adenocarcinoma cells, negatively regulating Nrf2 signaling and downstream antioxidants. This suppresses tumor cell proliferation and activates autophagy.","method":"Co-immunoprecipitation (TRIM13 with p62), ubiquitination assay, RING domain deletion mutant, Nrf2 pathway reporter/Western blot, xenograft in vivo model","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay with domain mutant, pathway analysis, in vivo xenograft; single lab","pmids":["37245083"],"is_preprint":false},{"year":1998,"finding":"The LEU5 (RFP2/TRIM13) gene was identified within the minimally deleted 13q14.3 region in B-CLL; its cDNA encodes a RING-type zinc-finger domain with homology to other RING proteins involved in tumorigenesis and embryogenesis (RET finger protein, BRCA1, MID1).","method":"Cosmid contig construction, cDNA cloning and sequencing, mapping to 13q14 deletion region","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 4 / Weak — gene identification and sequence/domain inference only; no functional experiment performed on the protein","pmids":["9599022"],"is_preprint":false}],"current_model":"TRIM13 (RFP2/LEU5/DLEU5/RNF77) is an ER-resident, transmembrane RING-type E3 ubiquitin ligase that regulates ERAD (ubiquitinating substrates such as Cav1.2 and CD3-delta via the VCP/p97 complex), controls innate immune signaling by ubiquitinating MDA5, STING (K6-linked), and TRAF6 (K29-linked), modulates NF-κB by targeting NEMO for ubiquitination and turnover, promotes autophagy through its coiled-coil domain and interaction with p62/SQSTM1, induces K63-linked ubiquitination of caspase-8 to drive ER stress-linked apoptosis, and ubiquitinates additional substrates including Nur77, CHOP, LXRα/β, and SOCS1/3, collectively placing it as a multi-substrate ER-anchored ubiquitin ligase at the intersection of protein quality control, antiviral immunity, inflammatory signaling, and lipid metabolism."},"narrative":{"mechanistic_narrative":"TRIM13 is an endoplasmic reticulum-anchored RING-type E3 ubiquitin ligase that operates at the intersection of protein quality control, innate immune signaling, inflammatory regulation, and lipid metabolism [PMID:17314412, PMID:35080984]. Its C-terminal transmembrane domain confers ER localization, and an intact RING domain is required for its auto-polyubiquitination and substrate ubiquitination activity; it physically associates with the VCP/p97 ERAD machinery and routes ERAD substrates such as CD3-delta and, in the absence of the Cavβ subunit, Cav1.2 L-type calcium channels to proteasomal degradation via derlin-1 and p97 [PMID:17314412, PMID:21186355]. Beyond canonical ERAD, TRIM13 controls innate antiviral and inflammatory signaling through linkage-specific ubiquitination: it interacts with MDA5 and RIG-I to differentially tune type I IFN output [PMID:25008915], catalyzes K6-linked ubiquitination of STING to accelerate its ER-initiated degradation and restrain DNA-triggered inflammation [PMID:35080984], catalyzes K29-linked ubiquitination of TRAF6 to potentiate TLR2-driven NF-κB activation [PMID:28087809], and modulates NEMO ubiquitination and turnover to suppress TNF-induced NF-κB activity in a manner dependent on its RING domain and ER localization but independent of autophagy [PMID:25152375]. During ER stress TRIM13 is stabilized, induces autophagy through its coiled-coil domain together with p62/SQSTM1, and drives K63-linked ubiquitination of caspase-8 to couple autophagosomal translocation to ER stress-induced cell death [PMID:22178386, PMID:24021263]. It additionally degrades a panel of substrates—Nur77, CHOP, LXRα/β and SOCS1/3—linking it to cytokine production, collagen synthesis in diabetic nephropathy, and cholesterol efflux and foam-cell formation in atherosclerosis [PMID:30224829, PMID:31901873, PMID:38537695]. The gene was originally identified within the minimally deleted 13q14.3 region in B-CLL [PMID:9599022].","teleology":[{"year":1998,"claim":"Established the gene's existence and a candidate disease context by mapping LEU5/RFP2/TRIM13 to a B-CLL deletion region, but left its function entirely unknown.","evidence":"Cosmid contig construction, cDNA cloning and sequencing within the 13q14 deletion region","pmids":["9599022"],"confidence":"Low","gaps":["No functional experiment performed on the protein","RING-domain enzymatic activity inferred only from sequence homology","No causal link between TRIM13 loss and B-CLL demonstrated"]},{"year":2007,"claim":"Answered what biochemical activity TRIM13 has by showing it is a RING-dependent ER-resident E3 ligase that engages the ERAD machinery, defining its core molecular identity.","evidence":"In vitro/in vivo ubiquitination assays, RING mutagenesis, immunopurification + mass spectrometry, ER co-localization, CD3-delta degradation assay","pmids":["17314412"],"confidence":"High","gaps":["Direct substrate beyond CD3-delta not defined","Mechanism of substrate selection within ERAD unclear","Ubiquitin linkage type for ERAD substrates not resolved"]},{"year":2010,"claim":"Extended the ERAD role to a physiological client by showing TRIM13 ubiquitinates Cav1.2 channels to control their surface expression, demonstrating regulatory rather than purely degradative function.","evidence":"Reciprocal Co-IP with derlin-1/p97, ubiquitination assay, MG132 rescue, RFP2 overexpression/knockdown","pmids":["21186355"],"confidence":"High","gaps":["Linkage type on Cav1.2 not specified","How Cavβ blocks ubiquitination structurally unknown","Physiological consequence in native excitable cells not tested"]},{"year":2011,"claim":"Connected TRIM13 to autophagy by mapping autophagy induction to its coiled-coil domain and showing ER-stress stabilization and p62 interaction, broadening its role beyond ubiquitin transfer.","evidence":"Ectopic expression, CC-domain deletion mapping, Co-IP with p62, DFCP1 co-localization, clonogenic assay","pmids":["22178386"],"confidence":"Medium","gaps":["Single lab","Whether autophagy induction requires ligase activity not established","Direct autophagy machinery target not identified"]},{"year":2013,"claim":"Linked TRIM13's ubiquitin and autophagy activities to cell fate by showing K63-linked ubiquitination of caspase-8 drives its autophagosomal translocation and ER stress-induced death.","evidence":"K63-linkage-specific ubiquitination assay, caspase-8 activation and translocation assays, lysosome fusion assay, overexpression/knockdown","pmids":["24021263"],"confidence":"Medium","gaps":["Single lab","Direct vs indirect caspase-8 ubiquitination not fully resolved","Physiological stress contexts beyond model systems untested"]},{"year":2014,"claim":"Defined opposing roles in RNA-sensing innate immunity, with TRIM13 negatively regulating MDA5-driven IFN while interacting with RIG-I, using genetic knockout for in vivo validation.","evidence":"Reciprocal Co-IP with MDA5/RIG-I, Trim13-/- mice and MEFs, IFN-β ELISA, EMCV and Sendai virus challenge","pmids":["25008915"],"confidence":"High","gaps":["Whether TRIM13 ubiquitinates MDA5/RIG-I directly not shown","Mechanism of opposite RIG-I vs MDA5 effects unresolved","Linkage type not defined"]},{"year":2014,"claim":"Showed TRIM13 restrains TNF-induced NF-κB by modulating NEMO ubiquitination and turnover, requiring RING activity and ER localization but not autophagy.","evidence":"Co-IP with NEMO, ubiquitination assay, NF-κB reporter, RING and ER-localization mutants","pmids":["25152375"],"confidence":"Medium","gaps":["Single lab","Ubiquitin linkage on NEMO not specified","Reconciliation with TRAF6-potentiating role not addressed"]},{"year":2017,"claim":"Revealed a context-dependent positive arm of inflammatory signaling, with K29-linked ubiquitination of TRAF6 potentiating TLR2-driven NF-κB activation.","evidence":"Co-IP with TRAF6, K29-linkage-specific ubiquitination assay, C10/13A catalytic mutagenesis, NF-κB reporter, knockdown","pmids":["28087809"],"confidence":"Medium","gaps":["Single lab","How TRIM13 toggles between suppressing (NEMO) and activating (TRAF6) NF-κB unclear","In vivo relevance not established"]},{"year":2018,"claim":"Identified a phosphodegron-controlled substrate by showing CK2α phosphorylation of Nur77 promotes TRIM13-mediated degradation, controlling TNFα-driven IL-6.","evidence":"Co-IP with Nur77, ubiquitination assay with E2 panel (UbcH5), Lys539 mutagenesis, CK2 inhibition/mutant, IL-6 measurement","pmids":["30224829"],"confidence":"Medium","gaps":["Single lab","Generality of CK2-priming for other TRIM13 substrates unknown","In vivo confirmation lacking"]},{"year":2020,"claim":"Placed TRIM13 in a disease pathway by showing it degrades CHOP to suppress collagen synthesis, with promoter methylation silencing TRIM13 in diabetic nephropathy.","evidence":"Ubiquitination assay, overexpression in mesangial cells and diabetic mice, promoter methylation analysis, collagen synthesis assay","pmids":["31901873"],"confidence":"Medium","gaps":["Single lab","Ubiquitin linkage on CHOP not specified","Direct vs indirect CHOP regulation not fully separated"]},{"year":2022,"claim":"Resolved a precise mechanism in DNA-sensing immunity by showing TM-domain-mediated, K6-linked ubiquitination of STING decelerates ER exit and accelerates its degradation, with epistasis confirming the STING axis in vivo.","evidence":"Co-IP via TRIM13 TM domain, K6-linkage-specific ubiquitination assay, Trim13-/- mice, STING double-knockout epistasis, ER exit/degradation and cytokine assays","pmids":["35080984"],"confidence":"High","gaps":["Structural basis of TM-domain STING engagement unknown","Relationship to other innate substrates not integrated","Human relevance of age-related autoinflammation not tested"]},{"year":2023,"claim":"Connected TRIM13 to redox and tumor biology by showing RING-dependent ubiquitination of p62 dampens Nrf2 signaling and suppresses lung adenocarcinoma growth.","evidence":"Co-IP with p62, ubiquitination assay, RING deletion mutant, Nrf2 pathway readouts, xenograft model","pmids":["37245083"],"confidence":"Medium","gaps":["Single lab","Reconciliation with p62 acting as autophagy partner (idx 2) unaddressed","Ubiquitin linkage on p62 not specified"]},{"year":2024,"claim":"Established a metabolic-vascular role by showing TRIM13 degrades LXRα/β and SOCS1/3 to impair cholesterol efflux and promote foam-cell formation, with knockout protecting against atherosclerosis.","evidence":"Ubiquitination assays for multiple substrates, Trim13 KO in ApoE-/- mice, cholesterol efflux and foam cell assays, human coronary tissue analysis","pmids":["38537695"],"confidence":"High","gaps":["Linkage types on LXR/SOCS not specified","Which substrate dominates the atherosclerosis phenotype unclear","Upstream regulation of TRIM13 in macrophages undefined"]},{"year":null,"claim":"How a single ER-anchored ligase coordinates its opposing roles (NF-κB suppression vs potentiation, RIG-I vs MDA5, autophagy partner vs degrader of p62) and how substrate selection is governed remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate recognition","Ubiquitin linkage codes across substrates not systematically compared","Mechanism switching TRIM13 between activating and inhibitory outputs unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,6,9,10]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,7,9,10]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,9]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,6,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[10]}],"complexes":[],"partners":["VCP","MDA5","RIG-I","STING","TRAF6","NEMO","SQSTM1","NUR77"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60858","full_name":"E3 ubiquitin-protein ligase TRIM13","aliases":["B-cell chronic lymphocytic leukemia tumor suppressor Leu5","Leukemia-associated protein 5","Putative tumor suppressor RFP2","RING finger protein 77","RING-type E3 ubiquitin transferase TRIM13","Ret finger protein 2","Tripartite motif-containing protein 13"],"length_aa":407,"mass_kda":47.0,"function":"Endoplasmic reticulum (ER) membrane anchored E3 ligase involved in the retrotranslocation and turnover of membrane and secretory proteins from the ER through a set of processes named ER-associated degradation (ERAD). This process acts on misfolded proteins as well as in the regulated degradation of correctly folded proteins. Enhances ionizing radiation-induced p53/TP53 stability and apoptosis via ubiquitinating MDM2 and AKT1 and decreasing AKT1 kinase activity through MDM2 and AKT1 proteasomal degradation. Regulates ER stress-induced autophagy, and may act as a tumor suppressor (PubMed:22178386). Also plays a role in innate immune response by stimulating NF-kappa-B activity in the TLR2 signaling pathway. Ubiquitinates TRAF6 via the 'Lys-29'-linked polyubiquitination chain resulting in NF-kappa-B activation (PubMed:28087809). Participates as well in T-cell receptor-mediated NF-kappa-B activation (PubMed:25088585). 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cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31762344","citation_count":21,"is_preprint":false},{"pmid":"2554179","id":"PMC_2554179","title":"Multi-dimensional analysis of behavior in mice treated with the delta opioid agonists DADL (D-Ala2-D-Leu5-enkephalin) and DPLPE (D-Pen2-L-Pen5-enkephalin).","date":"1989","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/2554179","citation_count":21,"is_preprint":false},{"pmid":"2173752","id":"PMC_2173752","title":"Opioid agonist and antagonist antinociceptive properties of [D-Ala2,Leu5,Cys6]enkephalin: selective actions at the deltanoncomplexed site.","date":"1990","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/2173752","citation_count":20,"is_preprint":false},{"pmid":"2997393","id":"PMC_2997393","title":"Evidence for [D-Ala2,D-Leu5]enkephalin-induced supersensitivity to 5-hydroxytryptamine in a neurotumor x brain hybrid cell line (NCB-20).","date":"1985","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2997393","citation_count":20,"is_preprint":false},{"pmid":"22943142","id":"PMC_22943142","title":"Protective effects of the delta opioid peptide [D-Ala2, D-Leu5]enkephalin in an ex vivo model of ischemia/reperfusion in brain slices.","date":"2012","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/22943142","citation_count":20,"is_preprint":false},{"pmid":"17207574","id":"PMC_17207574","title":"Delta opioid receptors stimulation with [D-Ala2, D-Leu5] enkephalin does not provide neuroprotection in the hippocampus in rats subjected to forebrain ischemia.","date":"2006","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/17207574","citation_count":20,"is_preprint":false},{"pmid":"6280202","id":"PMC_6280202","title":"D-Ala2,D-Leu5-enkephalin generalizes to a discriminative stimulus produced by fentanyl but not ethylketocyclazocine.","date":"1982","source":"Pharmacology, biochemistry, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/6280202","citation_count":19,"is_preprint":false},{"pmid":"10082218","id":"PMC_10082218","title":"[D-Ala2, D-Leu5]enkephalin blocks the methamphetamine-induced c-fos mRNA increase in mouse striatum.","date":"1999","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/10082218","citation_count":19,"is_preprint":false},{"pmid":"7568065","id":"PMC_7568065","title":"[Leu5]enkephalin-encoding sequences are targets for a specific DNA-binding factor.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7568065","citation_count":18,"is_preprint":false},{"pmid":"2574823","id":"PMC_2574823","title":"Nuclear gene for mitochondrial leucyl-tRNA synthetase of Neurospora crassa: isolation, sequence, chromosomal mapping, and evidence that the leu-5 locus specifies structural information.","date":"1989","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2574823","citation_count":18,"is_preprint":false},{"pmid":"1647317","id":"PMC_1647317","title":"Pharmacological characterization of [D-Ala2,Leu5,Ser6]enkephalin (DALES): antinociceptive actions at the delta non-complexed-opioid receptor.","date":"1991","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/1647317","citation_count":18,"is_preprint":false},{"pmid":"19569087","id":"PMC_19569087","title":"Modification with organometallic compounds improves crossing of the blood-brain barrier of [Leu5]-enkephalin derivatives in an in vitro model system.","date":"2009","source":"Chembiochem : a European journal of chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/19569087","citation_count":18,"is_preprint":false},{"pmid":"37245083","id":"PMC_37245083","title":"TRIM13 inhibits cell proliferation and induces autophagy in lung adenocarcinoma by regulating KEAP1/NRF2 pathway.","date":"2023","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/37245083","citation_count":17,"is_preprint":false},{"pmid":"30666890","id":"PMC_30666890","title":"Delta Opioid Peptide [d-Ala2, d-Leu5] Enkephalin (DADLE) Exerts a Cytoprotective Effect in Astrocytes Exposed to Oxygen-Glucose Deprivation by Inducing Autophagy.","date":"2019","source":"Cell transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/30666890","citation_count":17,"is_preprint":false},{"pmid":"1831883","id":"PMC_1831883","title":"Increased dopamine receptor sensitivity in the rat following acute administration of sufentanil, U50,488H and D-Ala2-D-Leu5-enkephalin.","date":"1991","source":"Naunyn-Schmiedeberg's archives of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/1831883","citation_count":17,"is_preprint":false},{"pmid":"1634326","id":"PMC_1634326","title":"Glycoconjugates of opioid peptides. Synthesis and biological activity of [Leu5]enkephalin related glycoconjugates with amide type of linkage.","date":"1992","source":"International journal of peptide and protein research","url":"https://pubmed.ncbi.nlm.nih.gov/1634326","citation_count":17,"is_preprint":false},{"pmid":"11169780","id":"PMC_11169780","title":"Delta opioid peptide [D-Ala2, D-Leu5]enkephalin causes a near complete blockade of the neuronal damage caused by a single high dose of methamphetamine: examining the role of p53.","date":"2001","source":"Synapse (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11169780","citation_count":16,"is_preprint":false},{"pmid":"29163008","id":"PMC_29163008","title":"Antioxidative and Antiapoptotic Effects of Delta-Opioid Peptide [D-Ala2, D-Leu5] Enkephalin on Spinal Cord Ischemia-Reperfusion Injury in Rabbits.","date":"2017","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29163008","citation_count":16,"is_preprint":false},{"pmid":"21551984","id":"PMC_21551984","title":"Delayed administration of D-Ala2-D-Leu5-enkephalin, a delta-opioid receptor agonist, improves survival in a rat model of sepsis.","date":"2011","source":"The Tohoku journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21551984","citation_count":16,"is_preprint":false},{"pmid":"38537695","id":"PMC_38537695","title":"TRIM13 reduces cholesterol efflux and increases oxidized LDL uptake leading to foam cell formation and atherosclerosis.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38537695","citation_count":15,"is_preprint":false},{"pmid":"2575993","id":"PMC_2575993","title":"Selective effects of [D-Ser2(O-t-butyl),Leu5]enkephalyl-Thr6 and [D-Ser2(O-t-butyl),Leu5]enkephalyl-Thr6 (O-t-butyl), two new enkephalin analogues, on neurotransmitter release and adenylate cyclase in rat brain slices.","date":"1989","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/2575993","citation_count":15,"is_preprint":false},{"pmid":"12015787","id":"PMC_12015787","title":"The effect of enzyme inhibitor and absorption site following [D-ala2, D-leu5]enkephalin oral administration in rats.","date":"2002","source":"Biopharmaceutics & drug disposition","url":"https://pubmed.ncbi.nlm.nih.gov/12015787","citation_count":15,"is_preprint":false},{"pmid":"7162338","id":"PMC_7162338","title":"In vivo modulation of small bowel motility by morphine and D-Ala2 D-Leu5 enkephalin.","date":"1982","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/7162338","citation_count":15,"is_preprint":false},{"pmid":"3014499","id":"PMC_3014499","title":"Preparation of [125I-Tyr27,Leu5]beta h-endorphin and its use for crosslinking of opioid binding sites in human striatum and NG108-15 neuroblastoma-glioma cells.","date":"1986","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/3014499","citation_count":15,"is_preprint":false},{"pmid":"2842267","id":"PMC_2842267","title":"Synthesis and biological activity of [Leu5]enkephalin derivatives containing D-glucose.","date":"1988","source":"International journal of peptide and protein research","url":"https://pubmed.ncbi.nlm.nih.gov/2842267","citation_count":15,"is_preprint":false},{"pmid":"2865158","id":"PMC_2865158","title":"Conversion of dynorphin-(1-9) to [Leu5]enkephalin by the mouse vas deferens in vitro.","date":"1985","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/2865158","citation_count":15,"is_preprint":false},{"pmid":"6317398","id":"PMC_6317398","title":"Inhibition of the antisecretory effects of [D-Ala2,D-Leu5]enkephalin in the guinea-pig ileum by a selective delta opioid antagonist.","date":"1983","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/6317398","citation_count":15,"is_preprint":false},{"pmid":"3551962","id":"PMC_3551962","title":"[The vector containing a signal for specific degradation of chimeric proteins. Synthesis of [Leu5]enkephalin using enteropeptidase].","date":"1987","source":"Bioorganicheskaia khimiia","url":"https://pubmed.ncbi.nlm.nih.gov/3551962","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48807,"output_tokens":3952,"usd":0.10285,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11692,"output_tokens":4622,"usd":0.087005,"stage2_stop_reason":"end_turn"},"total_usd":0.189855,"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\": 2007,\n      \"finding\": \"RFP2 (TRIM13) is an ER-resident E3 ubiquitin ligase: it exhibits auto-polyubiquitination activity in vivo and in vitro dependent on an intact RING domain; RING-deficient mutants fail to drive polyubiquitination in vitro and are stabilized in vivo. RFP2 co-immunopurifies with VCP/p97 (an ERAD component) and regulates degradation of the ERAD substrate CD3-delta but not an N-end rule substrate. A C-terminal transmembrane domain is required for ER localization.\",\n      \"method\": \"In vitro ubiquitination assay, in vivo ubiquitination assay, RING domain mutagenesis, immunopurification + tandem mass spectrometry, co-localization with ER markers, CD3-delta degradation assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro and in vivo ubiquitination assays with mutagenesis, mass spectrometry identification of interacting partners, functional substrate degradation assay, all in one rigorous study\",\n      \"pmids\": [\"17314412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRIM13 (RFP2) ubiquitinates Cav1.2 L-type calcium channels in the absence of the Cavβ subunit, targeting them to the ERAD complex (via derlin-1 and p97) and proteasomal degradation. Cavβ co-expression interferes with TRIM13-mediated ubiquitination, thereby preventing ER-associated degradation and promoting channel surface expression.\",\n      \"method\": \"Co-immunoprecipitation of channel with ERAD components (derlin-1, p97), ubiquitination assay, proteasome inhibitor (MG132) rescue experiment, overexpression/knockdown of RFP2\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal Co-IP, ubiquitination assay, proteasome rescue, multiple orthogonal methods in one study with clear mechanistic chain\",\n      \"pmids\": [\"21186355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRIM13 induces autophagy when ectopically expressed in HEK-293 cells; the coiled-coil (CC) domain is required for autophagy induction. TRIM13 is stabilized during ER stress, interacts with p62/SQSTM1, and co-localizes with the autophagosome marker DFCP1. TRIM13 regulates initiation of autophagy during ER stress and decreases clonogenic ability of cells.\",\n      \"method\": \"Ectopic expression, domain deletion mapping (CC domain mutants), co-immunoprecipitation with p62/SQSTM1, co-localization with DFCP1 by fluorescence microscopy, clonogenic assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — domain mapping with multiple deletion constructs, Co-IP, co-localization imaging, functional clonogenic readout; single lab\",\n      \"pmids\": [\"22178386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRIM13 induces K63-linked polyubiquitination of caspase-8, resulting in caspase-8 stabilization and activation during ER stress. TRIM13-induced autophagy is essential for caspase-8 translocation to autophagosomes and lysosomal fusion, linking TRIM13-mediated ubiquitination to ER stress-induced cell death.\",\n      \"method\": \"Ubiquitination assay (K63-linkage specific), caspase-8 activation assay, autophagosome translocation assay (co-localization), lysosome fusion assay, TRIM13 overexpression and knockdown\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — linkage-specific ubiquitination assay, translocation co-localization, functional cell death readout; single lab\",\n      \"pmids\": [\"24021263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIM13 interacts with MDA5 and negatively regulates MDA5-mediated type I IFN production, acting upstream of IRF3. Trim13-/- mice and MEFs challenged with EMCV (sensed by MDA5) produce increased IFN-β. TRIM13 also interacts with RIG-I, and Trim13-/- MEFs show diminished IFN-β responses to RIG-I-activating Sendai virus, suggesting TRIM13 may positively regulate RIG-I signaling.\",\n      \"method\": \"Co-immunoprecipitation (TRIM13 with MDA5 and RIG-I), TRIM13 knockout mouse generation, IFN-β ELISA in MEFs and in vivo, viral challenge (EMCV, Sendai virus), poly(I:C) stimulation\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic knockout mouse model, multiple viral and ligand systems, consistent in vitro and in vivo results\",\n      \"pmids\": [\"25008915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIM13 interacts with NEMO (NF-κB essential modulator), modulates NEMO ubiquitination and turnover, and thereby suppresses TNF-induced NF-κB activation. E3 ligase activity (RING domain) and ER localization are required for NF-κB suppression; TRIM13-regulated autophagy is not required for this function.\",\n      \"method\": \"Co-immunoprecipitation (TRIM13 with NEMO), ubiquitination assay, TRIM13 knockdown/overexpression, NF-κB reporter assay, RING domain mutant and ER-localization mutant analysis\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, domain mutants, functional NF-κB readout; single lab\",\n      \"pmids\": [\"25152375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIM13 potentiates TLR2-mediated NF-κB activation by interacting with TRAF6 and catalyzing K29-linked polyubiquitination of TRAF6. RING domain mutants (C10/13A or RING deletion) abolish TRAF6 ubiquitination and NF-κB activation, confirming dependence on E3 ligase activity. TRIM13 is upregulated in macrophages upon TLR2 ligand stimulation.\",\n      \"method\": \"Co-immunoprecipitation (TRIM13 with TRAF6), K29-linkage-specific ubiquitination assay, RING domain active-site mutagenesis (C10/13A), NF-κB reporter assay, TRIM13 knockdown\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination assay, catalytic site mutagenesis, functional NF-κB readout; single lab\",\n      \"pmids\": [\"28087809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM13 ubiquitinates the nuclear receptor Nur77 at Lys539, leading to its proteasomal degradation; optimal ubiquitination requires the E2 enzyme UbcH5. TRIM13–Nur77 interaction was confirmed by co-immunoprecipitation. CK2α phosphorylates Nur77 at Ser154 to promote TRIM13-mediated ubiquitination and degradation, and this CK2α–TRIM13 axis controls TNFα-mediated IL-6 production.\",\n      \"method\": \"Co-immunoprecipitation (TRIM13 with Nur77), ubiquitination assay with E2 enzyme panel, site-directed mutagenesis (Lys539), CK2 pharmacological inhibition and CK2α overexpression/inactive mutant, IL-6 cytokine measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay with mutagenesis, kinase inhibitor and mutant orthogonal validation; single lab\",\n      \"pmids\": [\"30224829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM13 promotes ubiquitination and degradation of CHOP in renal mesangial cells, thereby suppressing collagen synthesis. TRIM13 promoter methylation is increased in diabetic nephropathy, correlating with reduced TRIM13 expression and elevated CHOP. Restoring TRIM13 expression attenuated DN-induced collagen synthesis and improved renal function in vitro and in vivo.\",\n      \"method\": \"Ubiquitination assay (TRIM13 ubiquitinates CHOP), TRIM13 overexpression in mesangial cells and diabetic mouse model, promoter methylation analysis, collagen synthesis assay\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ubiquitination assay, in vitro and in vivo functional rescue, methylation analysis; single lab\",\n      \"pmids\": [\"31901873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM13 interacts with STING via its transmembrane domain and catalyzes Lys6-linked polyubiquitination of STING, leading to decelerated ER exit and accelerated ER-initiated degradation of STING. TRIM13 deficiency enhances pathogenic-DNA-triggered inflammatory cytokine production and causes age-related autoinflammation; STING deficiency reverses enhanced innate responses in TRIM13-knockout mice.\",\n      \"method\": \"Co-immunoprecipitation (TRIM13 TM domain with STING), K6-linkage-specific ubiquitination assay, TRIM13 knockout mice, STING double-knockout epistasis, STING ER exit/degradation assay, cytokine measurement\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — domain-specific interaction mapping, linkage-specific ubiquitination, double-knockout epistasis, multiple orthogonal methods with in vivo validation\",\n      \"pmids\": [\"35080984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM13 ubiquitinates and degrades LXRα/β, downregulating ABCA1/G1 expression and inhibiting cholesterol efflux in macrophages and smooth muscle cells. TRIM13 also ubiquitinates and degrades SOCS1/3, leading to STAT1 activation, CD36 upregulation, and foam cell formation. Genetic deletion of TRIM13 rescues cholesterol efflux and protects against diet-induced atherosclerosis in ApoE-/- mice.\",\n      \"method\": \"Ubiquitination assay (TRIM13 ubiquitinates LXRα/β and SOCS1/3), TRIM13 knockout mouse model, cholesterol efflux assay, foam cell assay, Western blot for ABCA1/G1/CD36/STAT1, human coronary artery tissue analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple substrate ubiquitination assays, KO mouse model, functional cholesterol efflux assay, human tissue correlation, multiple orthogonal methods\",\n      \"pmids\": [\"38537695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM13 interacts with p62/SQSTM1 and mediates its ubiquitination and degradation via the RING finger domain in lung adenocarcinoma cells, negatively regulating Nrf2 signaling and downstream antioxidants. This suppresses tumor cell proliferation and activates autophagy.\",\n      \"method\": \"Co-immunoprecipitation (TRIM13 with p62), ubiquitination assay, RING domain deletion mutant, Nrf2 pathway reporter/Western blot, xenograft in vivo model\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay with domain mutant, pathway analysis, in vivo xenograft; single lab\",\n      \"pmids\": [\"37245083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The LEU5 (RFP2/TRIM13) gene was identified within the minimally deleted 13q14.3 region in B-CLL; its cDNA encodes a RING-type zinc-finger domain with homology to other RING proteins involved in tumorigenesis and embryogenesis (RET finger protein, BRCA1, MID1).\",\n      \"method\": \"Cosmid contig construction, cDNA cloning and sequencing, mapping to 13q14 deletion region\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — gene identification and sequence/domain inference only; no functional experiment performed on the protein\",\n      \"pmids\": [\"9599022\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM13 (RFP2/LEU5/DLEU5/RNF77) is an ER-resident, transmembrane RING-type E3 ubiquitin ligase that regulates ERAD (ubiquitinating substrates such as Cav1.2 and CD3-delta via the VCP/p97 complex), controls innate immune signaling by ubiquitinating MDA5, STING (K6-linked), and TRAF6 (K29-linked), modulates NF-κB by targeting NEMO for ubiquitination and turnover, promotes autophagy through its coiled-coil domain and interaction with p62/SQSTM1, induces K63-linked ubiquitination of caspase-8 to drive ER stress-linked apoptosis, and ubiquitinates additional substrates including Nur77, CHOP, LXRα/β, and SOCS1/3, collectively placing it as a multi-substrate ER-anchored ubiquitin ligase at the intersection of protein quality control, antiviral immunity, inflammatory signaling, and lipid metabolism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM13 is an endoplasmic reticulum-anchored RING-type E3 ubiquitin ligase that operates at the intersection of protein quality control, innate immune signaling, inflammatory regulation, and lipid metabolism [#0, #9]. Its C-terminal transmembrane domain confers ER localization, and an intact RING domain is required for its auto-polyubiquitination and substrate ubiquitination activity; it physically associates with the VCP/p97 ERAD machinery and routes ERAD substrates such as CD3-delta and, in the absence of the Cavβ subunit, Cav1.2 L-type calcium channels to proteasomal degradation via derlin-1 and p97 [#0, #1]. Beyond canonical ERAD, TRIM13 controls innate antiviral and inflammatory signaling through linkage-specific ubiquitination: it interacts with MDA5 and RIG-I to differentially tune type I IFN output [#4], catalyzes K6-linked ubiquitination of STING to accelerate its ER-initiated degradation and restrain DNA-triggered inflammation [#9], catalyzes K29-linked ubiquitination of TRAF6 to potentiate TLR2-driven NF-κB activation [#6], and modulates NEMO ubiquitination and turnover to suppress TNF-induced NF-κB activity in a manner dependent on its RING domain and ER localization but independent of autophagy [#5]. During ER stress TRIM13 is stabilized, induces autophagy through its coiled-coil domain together with p62/SQSTM1, and drives K63-linked ubiquitination of caspase-8 to couple autophagosomal translocation to ER stress-induced cell death [#2, #3]. It additionally degrades a panel of substrates—Nur77, CHOP, LXRα/β and SOCS1/3—linking it to cytokine production, collagen synthesis in diabetic nephropathy, and cholesterol efflux and foam-cell formation in atherosclerosis [#7, #8, #10]. The gene was originally identified within the minimally deleted 13q14.3 region in B-CLL [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the gene's existence and a candidate disease context by mapping LEU5/RFP2/TRIM13 to a B-CLL deletion region, but left its function entirely unknown.\",\n      \"evidence\": \"Cosmid contig construction, cDNA cloning and sequencing within the 13q14 deletion region\",\n      \"pmids\": [\"9599022\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional experiment performed on the protein\", \"RING-domain enzymatic activity inferred only from sequence homology\", \"No causal link between TRIM13 loss and B-CLL demonstrated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Answered what biochemical activity TRIM13 has by showing it is a RING-dependent ER-resident E3 ligase that engages the ERAD machinery, defining its core molecular identity.\",\n      \"evidence\": \"In vitro/in vivo ubiquitination assays, RING mutagenesis, immunopurification + mass spectrometry, ER co-localization, CD3-delta degradation assay\",\n      \"pmids\": [\"17314412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate beyond CD3-delta not defined\", \"Mechanism of substrate selection within ERAD unclear\", \"Ubiquitin linkage type for ERAD substrates not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended the ERAD role to a physiological client by showing TRIM13 ubiquitinates Cav1.2 channels to control their surface expression, demonstrating regulatory rather than purely degradative function.\",\n      \"evidence\": \"Reciprocal Co-IP with derlin-1/p97, ubiquitination assay, MG132 rescue, RFP2 overexpression/knockdown\",\n      \"pmids\": [\"21186355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Linkage type on Cav1.2 not specified\", \"How Cavβ blocks ubiquitination structurally unknown\", \"Physiological consequence in native excitable cells not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected TRIM13 to autophagy by mapping autophagy induction to its coiled-coil domain and showing ER-stress stabilization and p62 interaction, broadening its role beyond ubiquitin transfer.\",\n      \"evidence\": \"Ectopic expression, CC-domain deletion mapping, Co-IP with p62, DFCP1 co-localization, clonogenic assay\",\n      \"pmids\": [\"22178386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether autophagy induction requires ligase activity not established\", \"Direct autophagy machinery target not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked TRIM13's ubiquitin and autophagy activities to cell fate by showing K63-linked ubiquitination of caspase-8 drives its autophagosomal translocation and ER stress-induced death.\",\n      \"evidence\": \"K63-linkage-specific ubiquitination assay, caspase-8 activation and translocation assays, lysosome fusion assay, overexpression/knockdown\",\n      \"pmids\": [\"24021263\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct vs indirect caspase-8 ubiquitination not fully resolved\", \"Physiological stress contexts beyond model systems untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined opposing roles in RNA-sensing innate immunity, with TRIM13 negatively regulating MDA5-driven IFN while interacting with RIG-I, using genetic knockout for in vivo validation.\",\n      \"evidence\": \"Reciprocal Co-IP with MDA5/RIG-I, Trim13-/- mice and MEFs, IFN-β ELISA, EMCV and Sendai virus challenge\",\n      \"pmids\": [\"25008915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRIM13 ubiquitinates MDA5/RIG-I directly not shown\", \"Mechanism of opposite RIG-I vs MDA5 effects unresolved\", \"Linkage type not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed TRIM13 restrains TNF-induced NF-κB by modulating NEMO ubiquitination and turnover, requiring RING activity and ER localization but not autophagy.\",\n      \"evidence\": \"Co-IP with NEMO, ubiquitination assay, NF-κB reporter, RING and ER-localization mutants\",\n      \"pmids\": [\"25152375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Ubiquitin linkage on NEMO not specified\", \"Reconciliation with TRAF6-potentiating role not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a context-dependent positive arm of inflammatory signaling, with K29-linked ubiquitination of TRAF6 potentiating TLR2-driven NF-κB activation.\",\n      \"evidence\": \"Co-IP with TRAF6, K29-linkage-specific ubiquitination assay, C10/13A catalytic mutagenesis, NF-κB reporter, knockdown\",\n      \"pmids\": [\"28087809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"How TRIM13 toggles between suppressing (NEMO) and activating (TRAF6) NF-κB unclear\", \"In vivo relevance not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a phosphodegron-controlled substrate by showing CK2α phosphorylation of Nur77 promotes TRIM13-mediated degradation, controlling TNFα-driven IL-6.\",\n      \"evidence\": \"Co-IP with Nur77, ubiquitination assay with E2 panel (UbcH5), Lys539 mutagenesis, CK2 inhibition/mutant, IL-6 measurement\",\n      \"pmids\": [\"30224829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Generality of CK2-priming for other TRIM13 substrates unknown\", \"In vivo confirmation lacking\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed TRIM13 in a disease pathway by showing it degrades CHOP to suppress collagen synthesis, with promoter methylation silencing TRIM13 in diabetic nephropathy.\",\n      \"evidence\": \"Ubiquitination assay, overexpression in mesangial cells and diabetic mice, promoter methylation analysis, collagen synthesis assay\",\n      \"pmids\": [\"31901873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Ubiquitin linkage on CHOP not specified\", \"Direct vs indirect CHOP regulation not fully separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved a precise mechanism in DNA-sensing immunity by showing TM-domain-mediated, K6-linked ubiquitination of STING decelerates ER exit and accelerates its degradation, with epistasis confirming the STING axis in vivo.\",\n      \"evidence\": \"Co-IP via TRIM13 TM domain, K6-linkage-specific ubiquitination assay, Trim13-/- mice, STING double-knockout epistasis, ER exit/degradation and cytokine assays\",\n      \"pmids\": [\"35080984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TM-domain STING engagement unknown\", \"Relationship to other innate substrates not integrated\", \"Human relevance of age-related autoinflammation not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected TRIM13 to redox and tumor biology by showing RING-dependent ubiquitination of p62 dampens Nrf2 signaling and suppresses lung adenocarcinoma growth.\",\n      \"evidence\": \"Co-IP with p62, ubiquitination assay, RING deletion mutant, Nrf2 pathway readouts, xenograft model\",\n      \"pmids\": [\"37245083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Reconciliation with p62 acting as autophagy partner (idx 2) unaddressed\", \"Ubiquitin linkage on p62 not specified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a metabolic-vascular role by showing TRIM13 degrades LXRα/β and SOCS1/3 to impair cholesterol efflux and promote foam-cell formation, with knockout protecting against atherosclerosis.\",\n      \"evidence\": \"Ubiquitination assays for multiple substrates, Trim13 KO in ApoE-/- mice, cholesterol efflux and foam cell assays, human coronary tissue analysis\",\n      \"pmids\": [\"38537695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Linkage types on LXR/SOCS not specified\", \"Which substrate dominates the atherosclerosis phenotype unclear\", \"Upstream regulation of TRIM13 in macrophages undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single ER-anchored ligase coordinates its opposing roles (NF-κB suppression vs potentiation, RIG-I vs MDA5, autophagy partner vs degrader of p62) and how substrate selection is governed remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate recognition\", \"Ubiquitin linkage codes across substrates not systematically compared\", \"Mechanism switching TRIM13 between activating and inhibitory outputs unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 6, 9, 10]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 7, 9, 10]},\n      {\"term_id\": \"GO:0061630\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 6, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VCP\", \"MDA5\", \"RIG-I\", \"STING\", \"TRAF6\", \"NEMO\", \"SQSTM1\", \"Nur77\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}