{"gene":"TRIM31","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2016,"finding":"TRIM31 directly binds NLRP3 and promotes K48-linked polyubiquitination of NLRP3, leading to its proteasomal degradation, thereby attenuating NLRP3 inflammasome activation. TRIM31 deficiency enhances NLRP3 inflammasome activation in vivo.","method":"Co-immunoprecipitation, ubiquitination assay (K48-specific), proteasome inhibition, TRIM31-deficient mice with alum-induced peritonitis and DSS-induced colitis models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo knockout models, multiple orthogonal methods; independently replicated across multiple subsequent studies","pmids":["27929086"],"is_preprint":false},{"year":2016,"finding":"TRIM31 is recruited to mitochondria after viral infection, interacts with MAVS, and catalyzes K63-linked polyubiquitination at Lys10, Lys311, and Lys461 on MAVS. This modification promotes prion-like aggregate formation of MAVS, activating antiviral signaling. TRIM31-deficient mice are more susceptible to RNA virus infection.","method":"Co-immunoprecipitation, site-specific ubiquitination assay (K63-linked), MAVS aggregate assay, TRIM31-knockout mice infected with RNA virus, subcellular fractionation/mitochondrial localization","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP, site-directed mutagenesis of ubiquitination sites, in vivo knockout, multiple orthogonal methods in one study","pmids":["27992402"],"is_preprint":false},{"year":2017,"finding":"TRIM31 directly interacts with the TSC1-TSC2 complex and promotes K48-linked ubiquitination and proteasomal degradation of TSC1 and TSC2, leading to overactivation of the mTORC1 pathway in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linked), gain- and loss-of-function assays in HCC cell lines, mTORC1 pathway readouts","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, K48 ubiquitination assay, functional rescue; single lab, two orthogonal methods","pmids":["28967907"],"is_preprint":false},{"year":2016,"finding":"Human TRIM31 is an intestine-specific protein localized in mitochondria that directly interacts with phosphatidylethanolamine in a palmitoylation-dependent manner, promoting LPS-induced Atg5/Atg7-independent autolysosome formation and protecting against intracellular bacteria.","method":"Subcellular fractionation/confocal microscopy for mitochondrial localization, lipid-binding assay (phosphatidylethanolamine pulldown), palmitoylation mutants, TRIM31 depletion with bacterial invasion assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct lipid-binding assay, mutagenesis of palmitoylation sites, localization experiments with functional consequence, bacterial invasion phenotype","pmids":["27216961"],"is_preprint":false},{"year":2018,"finding":"TRIM31 promotes K63-linked polyubiquitination of TRAF2, sustaining NF-κB activation and conferring gemcitabine resistance in pancreatic cancer cells.","method":"Co-immunoprecipitation, K63-specific ubiquitination assay, NF-κB luciferase reporter assay, in vitro and in vivo drug resistance assays","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, K63 ubiquitination assay, luciferase reporter; single lab, multiple methods","pmids":["29930725"],"is_preprint":false},{"year":2021,"finding":"TRIM31 interacts with and catalyzes K48-linked polyubiquitination at lysine 72 of MAP3K7 (TAK1), leading to its proteasomal degradation and negative regulation of TGF-β1-mediated Smad and MAPK/NF-κB signaling pathways in hypertensive nephropathy.","method":"Co-immunoprecipitation, site-specific ubiquitination assay (K48, K72 site), TRIM31-knockout and AAV-mediated overexpression mice with AngII-induced renal disease model","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, site-directed mutagenesis at K72, in vivo KO and OE models, multiple orthogonal methods","pmids":["34584221"],"is_preprint":false},{"year":2021,"finding":"TRIM31 acts as an E3 ubiquitin ligase for TIGAR, interacting with it and promoting its K48-linked polyubiquitination and proteasomal degradation, thereby reducing pentose phosphate pathway flux and increasing ROS during cerebral ischemia.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, TIGAR knockdown rescue experiments in TRIM31-deficient neurons","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, polyubiquitination assay, genetic epistasis by TIGAR knockdown rescue; single lab, two orthogonal methods","pmids":["34218200"],"is_preprint":false},{"year":2021,"finding":"TRIM31 facilitates K27-linked polyubiquitination of SYK at Lys375 and Lys517, promoting SYK plasma membrane translocation and interaction with C-type lectin receptors (CLRs), while preventing interaction with phosphatase SHP-1, thus activating antifungal immunity.","method":"Co-immunoprecipitation, site-specific K27 ubiquitination assay, subcellular fractionation, receptor co-localization, SHP-1 interaction assays, TRIM31-knockout mice with Candida albicans infection","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, K27 ubiquitination at specific lysine sites by mutagenesis, in vivo KO model, multiple orthogonal methods","pmids":["34362877"],"is_preprint":false},{"year":2022,"finding":"TRIM31 directly binds to Rhbdf2 and facilitates its proteasomal degradation via ubiquitination, acting as an endogenous inhibitor of Rhbdf2 signaling in hepatocytes. Hepatocyte-specific TRIM31 ablation exacerbates NAFLD phenotypes.","method":"Co-immunoprecipitation, ubiquitination/degradation assay, hepatocyte-specific knockout mice (TRIM31Hep-cKO), transgenic overexpression and ex vivo gene therapy in NAFLD mouse models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ubiquitination assay, tissue-specific KO and gain-of-function models in vivo, multiple orthogonal methods","pmids":["35217669"],"is_preprint":false},{"year":2008,"finding":"TRIM31 is an RBCC protein with in vitro autoubiquitylating (E3 ligase) activity, undergoes homo-oligomerization, and localizes primarily to the cytoplasm with a fraction associated with mitochondria. TRIM31 overexpression suppresses colony formation, indicating a negative role in cell proliferation.","method":"In vitro ubiquitylation assay, subcellular fractionation, confocal microscopy, siRNA knockdown, colony formation assay","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro ubiquitylation assay and localization experiments; single lab, multiple methods","pmids":["18773414"],"is_preprint":false},{"year":2011,"finding":"TRIM31 is subject to polyubiquitylation followed by proteasomal degradation, establishing that the ubiquitin-proteasome system regulates endogenous TRIM31 protein abundance. The intracellular level of TRIM31 is also controlled by inducible transcription and alternative splicing.","method":"Exogenous expression in 293 cells and endogenous detection in AsPC-1 cells; proteasome inhibitor treatment, ubiquitylation assay","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteasome inhibitor experiment, ubiquitylation assay; single lab, two methods","pmids":["21231912"],"is_preprint":false},{"year":2015,"finding":"TRIM31 interacts with MAGEA1 via its coiled-coil domain (binding both WH/A and WH/B motifs of MAGEA1). MAGEA1 stimulates TRIM31 E3 ubiquitin-ligase activity. TRIM31 also directly binds NSE4, suggesting the existence of a TRIM31-MAGEA1-NSE4 trimeric complex.","method":"Yeast two-hybrid screen, co-immunoprecipitation, in vitro E3 ligase activity assay with and without MAGEA1","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vitro ubiquitin-ligase assay; single lab, two orthogonal methods","pmids":["25590999"],"is_preprint":false},{"year":2009,"finding":"TRIM31 interacts with p52(Shc) via a region outside the RING domain. Overexpression of TRIM31 does not affect p52(Shc) stability but suppresses anchorage-independent cell growth induced by active c-Src, suggesting TRIM31 attenuates c-Src/Shc signaling.","method":"Co-immunoprecipitation, binding domain mapping, pulse-chase stability analysis, soft agar anchorage-independent growth assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, domain mapping, functional assay; single lab, multiple methods","pmids":["19665990"],"is_preprint":false},{"year":2020,"finding":"TRIM31 interacts with and ubiquitinates TAK1 (MAP3K7), resulting in TAK1 activation and subsequent induction of NF-κB signaling, promoting apoptosis in LPS-induced sepsis-induced myocardial dysfunction model.","method":"Co-immunoprecipitation, ubiquitination assay, NF-κB signaling readouts, TRIM31 knockdown/overexpression in cardiomyocytes and LPS-treated mice","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo model; single lab, two orthogonal methods","pmids":["33016203"],"is_preprint":false},{"year":2024,"finding":"TRIM31 interacts with VDAC1 and promotes its K48-linked polyubiquitination and proteasomal degradation. TRIM31 deficiency in mice leads to age-associated motor defects and dopaminergic neurodegeneration, and TRIM31-/- mice show aggravated MPTP-induced dopaminergic neurotoxicity.","method":"Co-immunoprecipitation, K48 ubiquitination assay, TRIM31-knockout mice (spontaneous and MPTP model), proteasome inhibitor experiments","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, K48 ubiquitination assay, in vivo KO phenotype with two models; multiple orthogonal methods","pmids":["38918620"],"is_preprint":false},{"year":2023,"finding":"TRIM31 promotes K63-linked polyubiquitination of MEF2C at Lys25, which increases MEF2C recruitment to the PD-L1 promoter and drives PD-L1 gene transcription in NSCLC cells stimulated with IL-17.","method":"Co-immunoprecipitation, site-specific K63 ubiquitination assay with mutagenesis, ChIP, luciferase reporter assay, isograft tumor model","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, site-specific ubiquitination, ChIP; single lab, multiple orthogonal methods","pmids":["39810133"],"is_preprint":false},{"year":2021,"finding":"TRIM31 interacts with NLRP3 and promotes K48-linked polyubiquitination and proteasomal degradation of NLRP3 in retinal pigment epithelial cells, suppressing NLRP3 inflammasome activation and pyroptosis.","method":"Co-immunoprecipitation, overexpression and ubiquitination assay in ARPE-19 cells, NLRP3 inhibitor rescue","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, ubiquitination assay; single lab, replicates the NLRP3-TRIM31 interaction in a new cell type","pmids":["32716108"],"is_preprint":false},{"year":2022,"finding":"The transcription factor Cdx2 transcriptionally regulates TRIM31 expression; loss of Cdx2 leads to decreased TRIM31 and elevated NLRP3 levels in mouse colon, revealing a Cdx2-TRIM31-NLRP3 signaling axis in intestinal homeostasis.","method":"Conditional Cdx2 knockout mice, TRIM31 and NLRP3 expression analysis, NLRP3 inhibitor rescue experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO with pathway analysis, NLRP3 inhibitor rescue; single lab, genetic epistasis approach","pmids":["35985421"],"is_preprint":false},{"year":2025,"finding":"TRIM31 promotes K48-linked ubiquitination of LOX-1 at lysine 12, facilitating LOX-1 proteasomal degradation in macrophages. This reduces oxidized LDL uptake and foam cell formation, limiting atherosclerotic plaque formation. The atheroprotective effect of TRIM31 is abolished in Lox-1-/- or K12R-LOX-1 rescue models.","method":"Co-immunoprecipitation, proteomic/immunoprecipitation-mass spectrometry, site-directed mutagenesis (K12R), K48-specific ubiquitination assay, macrophage-specific Trim31 KO and OE mice, Lox-1-/- and K12R rescue experiments in vivo","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — site-directed mutagenesis of ubiquitination site, in vivo KO/OE/rescue models, mass spectrometry identification; multiple orthogonal methods in one study","pmids":["41410044"],"is_preprint":false},{"year":2023,"finding":"TRIM31 regulates HSC homeostasis by promoting ubiquitin-mediated degradation of CDK8; TRIM31 deficiency leads to CDK8 accumulation, which induces transcriptional expression of PBX1 and cyclin D1, promoting HSPC proliferation and HSC exhaustion.","method":"TRIM31-knockout mice, serial competitive transplantation, Western blot for CDK8/PBX1/cyclin D1, 5-FU stress model","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model with functional reconstitution, CDK8 as substrate; single lab, pathway placement via genetic approach","pmids":["36632737"],"is_preprint":false},{"year":2021,"finding":"TRIM31 promotes HBx ubiquitination and degradation; a patient-derived frameshift mutation in TRIM31 (truncated at 768 bp) abolishes this activity and blocks inhibition of HBV replication. TRIM31 was identified as a type III interferon-stimulated gene (not type I or II) required for anti-HBV innate immunity.","method":"Ubiquitination assay for HBx, truncation mutant analysis, interferon stimulation experiments, TRIM31-TRIM5γ-HBx co-immunoprecipitation","journal":"Virus research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutant-based functional assay, Co-IP, IFN induction; single lab, multiple methods","pmids":["34863820"],"is_preprint":false},{"year":2025,"finding":"TRIM31 interacts with YBX1 and catalyzes K63-linked polyubiquitination at Lys81 of YBX1, leading to stabilization (not degradation) of YBX1 protein. Stabilized YBX1 enhances mRNA stability of EREG, GAS6, and MAFG. NF-κB p65 activates TRIM31 transcription, and TRIM31 in turn facilitates p65 nuclear entry, creating a positive feedback loop.","method":"Co-immunoprecipitation, K63 ubiquitination assay with site mutagenesis (K81), mRNA stability assay, ChIP for p65 on TRIM31 promoter, p65 nuclear translocation assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, site-specific ubiquitination, mRNA stability assay, ChIP; single lab, multiple orthogonal methods","pmids":["40819060"],"is_preprint":false},{"year":2025,"finding":"USP13 competes with TRIM31 to interact with NLRP3, preventing TRIM31-mediated K48-linked ubiquitination of NLRP3 at K192 and K496 sites. USP13 thereby stabilizes NLRP3 protein and promotes inflammasome assembly, independently of USP13 deubiquitinase activity.","method":"Co-immunoprecipitation, competitive binding assay (USP13 vs TRIM31 for NLRP3), site-specific ubiquitination assay, USP13-deficient macrophages, mouse peritonitis model","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — competitive Co-IP, site-directed mutagenesis of ubiquitination sites, in vivo model, mechanistic dissection of USP13 vs TRIM31 interaction","pmids":["41004574"],"is_preprint":false},{"year":2024,"finding":"TRIM31 interacts with Drp1 and promotes its ubiquitination and degradation via the proteasome pathway, improving mitochondrial function in a Parkinson's disease model. TRIM31 knockdown partially attenuates lutein's protective effects on Drp1 ubiquitination.","method":"Ubiquitination assay, Western blot for Drp1 protein levels, TRIM31 overexpression and knockdown in SH-SY5Y cells and MPTP mouse model, mitochondrial function readouts (ROS, membrane potential, ATP)","journal":"Journal of integrative neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, ubiquitination assay without site-specific mapping; functional readout present but indirect","pmids":["41609041"],"is_preprint":false},{"year":2022,"finding":"In hepatocytes, TRIM31 activates Nrf2 signaling; hepatocyte-specific TRIM31 knockout mice show impaired Nrf2 activation and increased hepatic oxidative stress, and the anti-fibrotic effects of mulberrin are dependent on the TRIM31/Nrf2 axis.","method":"Hepatocyte-specific TRIM31 knockout mice (TRIM31Hep-cKO), Nrf2-KO primary hepatocytes, CCl4 liver fibrosis model, oxidative stress measurement","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO in vivo, genetic epistasis with Nrf2-KO; single lab, two orthogonal genetic models","pmids":["35240537"],"is_preprint":false},{"year":2023,"finding":"TRIM31 negatively regulates NLRP3 inflammasome activation in H. pylori-associated gastritis by reducing mitochondrial ROS and maintaining autophagy flux; TRIM31-deficient gastric epithelial cells show impaired lysosomal cathepsin B and D expression and disrupted autophagic flux upon H. pylori infection.","method":"TRIM31 knockdown in GES-1 cells, flow cytometry for mitochondrial membrane potential and ROS, mCherry-EGFP-LC3 autophagy flux assay, lysosomal acidification and cathepsin expression analysis, chronic Hp mouse infection model","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cellular assays in one study; single lab, autophagy flux and ROS mechanistically linked to TRIM31 loss","pmids":["36597090"],"is_preprint":false},{"year":2025,"finding":"TRIM31 promotes ubiquitination and degradation of BBOX1 (gamma-butyrobetaine dioxygenase) in esophageal cancer cells, enhancing their proliferation, migration, and invasion.","method":"Co-immunoprecipitation, ubiquitination assay, loss-of-function assays in Eca109 cells and in vivo xenograft","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination assay without site mapping; single lab, single paper","pmids":["40651686"],"is_preprint":false}],"current_model":"TRIM31 is a RING finger/RBCC domain E3 ubiquitin ligase that localizes primarily to the cytoplasm and mitochondria, and functions by ubiquitinating a diverse set of substrates—including NLRP3 (K48-linked, proteasomal degradation), MAVS (K63-linked, promoting prion-like aggregation for antiviral signaling), TSC1/TSC2 (K48-linked, mTORC1 activation), MAP3K7/TAK1 (K48-linked), SYK (K27-linked, membrane translocation), TRAF2 (K63-linked, NF-κB activation), TIGAR, VDAC1, CDK8, Rhbdf2, LOX-1, YBX1 (K63-linked, stabilization), MEF2C (K63-linked, transcriptional activation), and Drp1—thereby acting as a context-dependent regulator of innate immune signaling (NLRP3 inflammasome, RLR-MAVS antiviral, and CLR-SYK antifungal pathways), autophagy, mitochondrial homeostasis, and mTOR/NF-κB/Wnt signaling in cancer and metabolic disease."},"narrative":{"mechanistic_narrative":"TRIM31 is an RBCC/RING-finger E3 ubiquitin ligase that operates as a context-dependent regulator of innate immune signaling, mitochondrial homeostasis, and cell-growth pathways by assembling distinct polyubiquitin linkages on substrate-specific lysines [PMID:18773414, PMID:27929086, PMID:27992402]. It autoubiquitylates in vitro, homo-oligomerizes, and partitions between the cytoplasm and mitochondria, where its ligase activity can be stimulated by the cofactor MAGEA1 [PMID:18773414, PMID:25590999]. A central theme is reciprocal control of the NLRP3 inflammasome: TRIM31 binds NLRP3 and catalyzes K48-linked polyubiquitination driving proteasomal degradation, dampening inflammasome activation in vivo, with site-specific K48 marks at K192/K496 antagonized by competitive USP13 binding [PMID:27929086, PMID:32716108, PMID:41004574]. Beyond NLRP3, TRIM31 builds K48-linked degradative chains on TSC1/TSC2 to activate mTORC1, on MAP3K7/TAK1, TIGAR, VDAC1, and LOX-1 (at K12, limiting oxLDL uptake and atherosclerosis), and on Rhbdf2 in hepatocytes [PMID:28967907, PMID:34584221, PMID:34218200, PMID:38918620, PMID:41410044, PMID:35217669]. In parallel it deploys non-degradative linkages: K63-linked ubiquitination of MAVS at K10/K311/K461 to drive prion-like aggregation and antiviral RLR signaling, K63 chains on TRAF2 and YBX1 (K81, stabilizing) to sustain NF-κB and mRNA-stability programs, and K27-linked ubiquitination of SYK at K375/K517 to direct membrane translocation and antifungal immunity [PMID:27992402, PMID:29930725, PMID:40819060, PMID:34362877]. TRIM31 also engages mitochondrial and autophagic biology directly, binding phosphatidylethanolamine in a palmitoylation-dependent manner to promote Atg5/Atg7-independent autolysosome formation against intracellular bacteria [PMID:27216961]. In vivo loss-of-function models tie TRIM31 to protection against dopaminergic neurodegeneration, hypertensive nephropathy, NAFLD, and HSC exhaustion, while its own abundance is set by inducible transcription, alternative splicing, and proteasomal turnover [PMID:38918620, PMID:34584221, PMID:35217669, PMID:36632737, PMID:21231912].","teleology":[{"year":2008,"claim":"Established TRIM31 as a bona fide E3 ubiquitin ligase, answering whether the RBCC protein had intrinsic catalytic activity and where it acts.","evidence":"in vitro autoubiquitylation assay, subcellular fractionation and confocal microscopy, colony-formation assay","pmids":["18773414"],"confidence":"Medium","gaps":["No physiological substrate identified at this stage","Mechanism linking ligase activity to growth suppression unresolved"]},{"year":2009,"claim":"Identified a partner (p52-Shc) and a growth-suppressive role outside the RING domain, indicating TRIM31 functions partly through binding rather than degradation.","evidence":"Co-IP, domain mapping, pulse-chase stability, soft-agar growth assay","pmids":["19665990"],"confidence":"Medium","gaps":["No ubiquitination of p52-Shc demonstrated","Mechanism of c-Src/Shc attenuation undefined"]},{"year":2011,"claim":"Showed TRIM31 abundance is itself controlled by the ubiquitin-proteasome system plus transcription and splicing, framing it as a tightly regulated node.","evidence":"proteasome inhibitor treatment and ubiquitylation assay in 293 and AsPC-1 cells","pmids":["21231912"],"confidence":"Medium","gaps":["E3 ligase responsible for TRIM31 turnover not identified","Physiological triggers of regulated turnover unknown"]},{"year":2015,"claim":"Revealed a cofactor mechanism: MAGEA1 binds the coiled-coil domain and stimulates TRIM31 ligase activity, suggesting regulated substrate-independent activation.","evidence":"yeast two-hybrid, Co-IP, in vitro ligase assay +/- MAGEA1","pmids":["25590999"],"confidence":"Medium","gaps":["Substrates of the MAGEA1-stimulated complex not defined","Role of proposed TRIM31-MAGEA1-NSE4 trimer untested in cells"]},{"year":2016,"claim":"Defined opposing innate-immune roles via linkage-specific ubiquitination: K48 degradation of NLRP3 to restrain inflammasomes, and K63 modification of MAVS to drive antiviral signaling.","evidence":"reciprocal Co-IP, linkage- and site-specific ubiquitination assays, MAVS aggregation assay, TRIM31-knockout mice in colitis/peritonitis and RNA virus models","pmids":["27929086","27992402"],"confidence":"High","gaps":["What dictates K48 vs K63 linkage choice between substrates unresolved","Signals controlling mitochondrial recruitment incompletely defined"]},{"year":2016,"claim":"Demonstrated a ubiquitination-independent activity: palmitoylation-dependent phosphatidylethanolamine binding drives Atg5/Atg7-independent autolysosome formation against intracellular bacteria.","evidence":"lipid-binding pulldown, palmitoylation mutants, mitochondrial localization, bacterial invasion assay","pmids":["27216961"],"confidence":"High","gaps":["Molecular machinery of the noncanonical autolysosome pathway undefined","Relationship to TRIM31 E3 activity unclear"]},{"year":2017,"claim":"Extended K48-degradative function to growth control by targeting the TSC1-TSC2 complex, placing TRIM31 upstream of mTORC1 in cancer.","evidence":"Co-IP, K48 ubiquitination assay, gain/loss-of-function in HCC lines with mTORC1 readouts","pmids":["28967907"],"confidence":"Medium","gaps":["Ubiquitination sites on TSC1/TSC2 not mapped","In vivo requirement not tested"]},{"year":2020,"claim":"Reported context-dependent TAK1 regulation, with TRIM31 activating TAK1/NF-kB and promoting apoptosis in septic myocardial dysfunction.","evidence":"Co-IP, ubiquitination assay, NF-kB readouts in cardiomyocytes and LPS-treated mice","pmids":["33016203"],"confidence":"Medium","gaps":["Linkage type not specified","Apparent conflict with later K48-degradative TAK1 finding unresolved"]},{"year":2021,"claim":"Expanded the linkage repertoire and substrate set: K27 ubiquitination of SYK for antifungal immunity, K48 degradation of TAK1 in nephropathy and TIGAR in ischemia, and replicated NLRP3 control in RPE cells.","evidence":"site-specific ubiquitination assays with mutagenesis, subcellular fractionation, TRIM31-knockout/overexpression mice and disease models","pmids":["34362877","34584221","34218200","32716108"],"confidence":"High","gaps":["How TRIM31 selects among K27/K48/K63 linkages per substrate unknown","Tissue determinants of opposing TAK1 outcomes undefined"]},{"year":2021,"claim":"Identified TRIM31 as a type III interferon-stimulated gene with antiviral activity against HBV via HBx ubiquitination, supported by a loss-of-function patient frameshift mutant.","evidence":"HBx ubiquitination assay, truncation-mutant analysis, IFN induction, TRIM31-TRIM5gamma-HBx Co-IP","pmids":["34863820"],"confidence":"Medium","gaps":["Clinical significance of the patient mutation in a cohort untested","Mechanism of type-III-specific induction undefined"]},{"year":2022,"claim":"Placed TRIM31 within tissue-protective circuits: as a Cdx2-regulated suppressor of NLRP3 in intestine, an inhibitor of Rhbdf2 in NAFLD, and an activator of Nrf2 antioxidant signaling in liver fibrosis.","evidence":"conditional/tissue-specific knockout mice, Nrf2-KO epistasis, NLRP3-inhibitor rescue, NAFLD and CCl4 fibrosis models","pmids":["35985421","35217669","35240537"],"confidence":"Medium","gaps":["Mechanism of Nrf2 activation not at the ubiquitination level resolved","Direct vs indirect Cdx2 regulation of TRIM31 promoter"]},{"year":2023,"claim":"Linked TRIM31 to hematopoietic and tumor-immune control through CDK8 degradation (HSC homeostasis), K63 MEF2C ubiquitination driving PD-L1, and autophagy/mitochondrial ROS control in gastritis.","evidence":"TRIM31-knockout mice with serial transplantation, site-specific K63 ubiquitination plus ChIP, autophagy-flux and ROS assays","pmids":["36632737","39810133","36597090"],"confidence":"Medium","gaps":["CDK8 ubiquitination linkage and sites not mapped","Connection between autophagy regulation and direct substrates unclear"]},{"year":2024,"claim":"Established mitochondrial substrates underlying neuroprotection: K48 degradation of VDAC1 and ubiquitination of Drp1, with TRIM31 loss causing dopaminergic neurodegeneration.","evidence":"Co-IP, K48 ubiquitination assays, TRIM31-knockout and MPTP Parkinson's models, mitochondrial function readouts","pmids":["38918620","41609041"],"confidence":"High","gaps":["Drp1 ubiquitination sites and linkage not mapped (Low-confidence)","Relative contribution of VDAC1 vs Drp1 to neurodegeneration unresolved"]},{"year":2025,"claim":"Resolved competitive regulation and non-degradative outputs: USP13 blocks TRIM31-mediated K48 NLRP3 ubiquitination at K192/K496, while TRIM31 stabilizes YBX1 via K63 chains and degrades LOX-1 (K12) and BBOX1, tying it to atherosclerosis and cancer.","evidence":"competitive Co-IP, site-directed mutagenesis, mRNA-stability and ChIP assays, macrophage-specific Trim31 KO/OE plus Lox-1-/- and K12R rescue in vivo","pmids":["41004574","40819060","41410044","40651686"],"confidence":"High","gaps":["BBOX1 targeting lacks site mapping (Low-confidence)","Generality of antagonist competition (USP13-type) across other substrates untested"]},{"year":null,"claim":"The central open question is the molecular rule by which TRIM31 selects K48 versus K63 versus K27 linkages and degradative versus signaling outcomes on different substrates within different tissues.","evidence":"no single study reconciles the linkage- and context-determinants across the substrate set","pmids":[],"confidence":"Medium","gaps":["No structural model of TRIM31-substrate or TRIM31-E2 pairing","Determinants of cytoplasm vs mitochondria partitioning incompletely defined","No unifying biochemical reconstitution explaining linkage switching"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[9,0,1,7,5,14,18]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,7,5,18]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[22,11]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[9,1,3,14]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4,5,21]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,5,14,18]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,25]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,24]}],"complexes":[],"partners":["NLRP3","MAVS","TSC1","TSC2","MAP3K7","SYK","VDAC1","USP13"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BZY9","full_name":"E3 ubiquitin-protein ligase TRIM31","aliases":["Tripartite motif-containing protein 31"],"length_aa":425,"mass_kda":48.2,"function":"E3 ubiquitin-protein ligase that acts as a regulator of antiviral immune response and inflammation by mediating ubiquitination of substrates (PubMed:18773414, PubMed:27929086, PubMed:27992402). Acts as a regulator of innate immune defense against viruses by mediating 'Lys-63'-linked ubiquitination of MAVS, promoting MAVS polymerization and formation of three-stranded helical filaments on mitochondria (PubMed:27992402). Acts as a negative regulator of the NLRP3 inflammasome by catalyzing 'Lys-48'-linked ubiquitination of NLRP3, leading to its degradation (PubMed:27929086). 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Association","url":"https://pubmed.ncbi.nlm.nih.gov/27789153","citation_count":10,"is_preprint":false},{"pmid":"36632737","id":"PMC_36632737","title":"The E3 ligase TRIM31 regulates hematopoietic stem cell homeostasis and MLL-AF9 leukemia.","date":"2023","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/36632737","citation_count":8,"is_preprint":false},{"pmid":"26184942","id":"PMC_26184942","title":"Complete Genome Sequence of Rnf- and Cytochrome-Containing Autotrophic Acetogen Clostridium aceticum DSM 1496.","date":"2015","source":"Genome announcements","url":"https://pubmed.ncbi.nlm.nih.gov/26184942","citation_count":8,"is_preprint":false},{"pmid":"38667290","id":"PMC_38667290","title":"Inhibition of Immunoproteasome Attenuates NLRP3 Inflammasome Response by Regulating E3 Ubiquitin Ligase TRIM31.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/38667290","citation_count":7,"is_preprint":false},{"pmid":"33370357","id":"PMC_33370357","title":"Ethnic variation and the relevance of homozygous RNF 213 p.R4810.K variant in the phenotype of Indian Moya moya disease.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/33370357","citation_count":7,"is_preprint":false},{"pmid":"27114876","id":"PMC_27114876","title":"The role of Rnf in ion gradient formation in Desulfovibrio alaskensis.","date":"2016","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/27114876","citation_count":7,"is_preprint":false},{"pmid":"36375322","id":"PMC_36375322","title":"Cynapanoside A exerts protective effects against obesity-induced diabetic nephropathy through ameliorating TRIM31-mediated inflammation, lipid synthesis and fibrosis.","date":"2022","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36375322","citation_count":7,"is_preprint":false},{"pmid":"39215331","id":"PMC_39215331","title":"Britannilactone 1-O-acetate induced ubiquitination of NLRP3 inflammasome through TRIM31 as a protective mechanism against reflux esophagitis-induced esophageal injury.","date":"2024","source":"Chinese medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39215331","citation_count":5,"is_preprint":false},{"pmid":"41004574","id":"PMC_41004574","title":"USP13 stabilizes NLRP3 to facilitate inflammasome activation by preventing TRIM31-mediated NLRP3 ubiquitination and degradation.","date":"2025","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/41004574","citation_count":4,"is_preprint":false},{"pmid":"39211324","id":"PMC_39211324","title":"FGF21 upregulation by hepatitis C virus via the eIF2α-ATF4 pathway: implications for interferon signaling suppression and TRIM31-mediated TSC degradation.","date":"2024","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/39211324","citation_count":4,"is_preprint":false},{"pmid":"35223862","id":"PMC_35223862","title":"Functions of RNF Family in the Tumor Microenvironment and Drugs Prediction in Grade II/III Gliomas.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35223862","citation_count":4,"is_preprint":false},{"pmid":"38978046","id":"PMC_38978046","title":"An investigation of the molecular characterization of the tripartite motif (TRIM) family and primary validation of TRIM31 in gastric cancer.","date":"2024","source":"Human genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38978046","citation_count":4,"is_preprint":false},{"pmid":"37498068","id":"PMC_37498068","title":"TRIM31 promotes the progression of oral squamous cell carcinoma through upregulating AKT phosphorylation and subsequent cellular glycolysis.","date":"2023","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/37498068","citation_count":3,"is_preprint":false},{"pmid":"40401912","id":"PMC_40401912","title":"Inactivation of the Fusobacterium nucleatum Rnf complex reduces FadA-mediated amyloid formation and tumor 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signalling","url":"https://pubmed.ncbi.nlm.nih.gov/40651686","citation_count":2,"is_preprint":false},{"pmid":"39810133","id":"PMC_39810133","title":"IL-17 triggers PD-L1 gene transcription in NSCLC cells via TRIM31-dependent MEF2C K63-linked polyubiquitination.","date":"2025","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39810133","citation_count":2,"is_preprint":false},{"pmid":"41410044","id":"PMC_41410044","title":"Macrophage-Specific E3 Ubiquitin Ligase TRIM31 Reduces Atherosclerotic Plaque Formation by Targeting LOX-1.","date":"2025","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/41410044","citation_count":1,"is_preprint":false},{"pmid":"34105476","id":"PMC_34105476","title":"[Effect of TRIM31 Gene Silencing on the Proliferation and Apoptosis of U266 Cells and Its Mechanism].","date":"2021","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/34105476","citation_count":1,"is_preprint":false},{"pmid":"41099845","id":"PMC_41099845","title":"Tenuigenin targets Trim31 and NF-κB pathway to protect dopaminergic neurons in Parkinson's disease mice.","date":"2025","source":"Naunyn-Schmiedeberg's archives of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41099845","citation_count":1,"is_preprint":false},{"pmid":"41609041","id":"PMC_41609041","title":"Lutein Attenuates Parkinson's Disease Progression by Regulating Mitochondrial Function via the TRIM31/Drp1 Signaling Pathway.","date":"2026","source":"Journal of integrative 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TRIM31 deficiency enhances NLRP3 inflammasome activation in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-specific), proteasome inhibition, TRIM31-deficient mice with alum-induced peritonitis and DSS-induced colitis models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo knockout models, multiple orthogonal methods; independently replicated across multiple subsequent studies\",\n      \"pmids\": [\"27929086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIM31 is recruited to mitochondria after viral infection, interacts with MAVS, and catalyzes K63-linked polyubiquitination at Lys10, Lys311, and Lys461 on MAVS. This modification promotes prion-like aggregate formation of MAVS, activating antiviral signaling. TRIM31-deficient mice are more susceptible to RNA virus infection.\",\n      \"method\": \"Co-immunoprecipitation, site-specific ubiquitination assay (K63-linked), MAVS aggregate assay, TRIM31-knockout mice infected with RNA virus, subcellular fractionation/mitochondrial localization\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP, site-directed mutagenesis of ubiquitination sites, in vivo knockout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"27992402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIM31 directly interacts with the TSC1-TSC2 complex and promotes K48-linked ubiquitination and proteasomal degradation of TSC1 and TSC2, leading to overactivation of the mTORC1 pathway in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linked), gain- and loss-of-function assays in HCC cell lines, mTORC1 pathway readouts\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, K48 ubiquitination assay, functional rescue; single lab, two orthogonal methods\",\n      \"pmids\": [\"28967907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human TRIM31 is an intestine-specific protein localized in mitochondria that directly interacts with phosphatidylethanolamine in a palmitoylation-dependent manner, promoting LPS-induced Atg5/Atg7-independent autolysosome formation and protecting against intracellular bacteria.\",\n      \"method\": \"Subcellular fractionation/confocal microscopy for mitochondrial localization, lipid-binding assay (phosphatidylethanolamine pulldown), palmitoylation mutants, TRIM31 depletion with bacterial invasion assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct lipid-binding assay, mutagenesis of palmitoylation sites, localization experiments with functional consequence, bacterial invasion phenotype\",\n      \"pmids\": [\"27216961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM31 promotes K63-linked polyubiquitination of TRAF2, sustaining NF-κB activation and conferring gemcitabine resistance in pancreatic cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, K63-specific ubiquitination assay, NF-κB luciferase reporter assay, in vitro and in vivo drug resistance assays\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, K63 ubiquitination assay, luciferase reporter; single lab, multiple methods\",\n      \"pmids\": [\"29930725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM31 interacts with and catalyzes K48-linked polyubiquitination at lysine 72 of MAP3K7 (TAK1), leading to its proteasomal degradation and negative regulation of TGF-β1-mediated Smad and MAPK/NF-κB signaling pathways in hypertensive nephropathy.\",\n      \"method\": \"Co-immunoprecipitation, site-specific ubiquitination assay (K48, K72 site), TRIM31-knockout and AAV-mediated overexpression mice with AngII-induced renal disease model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, site-directed mutagenesis at K72, in vivo KO and OE models, multiple orthogonal methods\",\n      \"pmids\": [\"34584221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM31 acts as an E3 ubiquitin ligase for TIGAR, interacting with it and promoting its K48-linked polyubiquitination and proteasomal degradation, thereby reducing pentose phosphate pathway flux and increasing ROS during cerebral ischemia.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, TIGAR knockdown rescue experiments in TRIM31-deficient neurons\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, polyubiquitination assay, genetic epistasis by TIGAR knockdown rescue; single lab, two orthogonal methods\",\n      \"pmids\": [\"34218200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM31 facilitates K27-linked polyubiquitination of SYK at Lys375 and Lys517, promoting SYK plasma membrane translocation and interaction with C-type lectin receptors (CLRs), while preventing interaction with phosphatase SHP-1, thus activating antifungal immunity.\",\n      \"method\": \"Co-immunoprecipitation, site-specific K27 ubiquitination assay, subcellular fractionation, receptor co-localization, SHP-1 interaction assays, TRIM31-knockout mice with Candida albicans infection\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, K27 ubiquitination at specific lysine sites by mutagenesis, in vivo KO model, multiple orthogonal methods\",\n      \"pmids\": [\"34362877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM31 directly binds to Rhbdf2 and facilitates its proteasomal degradation via ubiquitination, acting as an endogenous inhibitor of Rhbdf2 signaling in hepatocytes. Hepatocyte-specific TRIM31 ablation exacerbates NAFLD phenotypes.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination/degradation assay, hepatocyte-specific knockout mice (TRIM31Hep-cKO), transgenic overexpression and ex vivo gene therapy in NAFLD mouse models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ubiquitination assay, tissue-specific KO and gain-of-function models in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"35217669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRIM31 is an RBCC protein with in vitro autoubiquitylating (E3 ligase) activity, undergoes homo-oligomerization, and localizes primarily to the cytoplasm with a fraction associated with mitochondria. TRIM31 overexpression suppresses colony formation, indicating a negative role in cell proliferation.\",\n      \"method\": \"In vitro ubiquitylation assay, subcellular fractionation, confocal microscopy, siRNA knockdown, colony formation assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro ubiquitylation assay and localization experiments; single lab, multiple methods\",\n      \"pmids\": [\"18773414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRIM31 is subject to polyubiquitylation followed by proteasomal degradation, establishing that the ubiquitin-proteasome system regulates endogenous TRIM31 protein abundance. The intracellular level of TRIM31 is also controlled by inducible transcription and alternative splicing.\",\n      \"method\": \"Exogenous expression in 293 cells and endogenous detection in AsPC-1 cells; proteasome inhibitor treatment, ubiquitylation assay\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteasome inhibitor experiment, ubiquitylation assay; single lab, two methods\",\n      \"pmids\": [\"21231912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM31 interacts with MAGEA1 via its coiled-coil domain (binding both WH/A and WH/B motifs of MAGEA1). MAGEA1 stimulates TRIM31 E3 ubiquitin-ligase activity. TRIM31 also directly binds NSE4, suggesting the existence of a TRIM31-MAGEA1-NSE4 trimeric complex.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, in vitro E3 ligase activity assay with and without MAGEA1\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vitro ubiquitin-ligase assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"25590999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TRIM31 interacts with p52(Shc) via a region outside the RING domain. Overexpression of TRIM31 does not affect p52(Shc) stability but suppresses anchorage-independent cell growth induced by active c-Src, suggesting TRIM31 attenuates c-Src/Shc signaling.\",\n      \"method\": \"Co-immunoprecipitation, binding domain mapping, pulse-chase stability analysis, soft agar anchorage-independent growth assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, domain mapping, functional assay; single lab, multiple methods\",\n      \"pmids\": [\"19665990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM31 interacts with and ubiquitinates TAK1 (MAP3K7), resulting in TAK1 activation and subsequent induction of NF-κB signaling, promoting apoptosis in LPS-induced sepsis-induced myocardial dysfunction model.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, NF-κB signaling readouts, TRIM31 knockdown/overexpression in cardiomyocytes and LPS-treated mice\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo model; single lab, two orthogonal methods\",\n      \"pmids\": [\"33016203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM31 interacts with VDAC1 and promotes its K48-linked polyubiquitination and proteasomal degradation. TRIM31 deficiency in mice leads to age-associated motor defects and dopaminergic neurodegeneration, and TRIM31-/- mice show aggravated MPTP-induced dopaminergic neurotoxicity.\",\n      \"method\": \"Co-immunoprecipitation, K48 ubiquitination assay, TRIM31-knockout mice (spontaneous and MPTP model), proteasome inhibitor experiments\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, K48 ubiquitination assay, in vivo KO phenotype with two models; multiple orthogonal methods\",\n      \"pmids\": [\"38918620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM31 promotes K63-linked polyubiquitination of MEF2C at Lys25, which increases MEF2C recruitment to the PD-L1 promoter and drives PD-L1 gene transcription in NSCLC cells stimulated with IL-17.\",\n      \"method\": \"Co-immunoprecipitation, site-specific K63 ubiquitination assay with mutagenesis, ChIP, luciferase reporter assay, isograft tumor model\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, site-specific ubiquitination, ChIP; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39810133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM31 interacts with NLRP3 and promotes K48-linked polyubiquitination and proteasomal degradation of NLRP3 in retinal pigment epithelial cells, suppressing NLRP3 inflammasome activation and pyroptosis.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and ubiquitination assay in ARPE-19 cells, NLRP3 inhibitor rescue\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, ubiquitination assay; single lab, replicates the NLRP3-TRIM31 interaction in a new cell type\",\n      \"pmids\": [\"32716108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The transcription factor Cdx2 transcriptionally regulates TRIM31 expression; loss of Cdx2 leads to decreased TRIM31 and elevated NLRP3 levels in mouse colon, revealing a Cdx2-TRIM31-NLRP3 signaling axis in intestinal homeostasis.\",\n      \"method\": \"Conditional Cdx2 knockout mice, TRIM31 and NLRP3 expression analysis, NLRP3 inhibitor rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO with pathway analysis, NLRP3 inhibitor rescue; single lab, genetic epistasis approach\",\n      \"pmids\": [\"35985421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM31 promotes K48-linked ubiquitination of LOX-1 at lysine 12, facilitating LOX-1 proteasomal degradation in macrophages. This reduces oxidized LDL uptake and foam cell formation, limiting atherosclerotic plaque formation. The atheroprotective effect of TRIM31 is abolished in Lox-1-/- or K12R-LOX-1 rescue models.\",\n      \"method\": \"Co-immunoprecipitation, proteomic/immunoprecipitation-mass spectrometry, site-directed mutagenesis (K12R), K48-specific ubiquitination assay, macrophage-specific Trim31 KO and OE mice, Lox-1-/- and K12R rescue experiments in vivo\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — site-directed mutagenesis of ubiquitination site, in vivo KO/OE/rescue models, mass spectrometry identification; multiple orthogonal methods in one study\",\n      \"pmids\": [\"41410044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM31 regulates HSC homeostasis by promoting ubiquitin-mediated degradation of CDK8; TRIM31 deficiency leads to CDK8 accumulation, which induces transcriptional expression of PBX1 and cyclin D1, promoting HSPC proliferation and HSC exhaustion.\",\n      \"method\": \"TRIM31-knockout mice, serial competitive transplantation, Western blot for CDK8/PBX1/cyclin D1, 5-FU stress model\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model with functional reconstitution, CDK8 as substrate; single lab, pathway placement via genetic approach\",\n      \"pmids\": [\"36632737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM31 promotes HBx ubiquitination and degradation; a patient-derived frameshift mutation in TRIM31 (truncated at 768 bp) abolishes this activity and blocks inhibition of HBV replication. TRIM31 was identified as a type III interferon-stimulated gene (not type I or II) required for anti-HBV innate immunity.\",\n      \"method\": \"Ubiquitination assay for HBx, truncation mutant analysis, interferon stimulation experiments, TRIM31-TRIM5γ-HBx co-immunoprecipitation\",\n      \"journal\": \"Virus research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutant-based functional assay, Co-IP, IFN induction; single lab, multiple methods\",\n      \"pmids\": [\"34863820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM31 interacts with YBX1 and catalyzes K63-linked polyubiquitination at Lys81 of YBX1, leading to stabilization (not degradation) of YBX1 protein. Stabilized YBX1 enhances mRNA stability of EREG, GAS6, and MAFG. NF-κB p65 activates TRIM31 transcription, and TRIM31 in turn facilitates p65 nuclear entry, creating a positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, K63 ubiquitination assay with site mutagenesis (K81), mRNA stability assay, ChIP for p65 on TRIM31 promoter, p65 nuclear translocation assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, site-specific ubiquitination, mRNA stability assay, ChIP; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40819060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP13 competes with TRIM31 to interact with NLRP3, preventing TRIM31-mediated K48-linked ubiquitination of NLRP3 at K192 and K496 sites. USP13 thereby stabilizes NLRP3 protein and promotes inflammasome assembly, independently of USP13 deubiquitinase activity.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assay (USP13 vs TRIM31 for NLRP3), site-specific ubiquitination assay, USP13-deficient macrophages, mouse peritonitis model\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — competitive Co-IP, site-directed mutagenesis of ubiquitination sites, in vivo model, mechanistic dissection of USP13 vs TRIM31 interaction\",\n      \"pmids\": [\"41004574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM31 interacts with Drp1 and promotes its ubiquitination and degradation via the proteasome pathway, improving mitochondrial function in a Parkinson's disease model. TRIM31 knockdown partially attenuates lutein's protective effects on Drp1 ubiquitination.\",\n      \"method\": \"Ubiquitination assay, Western blot for Drp1 protein levels, TRIM31 overexpression and knockdown in SH-SY5Y cells and MPTP mouse model, mitochondrial function readouts (ROS, membrane potential, ATP)\",\n      \"journal\": \"Journal of integrative neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, ubiquitination assay without site-specific mapping; functional readout present but indirect\",\n      \"pmids\": [\"41609041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In hepatocytes, TRIM31 activates Nrf2 signaling; hepatocyte-specific TRIM31 knockout mice show impaired Nrf2 activation and increased hepatic oxidative stress, and the anti-fibrotic effects of mulberrin are dependent on the TRIM31/Nrf2 axis.\",\n      \"method\": \"Hepatocyte-specific TRIM31 knockout mice (TRIM31Hep-cKO), Nrf2-KO primary hepatocytes, CCl4 liver fibrosis model, oxidative stress measurement\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO in vivo, genetic epistasis with Nrf2-KO; single lab, two orthogonal genetic models\",\n      \"pmids\": [\"35240537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM31 negatively regulates NLRP3 inflammasome activation in H. pylori-associated gastritis by reducing mitochondrial ROS and maintaining autophagy flux; TRIM31-deficient gastric epithelial cells show impaired lysosomal cathepsin B and D expression and disrupted autophagic flux upon H. pylori infection.\",\n      \"method\": \"TRIM31 knockdown in GES-1 cells, flow cytometry for mitochondrial membrane potential and ROS, mCherry-EGFP-LC3 autophagy flux assay, lysosomal acidification and cathepsin expression analysis, chronic Hp mouse infection model\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cellular assays in one study; single lab, autophagy flux and ROS mechanistically linked to TRIM31 loss\",\n      \"pmids\": [\"36597090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM31 promotes ubiquitination and degradation of BBOX1 (gamma-butyrobetaine dioxygenase) in esophageal cancer cells, enhancing their proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, loss-of-function assays in Eca109 cells and in vivo xenograft\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination assay without site mapping; single lab, single paper\",\n      \"pmids\": [\"40651686\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM31 is a RING finger/RBCC domain E3 ubiquitin ligase that localizes primarily to the cytoplasm and mitochondria, and functions by ubiquitinating a diverse set of substrates—including NLRP3 (K48-linked, proteasomal degradation), MAVS (K63-linked, promoting prion-like aggregation for antiviral signaling), TSC1/TSC2 (K48-linked, mTORC1 activation), MAP3K7/TAK1 (K48-linked), SYK (K27-linked, membrane translocation), TRAF2 (K63-linked, NF-κB activation), TIGAR, VDAC1, CDK8, Rhbdf2, LOX-1, YBX1 (K63-linked, stabilization), MEF2C (K63-linked, transcriptional activation), and Drp1—thereby acting as a context-dependent regulator of innate immune signaling (NLRP3 inflammasome, RLR-MAVS antiviral, and CLR-SYK antifungal pathways), autophagy, mitochondrial homeostasis, and mTOR/NF-κB/Wnt signaling in cancer and metabolic disease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM31 is an RBCC/RING-finger E3 ubiquitin ligase that operates as a context-dependent regulator of innate immune signaling, mitochondrial homeostasis, and cell-growth pathways by assembling distinct polyubiquitin linkages on substrate-specific lysines [#9, #0, #1]. It autoubiquitylates in vitro, homo-oligomerizes, and partitions between the cytoplasm and mitochondria, where its ligase activity can be stimulated by the cofactor MAGEA1 [#9, #11]. A central theme is reciprocal control of the NLRP3 inflammasome: TRIM31 binds NLRP3 and catalyzes K48-linked polyubiquitination driving proteasomal degradation, dampening inflammasome activation in vivo, with site-specific K48 marks at K192/K496 antagonized by competitive USP13 binding [#0, #16, #22]. Beyond NLRP3, TRIM31 builds K48-linked degradative chains on TSC1/TSC2 to activate mTORC1, on MAP3K7/TAK1, TIGAR, VDAC1, and LOX-1 (at K12, limiting oxLDL uptake and atherosclerosis), and on Rhbdf2 in hepatocytes [#2, #5, #6, #14, #18, #8]. In parallel it deploys non-degradative linkages: K63-linked ubiquitination of MAVS at K10/K311/K461 to drive prion-like aggregation and antiviral RLR signaling, K63 chains on TRAF2 and YBX1 (K81, stabilizing) to sustain NF-\\u03baB and mRNA-stability programs, and K27-linked ubiquitination of SYK at K375/K517 to direct membrane translocation and antifungal immunity [#1, #4, #21, #7]. TRIM31 also engages mitochondrial and autophagic biology directly, binding phosphatidylethanolamine in a palmitoylation-dependent manner to promote Atg5/Atg7-independent autolysosome formation against intracellular bacteria [#3]. In vivo loss-of-function models tie TRIM31 to protection against dopaminergic neurodegeneration, hypertensive nephropathy, NAFLD, and HSC exhaustion, while its own abundance is set by inducible transcription, alternative splicing, and proteasomal turnover [#14, #5, #8, #19, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established TRIM31 as a bona fide E3 ubiquitin ligase, answering whether the RBCC protein had intrinsic catalytic activity and where it acts.\",\n      \"evidence\": \"in vitro autoubiquitylation assay, subcellular fractionation and confocal microscopy, colony-formation assay\",\n      \"pmids\": [\"18773414\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No physiological substrate identified at this stage\", \"Mechanism linking ligase activity to growth suppression unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified a partner (p52-Shc) and a growth-suppressive role outside the RING domain, indicating TRIM31 functions partly through binding rather than degradation.\",\n      \"evidence\": \"Co-IP, domain mapping, pulse-chase stability, soft-agar growth assay\",\n      \"pmids\": [\"19665990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ubiquitination of p52-Shc demonstrated\", \"Mechanism of c-Src/Shc attenuation undefined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed TRIM31 abundance is itself controlled by the ubiquitin-proteasome system plus transcription and splicing, framing it as a tightly regulated node.\",\n      \"evidence\": \"proteasome inhibitor treatment and ubiquitylation assay in 293 and AsPC-1 cells\",\n      \"pmids\": [\"21231912\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase responsible for TRIM31 turnover not identified\", \"Physiological triggers of regulated turnover unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a cofactor mechanism: MAGEA1 binds the coiled-coil domain and stimulates TRIM31 ligase activity, suggesting regulated substrate-independent activation.\",\n      \"evidence\": \"yeast two-hybrid, Co-IP, in vitro ligase assay +/- MAGEA1\",\n      \"pmids\": [\"25590999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrates of the MAGEA1-stimulated complex not defined\", \"Role of proposed TRIM31-MAGEA1-NSE4 trimer untested in cells\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined opposing innate-immune roles via linkage-specific ubiquitination: K48 degradation of NLRP3 to restrain inflammasomes, and K63 modification of MAVS to drive antiviral signaling.\",\n      \"evidence\": \"reciprocal Co-IP, linkage- and site-specific ubiquitination assays, MAVS aggregation assay, TRIM31-knockout mice in colitis/peritonitis and RNA virus models\",\n      \"pmids\": [\"27929086\", \"27992402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What dictates K48 vs K63 linkage choice between substrates unresolved\", \"Signals controlling mitochondrial recruitment incompletely defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated a ubiquitination-independent activity: palmitoylation-dependent phosphatidylethanolamine binding drives Atg5/Atg7-independent autolysosome formation against intracellular bacteria.\",\n      \"evidence\": \"lipid-binding pulldown, palmitoylation mutants, mitochondrial localization, bacterial invasion assay\",\n      \"pmids\": [\"27216961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular machinery of the noncanonical autolysosome pathway undefined\", \"Relationship to TRIM31 E3 activity unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended K48-degradative function to growth control by targeting the TSC1-TSC2 complex, placing TRIM31 upstream of mTORC1 in cancer.\",\n      \"evidence\": \"Co-IP, K48 ubiquitination assay, gain/loss-of-function in HCC lines with mTORC1 readouts\",\n      \"pmids\": [\"28967907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination sites on TSC1/TSC2 not mapped\", \"In vivo requirement not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reported context-dependent TAK1 regulation, with TRIM31 activating TAK1/NF-kB and promoting apoptosis in septic myocardial dysfunction.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, NF-kB readouts in cardiomyocytes and LPS-treated mice\",\n      \"pmids\": [\"33016203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Linkage type not specified\", \"Apparent conflict with later K48-degradative TAK1 finding unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded the linkage repertoire and substrate set: K27 ubiquitination of SYK for antifungal immunity, K48 degradation of TAK1 in nephropathy and TIGAR in ischemia, and replicated NLRP3 control in RPE cells.\",\n      \"evidence\": \"site-specific ubiquitination assays with mutagenesis, subcellular fractionation, TRIM31-knockout/overexpression mice and disease models\",\n      \"pmids\": [\"34362877\", \"34584221\", \"34218200\", \"32716108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRIM31 selects among K27/K48/K63 linkages per substrate unknown\", \"Tissue determinants of opposing TAK1 outcomes undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified TRIM31 as a type III interferon-stimulated gene with antiviral activity against HBV via HBx ubiquitination, supported by a loss-of-function patient frameshift mutant.\",\n      \"evidence\": \"HBx ubiquitination assay, truncation-mutant analysis, IFN induction, TRIM31-TRIM5gamma-HBx Co-IP\",\n      \"pmids\": [\"34863820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Clinical significance of the patient mutation in a cohort untested\", \"Mechanism of type-III-specific induction undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed TRIM31 within tissue-protective circuits: as a Cdx2-regulated suppressor of NLRP3 in intestine, an inhibitor of Rhbdf2 in NAFLD, and an activator of Nrf2 antioxidant signaling in liver fibrosis.\",\n      \"evidence\": \"conditional/tissue-specific knockout mice, Nrf2-KO epistasis, NLRP3-inhibitor rescue, NAFLD and CCl4 fibrosis models\",\n      \"pmids\": [\"35985421\", \"35217669\", \"35240537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Nrf2 activation not at the ubiquitination level resolved\", \"Direct vs indirect Cdx2 regulation of TRIM31 promoter\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked TRIM31 to hematopoietic and tumor-immune control through CDK8 degradation (HSC homeostasis), K63 MEF2C ubiquitination driving PD-L1, and autophagy/mitochondrial ROS control in gastritis.\",\n      \"evidence\": \"TRIM31-knockout mice with serial transplantation, site-specific K63 ubiquitination plus ChIP, autophagy-flux and ROS assays\",\n      \"pmids\": [\"36632737\", \"39810133\", \"36597090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CDK8 ubiquitination linkage and sites not mapped\", \"Connection between autophagy regulation and direct substrates unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established mitochondrial substrates underlying neuroprotection: K48 degradation of VDAC1 and ubiquitination of Drp1, with TRIM31 loss causing dopaminergic neurodegeneration.\",\n      \"evidence\": \"Co-IP, K48 ubiquitination assays, TRIM31-knockout and MPTP Parkinson's models, mitochondrial function readouts\",\n      \"pmids\": [\"38918620\", \"41609041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Drp1 ubiquitination sites and linkage not mapped (Low-confidence)\", \"Relative contribution of VDAC1 vs Drp1 to neurodegeneration unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved competitive regulation and non-degradative outputs: USP13 blocks TRIM31-mediated K48 NLRP3 ubiquitination at K192/K496, while TRIM31 stabilizes YBX1 via K63 chains and degrades LOX-1 (K12) and BBOX1, tying it to atherosclerosis and cancer.\",\n      \"evidence\": \"competitive Co-IP, site-directed mutagenesis, mRNA-stability and ChIP assays, macrophage-specific Trim31 KO/OE plus Lox-1-/- and K12R rescue in vivo\",\n      \"pmids\": [\"41004574\", \"40819060\", \"41410044\", \"40651686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"BBOX1 targeting lacks site mapping (Low-confidence)\", \"Generality of antagonist competition (USP13-type) across other substrates untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The central open question is the molecular rule by which TRIM31 selects K48 versus K63 versus K27 linkages and degradative versus signaling outcomes on different substrates within different tissues.\",\n      \"evidence\": \"no single study reconciles the linkage- and context-determinants across the substrate set\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of TRIM31-substrate or TRIM31-E2 pairing\", \"Determinants of cytoplasm vs mitochondria partitioning incompletely defined\", \"No unifying biochemical reconstitution explaining linkage switching\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [9, 0, 1, 7, 5, 14, 18]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 7, 5, 18]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [22, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [9, 1, 3, 14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4, 5, 21]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 5, 14, 18]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 25]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NLRP3\", \"MAVS\", \"TSC1\", \"TSC2\", \"MAP3K7\", \"SYK\", \"VDAC1\", \"USP13\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}