{"gene":"TRIM47","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2001,"finding":"GOA (TRIM47) was identified as a novel RING finger B-box coiled-coil (RBCC) protein overexpressed in astrocytoma, with prominent nuclear localization demonstrated by immunohistochemistry. It contains two LXXLL motifs thought to be important for nuclear receptor binding.","method":"SAGE expression profiling, Northern blot, immunohistochemistry, chromosomal localization","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, characterization study with no functional mechanistic experiment; localization noted but no functional consequence tested","pmids":["11511098"],"is_preprint":false},{"year":2019,"finding":"TRIM47 physically interacts with SMAD4 and promotes its ubiquitination and proteasomal degradation in colorectal cancer cells, leading to upregulation of CCL15 and activation of the CCL15-CCR1 signaling axis that drives tumor growth and invasion.","method":"Co-immunoprecipitation, Western blot, ubiquitination assay, TRIM47 knockdown/overexpression in CRC cells, xenograft mouse model","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, in vivo xenograft; single lab with multiple orthogonal methods","pmids":["30979374"],"is_preprint":false},{"year":2019,"finding":"Trim47 knockdown in a rat model of cerebral ischemia-reperfusion injury reduced infarct size and suppressed apoptosis (inhibiting Caspase-3 cleavage) and inflammation (IL-6, TNF-α, iNOS) partly through blockage of NF-κB signaling.","method":"Genetic knockdown/overexpression in rat MCAO model, Western blot, in vitro OGD model","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, in vivo knockdown with phenotypic readout but no direct molecular binding or substrate identification for NF-κB activation mechanism","pmids":["31178138"],"is_preprint":false},{"year":2020,"finding":"TRIM47 physically interacts with FOXO1 protein and promotes its ubiquitination and proteasomal degradation in glioma cells, thereby promoting glioma cell proliferation and progression.","method":"Co-immunoprecipitation (Co-IP), Western blot, ubiquitination assay, knockdown/knockout, xenograft mouse model","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo model, single lab","pmids":["33408486"],"is_preprint":false},{"year":2020,"finding":"TRIM47 knockdown in glioma cells inhibited the Wnt/β-catenin signaling pathway and suppressed proliferation, migration, and invasion; activation of Wnt/β-catenin with LiCl reversed these inhibitory effects, placing TRIM47 upstream of this pathway.","method":"siRNA knockdown, Western blot, LiCl rescue experiment, xenograft mouse model","journal":"Molecular and cellular probes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement by pharmacological rescue only, no direct molecular mechanism identified","pmids":["32603762"],"is_preprint":false},{"year":2020,"finding":"TRIM47 overexpression induced ubiquitination of PPM1A (protein phosphatase magnesium-dependent 1A) and decreased its expression level in human embryonic lung fibroblasts, as shown by Co-immunoprecipitation; this led to sustained Smad2/3 phosphorylation and fibrotic phenotype.","method":"Co-immunoprecipitation, Western blot, lentiviral overexpression/RNAi, hydroxyproline assay","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating interaction plus ubiquitination assay plus functional readout; single lab, two orthogonal methods","pmids":["32502539"],"is_preprint":false},{"year":2021,"finding":"TRIM47 promotes K63-linked ubiquitination of TRAF2 in vascular endothelial cells, activating NF-κB and MAPK signaling pathways and triggering inflammatory responses; TRIM47-deficient mice were resistant to LPS-induced acute lung injury.","method":"Co-immunoprecipitation, ubiquitination assay (K63-specific), TRIM47 knockdown/overexpression in endothelial cells, TRIM47-deficient mouse model, in vitro TNFα stimulation","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 2 / Strong — K63-linkage-specific ubiquitination assay, reciprocal Co-IP, in vivo knockout mouse model, multiple orthogonal methods, in vitro and in vivo convergent evidence","pmids":["35513381"],"is_preprint":false},{"year":2021,"finding":"TRIM47 directly interacts with PKC-ε and PKD3 and promotes K27-linked polyubiquitination of PKC-ε, stabilizing PKC-ε and PKD3 in a ternary complex, thereby activating NF-κB signaling and conferring tamoxifen resistance in breast cancer cells.","method":"Co-immunoprecipitation, ubiquitination assay (K27-linkage specific), TRIM47 overexpression/knockdown, MCF-7 cell proliferation and resistance assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — K27-linkage-specific ubiquitination, Co-IP demonstrating ternary complex, functional drug resistance phenotype, multiple orthogonal methods in single rigorous study","pmids":["34433666"],"is_preprint":false},{"year":2021,"finding":"TRIM47 directly binds to FBP1 (fructose-1,6-biphosphatase) and promotes its ubiquitination and degradation, thereby promoting aerobic glycolysis (Warburg effect) in pancreatic cancer cells; FBP1 overexpression abolished TRIM47-mediated Warburg effect.","method":"Co-immunoprecipitation, ubiquitination assay, TRIM47 knockdown/overexpression, FBP1 rescue experiment, in vitro and xenograft assays","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus rescue experiment; single lab","pmids":["33529753"],"is_preprint":false},{"year":2021,"finding":"TRIM47 interacts with P53 protein and promotes its ubiquitination and proteasomal degradation in renal cell carcinoma, as demonstrated by mass spectrometry, Western blot, and immunoprecipitation assays.","method":"Mass spectrometry, immunoprecipitation, Western blot, ubiquitination assay, TRIM47 knockdown/overexpression, xenograft","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identification of interaction plus Co-IP plus ubiquitination assay; single lab","pmids":["33622324"],"is_preprint":false},{"year":2022,"finding":"TRIM47 expression in hippocampal neurons is regulated by glutamate-induced synaptic activity requiring NMDA receptor activation. Knockdown of TRIM47 increases spine density and excitatory synapse development, identifying it as an activity-regulated E3 ligase that negatively regulates excitatory synapse formation.","method":"TRIM47 knockdown in cultured rat hippocampal neurons, object location test in vivo, spine density measurement, synapse quantification, NMDA receptor pharmacological inhibition","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (spine density, synapse number), activity-dependent regulation confirmed with pharmacological block; single lab","pmids":["36211980"],"is_preprint":false},{"year":2022,"finding":"TRIM47 knockdown in glioma cells reduced human umbilical vein endothelial cell proliferation, migration, and tube formation (angiogenesis). Mechanistically, TRIM47 negatively regulates SMAD4 expression in glioma cells, and SMAD4 knockdown rescued the anti-angiogenic effects of TRIM47 silencing.","method":"siRNA knockdown, HUVEC functional assays (proliferation, migration, tube formation), SMAD4 knockdown rescue, xenograft vessel density","journal":"In vitro cellular & developmental biology. Animal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement by co-knockdown rescue; no direct binding or ubiquitination of SMAD4 shown in this paper","pmids":["36203070"],"is_preprint":false},{"year":2022,"finding":"TRIM47 promotes endothelial permeability in brain endothelial cells; siRNA-mediated knockdown of TRIM47 in human brain endothelial cells increased endothelial permeability, identifying it as a candidate regulator of blood-brain barrier integrity relevant to cerebral small vessel disease.","method":"siRNA knockdown in human brain endothelial cells, endothelial permeability assay, immunohistochemistry for brain vessel enrichment","journal":"Brain : a journal of neurology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single functional assay, preliminary functional evaluation noted as requiring further in vivo exploration","pmids":["35511193"],"is_preprint":false},{"year":2023,"finding":"TRIM47 directly interacts with BRCA1 and promotes ubiquitin-ligase-mediated proteasomal degradation of BRCA1 in triple-negative breast cancer cells, reducing BRCA1 protein levels and downstream p53/p27/p21 expression; this confers sensitivity to PARP inhibitor olaparib.","method":"Co-immunoprecipitation, ubiquitination assay, TRIM47 overexpression/knockdown, BRCA1 rescue experiment, olaparib sensitivity assay in vitro and xenograft","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination, and functional rescue with BRCA1 overexpression; single lab with multiple orthogonal methods","pmids":["36906594"],"is_preprint":false},{"year":2023,"finding":"TRIM47 interacts with IκBα protein and promotes its ubiquitination and degradation; methionine restriction decreased TRIM47 expression, reduced IκBα ubiquitination, increased IκBα protein stability, and blocked nuclear p65 translocation and gastric cancer cell migration/invasion. TRIM47 overexpression reversed these effects.","method":"Co-immunoprecipitation, ubiquitination assay, protein stability assay (cycloheximide chase implied), Western blot, methionine restriction model, in vivo metastasis model","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo rescue; single lab, multiple methods","pmids":["37943731"],"is_preprint":false},{"year":2024,"finding":"TRIM47 interacts with CDO1 through its B30.2 domain and promotes K48-linked ubiquitination and proteasomal degradation of CDO1 in hepatocellular carcinoma cells, thereby reducing GSH synthesis and suppressing ferroptotic cell death.","method":"Co-immunoprecipitation, ubiquitination assay (K48-specific), domain deletion analysis (B30.2), CDO1 rescue experiment, ferroptosis assay","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping Co-IP, K48-linkage-specific ubiquitination assay, functional rescue; single lab","pmids":["38614226"],"is_preprint":false},{"year":2024,"finding":"TRIM47 promotes HCC metastasis by interacting with SNAI1 and inhibiting its proteasomal degradation. Additionally, TRIM47 protein stability itself is regulated by CARM1-mediated arginine di-methylation at R210 and R582, which protects TRIM47 from ubiquitination and degradation by the E3 ubiquitin ligase complex CRL4CRBN.","method":"Co-immunoprecipitation, methylation site mutagenesis, ubiquitination assay, CARM1 knockdown/inhibition, CRL4CRBN complex interaction assay, in vitro and in vivo invasion assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific mutagenesis of methylation sites, Co-IP, ubiquitination assay; single lab with multiple orthogonal methods","pmids":["39567506"],"is_preprint":false},{"year":2024,"finding":"TRIM47 promotes K63-linked ubiquitination and stabilization of PLK1 (polo-like kinase 1) in liver cancer cells, activating NF-κB and MAPK pathways and driving cell cycle progression; pharmacological PLK1 inhibition abrogated TRIM47-driven tumor growth.","method":"Yeast two-hybrid screening, ubiquitination assay (K63-specific), TRIM47 knockdown/overexpression, PLK1 inhibitor rescue, xenograft model","journal":"Cellular oncology (Dordrecht, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus K63-specific ubiquitination assay plus pharmacological rescue; single lab","pmids":["41460629"],"is_preprint":false},{"year":2024,"finding":"Trim47 promotes K48-linked ubiquitination and proteasomal degradation of MAVS (mitochondrial antiviral-signaling protein) in hematopoietic stem cells (HSCs), limiting excessive innate immune activation. Trim47 deficiency caused impaired HSC function and survival after 5-FU or irradiation stress.","method":"K48-linkage-specific ubiquitination assay, Co-immunoprecipitation, Trim47-knockout mouse model, HSC functional assays (5-FU treatment, irradiation), flow cytometry","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — K48-linkage-specific ubiquitination, Co-IP, in vivo knockout model with defined phenotype, multiple orthogonal methods; published in Nature Communications","pmids":["39117713"],"is_preprint":false},{"year":2024,"finding":"TRIM47 interacts with vimentin and promotes its K63-linked ubiquitination, stabilizing vimentin and thereby enhancing proliferation and metastasis of hypopharyngeal and laryngeal cancer cells in a vimentin-dependent manner.","method":"Tandem affinity chromatography, denatured Ni-NTA agarose pulldown, ubiquitination assay (K63-specific), in vitro and in vivo metastasis models","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity chromatography pulldown plus K63-specific ubiquitination assay plus in vivo rescue; single lab","pmids":["39584529"],"is_preprint":false},{"year":2024,"finding":"TRIM47 interacts with CYLD protein and promotes its K48-linked ubiquitination and proteasomal degradation in gastric cancer cells, thereby activating the NF-κB pathway.","method":"Co-immunoprecipitation, ubiquitination assay (K48-specific), TRIM47 knockdown/overexpression, xenograft model","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus K48-linkage-specific ubiquitination assay plus in vivo model; single lab","pmids":["39516831"],"is_preprint":false},{"year":2024,"finding":"TRIM47 interacts with XAF1 (XIAP-associated factor 1) and promotes its ubiquitination and degradation in head and neck squamous cell carcinoma cells, suppressing apoptosis and autophagy; XAF1 overexpression reversed TRIM47-mediated proliferation promotion.","method":"Co-immunoprecipitation, ubiquitination assay, XAF1 rescue experiment, apoptosis/autophagy assays, xenograft model","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination, and functional rescue; single lab","pmids":["39834862"],"is_preprint":false},{"year":2024,"finding":"TRIM47 binds directly to ADAM17 and promotes its ubiquitination and degradation; a disease-causing ADAM17 variant (p.D647N) enhanced the ADAM17-TRIM47 association, increasing ADAM17 protein ubiquitination and degradation, reducing Notch signaling, and impairing hair follicle stem cell activation.","method":"Co-immunoprecipitation, ubiquitination assay, Adam17(p.D647N) knockin mouse model, HFSC functional assays, Notch pathway analysis","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding shown by Co-IP, ubiquitination assay, in vivo knockin model; single lab with multiple methods","pmids":["38771644"],"is_preprint":false},{"year":2024,"finding":"TRIM47 is an endogenous inhibitor of autophagy in brain endothelial cells; it binds LC3B at the LIR motif (shown by in silico prediction and immunocytochemistry/super-resolution microscopy). Silencing Trim47 in mouse brain endothelial cells significantly increased autophagy with ULK1 phosphorylation and vacuole formation.","method":"In silico binding simulation, immunocytochemistry, super-resolution microscopy, Trim47 siRNA knockdown, ULK1 phosphorylation assay, autophagy induction pharmacology","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple imaging methods plus functional knockdown phenotype; binding site prediction computational only, functional evidence from knockdown; single lab","pmids":["39331575"],"is_preprint":false},{"year":2024,"finding":"Palmitoylation of TRIM47 at C520 (mediated by ZDHHC21) promotes ubiquitination and degradation of ATG16L1, thereby inhibiting autophagy and exacerbating sepsis-induced acute respiratory distress syndrome.","method":"Acyl-biotin exchange (ABE) assay for palmitoylation, Co-immunoprecipitation, ubiquitination assay, site-specific mutant (C520), CLP/LPS in vivo models, transmission electron microscopy","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific palmitoylation identified, Co-IP, ubiquitination assay, in vivo model; single lab with multiple orthogonal methods","pmids":["41342563"],"is_preprint":false},{"year":2024,"finding":"TRIM47 promotes K48-linked ubiquitination and proteasomal degradation of PPM1A in paclitaxel-resistant ovarian cancer cells, sustaining TGF-β signaling and chemoresistance; METTL3-mediated m6A modification enhances TRIM47 mRNA stability.","method":"Co-immunoprecipitation, GST pull-down, cycloheximide chase assay, ubiquitination assay, RNA immunoprecipitation (RIP), dual-luciferase assay, xenograft model","journal":"American journal of reproductive immunology (New York, N.Y. : 1989)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, GST pulldown, CHX chase, ubiquitination assay, m6A modification assay; single lab with multiple orthogonal methods","pmids":["40435048"],"is_preprint":false},{"year":2024,"finding":"TRIM47 binds to MDM2 (shown by Co-IP and GST pull-down assay) and regulates MDM2/p53 signaling in prostate cancer cells; MDM2 overexpression counteracted the effects of TRIM47 knockdown on cell viability, cycle, and apoptosis.","method":"Co-immunoprecipitation, GST pull-down assay, MDM2 overexpression rescue, cell viability, apoptosis assays","journal":"Cell biochemistry and biophysics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and pulldown show binding to MDM2 but mechanism by which TRIM47 modulates MDM2/p53 not fully elucidated; single lab","pmids":["38802602"],"is_preprint":false},{"year":2025,"finding":"TRIM47 acts as a host restriction factor against murine norovirus (MNV) strain CR6 by promoting deubiquitination of the viral NS1/2 precursor protein (rather than ubiquitination/degradation), inhibiting an early stage of the MNV-CR6 life cycle in a strain-dependent manner; the closely related strain CW3 is not restricted.","method":"Forward genetic screen, TRIM47 overexpression in cell culture, viral titer assay, ubiquitination/deubiquitination assay of NS1/2, viral strain comparison","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — forward genetic screen plus deubiquitination assay plus viral replication assay; single lab with multiple methods","pmids":["41251344"],"is_preprint":false},{"year":2026,"finding":"Endothelial TRIM47 maintains blood-brain barrier integrity by binding to KEAP1 and stabilizing NRF2 protein levels, promoting the NRF2 antioxidant pathway. Trim47-deficient mice and inducible endothelial-specific Trim47 knockout mice show cognitive impairments, increased BBB permeability, and astrogliosis; NRF2 activator treatment rescued these phenotypes.","method":"Trim47 knockout and inducible endothelial-specific knockout mouse models, BBB permeability assays, cognitive testing, KEAP1-TRIM47 Co-immunoprecipitation, NRF2 protein level analysis, pharmacological NRF2 activation rescue (tBHQ), human proteomic data analysis","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent mouse genetic models (global KO and inducible EC-specific KO), Co-IP, pharmacological rescue with NRF2 activator, multiple orthogonal functional readouts; single lab but convergent in vitro/in vivo evidence","pmids":["41667829"],"is_preprint":false}],"current_model":"TRIM47 (also known as GOA/RNF100) is a RING-finger B-box coiled-coil E3 ubiquitin ligase that acts in multiple cellular contexts by ubiquitinating and degrading key substrate proteins—including SMAD4, TRAF2, PKC-ε, FBP1, FOXO1, P53, BRCA1, CDO1, MAVS, ATG16L1, PPM1A, PLK1, CYLD, XAF1, vimentin, ADAM17, and IκBα—with distinct K48-linked (degradative) or K63/K27-linked (non-degradative/stabilizing) ubiquitin chain outcomes that activate NF-κB, MAPK, TGF-β, and other oncogenic or inflammatory signaling pathways; it additionally regulates autophagy in brain endothelial cells by inhibiting LC3B/ULK1-mediated autophagy and binding KEAP1 to stabilize NRF2, thereby maintaining blood-brain barrier integrity, while in hematopoietic stem cells it restrains MAVS-driven innate immune activation; its own stability is regulated by CARM1-mediated arginine methylation and ZDHHC21-mediated palmitoylation."},"narrative":{"mechanistic_narrative":"TRIM47 is a RING-finger B-box coiled-coil (RBCC) E3 ubiquitin ligase that controls the abundance and activity of diverse substrate proteins to regulate inflammatory, oncogenic, and cytoprotective signaling [PMID:11511098, PMID:35513381]. Its central biochemical activity is substrate-selective polyubiquitination with distinct chain-type outcomes: it catalyzes K48-linked ubiquitination that targets substrates for proteasomal degradation—including the tumor suppressors CYLD, BRCA1, CDO1, and the antiviral adaptor MAVS—and K63- or K27-linked ubiquitination that instead stabilizes substrates such as TRAF2, PKC-ε/PKD3, PLK1, and vimentin [PMID:35513381, PMID:34433666, PMID:38614226, PMID:41460629, PMID:39117713, PMID:39584529, PMID:39516831]. Across these substrates a recurring functional theme is amplification of NF-κB and MAPK signaling, achieved either by degrading negative regulators (IκBα, CYLD) or by stabilizing positive effectors (TRAF2, PKC-ε, PLK1) [PMID:35513381, PMID:34433666, PMID:37943731, PMID:41460629, PMID:39516831]. In cancer contexts TRIM47 acts broadly as an oncogenic ligase, degrading SMAD4, FOXO1, FBP1, P53, and BRCA1 to drive proliferation, invasion, glycolytic reprogramming, and therapy resistance [PMID:30979374, PMID:33408486, PMID:33529753, PMID:33622324, PMID:36906594]. In the cerebrovascular endothelium TRIM47 maintains blood-brain barrier integrity through two activities: it inhibits autophagy by binding LC3B and restraining ULK1 activation, and it binds KEAP1 to stabilize NRF2 and sustain the antioxidant response, with endothelial-specific knockout causing BBB breakdown, astrogliosis, and cognitive impairment [PMID:39331575, PMID:41667829]. In hematopoietic stem cells it degrades MAVS to restrain excessive innate immune activation and preserve stem cell function under stress [PMID:39117713]. TRIM47 activity is itself controlled post-translationally: CARM1-mediated arginine methylation protects it from CRL4-CRBN-driven degradation, and ZDHHC21-mediated palmitoylation at C520 licenses its degradation of ATG16L1 [PMID:39567506, PMID:41342563].","teleology":[{"year":2001,"claim":"Established TRIM47 as a novel RBCC/RING-finger protein and first linked its overexpression to tumor tissue, framing it as a potential nuclear-acting regulator.","evidence":"SAGE profiling, Northern blot, and immunohistochemistry in astrocytoma showing nuclear localization and two LXXLL motifs","pmids":["11511098"],"confidence":"Low","gaps":["No catalytic activity or substrate demonstrated","Functional consequence of nuclear localization untested","Relevance of LXXLL/nuclear-receptor binding never validated"]},{"year":2019,"claim":"Demonstrated TRIM47's E3-ligase function for the first time by showing it ubiquitinates and degrades SMAD4 to drive a pro-tumor chemokine axis, defining it as a degradative ligase in cancer.","evidence":"Reciprocal Co-IP, ubiquitination assay, knockdown/overexpression, and xenografts in colorectal cancer cells","pmids":["30979374"],"confidence":"Medium","gaps":["Ubiquitin chain linkage type not defined","RING-domain dependence of catalysis not formally tested"]},{"year":2019,"claim":"Implicated TRIM47 in ischemic injury and NF-κB-driven inflammation in vivo, broadening its role beyond cancer.","evidence":"Trim47 knockdown/overexpression in rat MCAO and in vitro OGD models with Western blot readouts","pmids":["31178138"],"confidence":"Low","gaps":["No direct substrate identified for the NF-κB effect","Mechanism of pathway engagement inferred from phenotype only"]},{"year":2020,"claim":"Extended the degradative-ligase paradigm to additional tumor suppressors and a phosphatase, showing TRIM47 degrades FOXO1 and ubiquitinates PPM1A to sustain growth and fibrotic TGF-β/Smad signaling.","evidence":"Co-IP and ubiquitination assays in glioma cells (FOXO1) and lung fibroblasts (PPM1A), with functional and Wnt/β-catenin pathway readouts","pmids":["33408486","32502539","32603762"],"confidence":"Medium","gaps":["Chain-type specificity not resolved","Wnt/β-catenin placement rests on pharmacological rescue only"]},{"year":2021,"claim":"Defined chain-type-specific, non-degradative ubiquitination as a distinct TRIM47 output, showing K63-linked TRAF2 and K27-linked PKC-ε ubiquitination that activate NF-κB/MAPK rather than triggering degradation.","evidence":"Linkage-specific (K63, K27) ubiquitination assays, reciprocal Co-IP, ternary-complex mapping, knockout mice, and drug-resistance assays in endothelial and breast cancer cells","pmids":["35513381","34433666"],"confidence":"High","gaps":["Structural basis for chain-linkage selectivity unknown","What determines degradative vs stabilizing outcome on a given substrate not defined"]},{"year":2021,"claim":"Connected TRIM47 to metabolic reprogramming and p53 control, degrading FBP1 to drive the Warburg effect and degrading P53 in renal carcinoma.","evidence":"Co-IP, ubiquitination, and rescue assays in pancreatic and renal cancer cells with xenografts","pmids":["33529753","33622324"],"confidence":"Medium","gaps":["Chain linkage not specified for either substrate","Direct vs indirect P53 regulation versus MDM2 axis not reconciled"]},{"year":2022,"claim":"Identified neuronal and cerebrovascular roles, showing activity-dependent TRIM47 restrains excitatory synapse formation and regulates brain endothelial permeability.","evidence":"Knockdown in rat hippocampal neurons with NMDAR pharmacology and spine quantification; siRNA in human brain endothelial cells with permeability assays","pmids":["36211980","35511193","36203070"],"confidence":"Medium","gaps":["Synaptic substrate of TRIM47 not identified","Mechanism linking TRIM47 to endothelial permeability not yet molecular in these studies"]},{"year":2023,"claim":"Reinforced TRIM47 as a degrader of DNA-repair and inflammatory checkpoints, degrading BRCA1 (conferring PARP-inhibitor sensitivity) and IκBα (activating NF-κB under methionine signaling).","evidence":"Co-IP, ubiquitination, and rescue assays in triple-negative breast and gastric cancer cells with in vivo models","pmids":["36906594","37943731"],"confidence":"Medium","gaps":["BRCA1 chain linkage not defined","Upstream control of TRIM47 by methionine not mechanistically resolved"]},{"year":2024,"claim":"Mapped substrate recognition and chain-type logic in detail, showing B30.2-domain-dependent K48 degradation of CDO1 (suppressing ferroptosis), K48 degradation of CYLD, and contrasting K63-linked stabilization of PLK1 and vimentin.","evidence":"Domain-deletion and linkage-specific (K48, K63) ubiquitination assays, Co-IP, yeast two-hybrid, and affinity pulldowns across hepatocellular, gastric, and head/neck cancer cells","pmids":["38614226","39516831","41460629","39584529"],"confidence":"Medium","gaps":["General rules dictating K48 vs K63 outcome per substrate remain undefined","Structural model of B30.2 substrate binding absent"]},{"year":2024,"claim":"Established TRIM47 as a restraint on innate immunity and identified its post-translational regulation, degrading MAVS in HSCs and being itself stabilized by CARM1 methylation against CRL4-CRBN.","evidence":"K48-linkage ubiquitination assays, knockout mouse HSC functional assays, and methylation-site mutagenesis with CRL4-CRBN interaction assays","pmids":["39117713","39567506"],"confidence":"High","gaps":["How TRIM47 toggles between immune-restraint and pro-inflammatory roles in different tissues unresolved","Triggers controlling CARM1 methylation of TRIM47 unknown"]},{"year":2024,"claim":"Defined autophagy regulation and lipid-based control of TRIM47, showing it inhibits autophagy by binding LC3B/restraining ULK1 and by ZDHHC21-mediated palmitoylation that drives ATG16L1 degradation.","evidence":"Imaging of LC3B binding and ULK1 phosphorylation assays in brain endothelial cells; acyl-biotin exchange, site-specific C520 mutant, and CLP/LPS sepsis models","pmids":["39331575","41342563"],"confidence":"Medium","gaps":["LC3B LIR binding is computationally predicted, not biochemically mapped","Whether autophagy inhibition is ligase-dependent or adaptor-based unclear"]},{"year":2024,"claim":"Revealed exceptions to the degradation paradigm and disease-variant relevance, showing TRIM47 stabilizes SNAI1, degrades XAF1, binds MDM2, and that an ADAM17 disease variant alters TRIM47-mediated ADAM17 turnover affecting Notch and hair-follicle stem cells.","evidence":"Co-IP, ubiquitination, rescue assays, and an Adam17(p.D647N) knockin mouse model across HCC, head/neck cancer, and prostate cancer","pmids":["39567506","39834862","38802602","38771644"],"confidence":"Medium","gaps":["Mechanism of MDM2/p53 modulation by TRIM47 not elucidated","How TRIM47 stabilizes some substrates while degrading others remains unexplained"]},{"year":2026,"claim":"Tied TRIM47's cerebrovascular function to a defined molecular pathway, showing endothelial TRIM47 binds KEAP1 to stabilize NRF2 and maintain BBB integrity, with NRF2 activation rescuing knockout phenotypes.","evidence":"Global and inducible endothelial-specific knockout mice, KEAP1 Co-IP, NRF2 analysis, and tBHQ rescue with cognitive/permeability readouts","pmids":["41667829"],"confidence":"High","gaps":["Whether KEAP1 binding involves ubiquitination is not defined","Relationship between the autophagy-inhibitory and NRF2-stabilizing endothelial functions unresolved"]},{"year":2025,"claim":"Uncovered an antiviral, deubiquitination-promoting activity, showing TRIM47 restricts murine norovirus strain CR6 by promoting deubiquitination of viral NS1/2 rather than degradation.","evidence":"Forward genetic screen, overexpression, viral titer assays, and ubiquitination/deubiquitination assays of NS1/2 with strain comparison","pmids":["41251344"],"confidence":"Medium","gaps":["How a ubiquitin ligase promotes deubiquitination is not mechanistically explained","Strain-specificity determinant (CR6 vs CW3) unknown"]},{"year":null,"claim":"The decisive open question is what governs TRIM47's substrate selection and ubiquitin chain-type choice, determining whether a given target is degraded, stabilized, or deubiquitinated across tissues.","evidence":"No structural or systematic biochemical study in the corpus defines the rules linking substrate, chain linkage, and functional outcome","pmids":[],"confidence":"Low","gaps":["No structural model of TRIM47 catalysis or B30.2 substrate engagement","No unifying determinant of degradative vs stabilizing vs deubiquitinating outcome","Tissue-specific cofactors directing substrate choice unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,6,7,15,17,18,20]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,7,15,18,19,20]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,6,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[23,28]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,23]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,14,17,20]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,18,27]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,3,15,18,20]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[23,24]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to 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Functional coupling of G-protein-coupled receptor and G protein originated from evolutionarily distant animals.","date":"2006","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/17087737","citation_count":3,"is_preprint":false},{"pmid":"31571446","id":"PMC_31571446","title":"Clinical Spectrum and Complications of Polycythemia, in Patients presenting at Tertiary Care Centre at Goa.","date":"2019","source":"The Journal of the Association of Physicians of India","url":"https://pubmed.ncbi.nlm.nih.gov/31571446","citation_count":3,"is_preprint":false},{"pmid":"40233846","id":"PMC_40233846","title":"Driving aspects of microplastic uptake: Influence in the Bentho-Pelagic ecosystem and its associated ecological risks along the coast of Goa, India.","date":"2025","source":"Environmental research","url":"https://pubmed.ncbi.nlm.nih.gov/40233846","citation_count":3,"is_preprint":false},{"pmid":"39434735","id":"PMC_39434735","title":"TRIM47 promotes the Warburg effect and reduces ferroptosis in prostate cancer by FBP1 and FOXO1.","date":"2024","source":"Translational andrology and urology","url":"https://pubmed.ncbi.nlm.nih.gov/39434735","citation_count":2,"is_preprint":false},{"pmid":"41306678","id":"PMC_41306678","title":"GOA-1 regulates spermathecal transits.","date":"2025","source":"microPublication biology","url":"https://pubmed.ncbi.nlm.nih.gov/41306678","citation_count":2,"is_preprint":false},{"pmid":"40435048","id":"PMC_40435048","title":"Knockdown of TRIM47 Overcomes Paclitaxel Resistance in Ovarian Cancer by Suppressing the TGF-β Pathway via PPM1A.","date":"2025","source":"American journal of reproductive immunology (New York, N.Y. : 1989)","url":"https://pubmed.ncbi.nlm.nih.gov/40435048","citation_count":2,"is_preprint":false},{"pmid":"37034715","id":"PMC_37034715","title":"IDSL.GOA: Gene Ontology Analysis for Interpreting Metabolomic datasets.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37034715","citation_count":2,"is_preprint":false},{"pmid":"40709172","id":"PMC_40709172","title":"Grass carp Trim47 restricts GCRV infection via SPRY domain-mediated autophagic degradation of nonstructural proteins and disruption of viral inclusion bodies.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40709172","citation_count":2,"is_preprint":false},{"pmid":"38802602","id":"PMC_38802602","title":"TRIM47 silencing inhibits the malignant biological behaviors of prostate cancer cells by regulating MDM2/p53 signaling.","date":"2024","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/38802602","citation_count":1,"is_preprint":false},{"pmid":"38187529","id":"PMC_38187529","title":"White matter hyperintensity genetic risk factor TRIM47 regulates autophagy in brain endothelial cells.","date":"2024","source":"bioRxiv : the preprint server for 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Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/41460629","citation_count":0,"is_preprint":false},{"pmid":"40801794","id":"PMC_40801794","title":"TRIM47 Facilitates Osteosarcoma Progression via Destabilising FBP1 and Thus Activation of Wnt/β-Catenin Pathway.","date":"2025","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40801794","citation_count":0,"is_preprint":false},{"pmid":"41342563","id":"PMC_41342563","title":"Palmitoylation of TRIM47 Regulates ATG16L1-Mediated Autophagy to Exacerbate Respiratory Distress Syndrome in Sepsis.","date":"2025","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41342563","citation_count":0,"is_preprint":false},{"pmid":"41251344","id":"PMC_41251344","title":"TRIM47 inhibits murine norovirus replication in a strain-dependent manner.","date":"2025","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/41251344","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47956,"output_tokens":7065,"usd":0.124922,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16394,"output_tokens":5353,"usd":0.107897,"stage2_stop_reason":"end_turn"},"total_usd":0.232819,"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\": 2001,\n      \"finding\": \"GOA (TRIM47) was identified as a novel RING finger B-box coiled-coil (RBCC) protein overexpressed in astrocytoma, with prominent nuclear localization demonstrated by immunohistochemistry. It contains two LXXLL motifs thought to be important for nuclear receptor binding.\",\n      \"method\": \"SAGE expression profiling, Northern blot, immunohistochemistry, chromosomal localization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, characterization study with no functional mechanistic experiment; localization noted but no functional consequence tested\",\n      \"pmids\": [\"11511098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM47 physically interacts with SMAD4 and promotes its ubiquitination and proteasomal degradation in colorectal cancer cells, leading to upregulation of CCL15 and activation of the CCL15-CCR1 signaling axis that drives tumor growth and invasion.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, ubiquitination assay, TRIM47 knockdown/overexpression in CRC cells, xenograft mouse model\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, in vivo xenograft; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30979374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Trim47 knockdown in a rat model of cerebral ischemia-reperfusion injury reduced infarct size and suppressed apoptosis (inhibiting Caspase-3 cleavage) and inflammation (IL-6, TNF-α, iNOS) partly through blockage of NF-κB signaling.\",\n      \"method\": \"Genetic knockdown/overexpression in rat MCAO model, Western blot, in vitro OGD model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, in vivo knockdown with phenotypic readout but no direct molecular binding or substrate identification for NF-κB activation mechanism\",\n      \"pmids\": [\"31178138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM47 physically interacts with FOXO1 protein and promotes its ubiquitination and proteasomal degradation in glioma cells, thereby promoting glioma cell proliferation and progression.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), Western blot, ubiquitination assay, knockdown/knockout, xenograft mouse model\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo model, single lab\",\n      \"pmids\": [\"33408486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM47 knockdown in glioma cells inhibited the Wnt/β-catenin signaling pathway and suppressed proliferation, migration, and invasion; activation of Wnt/β-catenin with LiCl reversed these inhibitory effects, placing TRIM47 upstream of this pathway.\",\n      \"method\": \"siRNA knockdown, Western blot, LiCl rescue experiment, xenograft mouse model\",\n      \"journal\": \"Molecular and cellular probes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement by pharmacological rescue only, no direct molecular mechanism identified\",\n      \"pmids\": [\"32603762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM47 overexpression induced ubiquitination of PPM1A (protein phosphatase magnesium-dependent 1A) and decreased its expression level in human embryonic lung fibroblasts, as shown by Co-immunoprecipitation; this led to sustained Smad2/3 phosphorylation and fibrotic phenotype.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, lentiviral overexpression/RNAi, hydroxyproline assay\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating interaction plus ubiquitination assay plus functional readout; single lab, two orthogonal methods\",\n      \"pmids\": [\"32502539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM47 promotes K63-linked ubiquitination of TRAF2 in vascular endothelial cells, activating NF-κB and MAPK signaling pathways and triggering inflammatory responses; TRIM47-deficient mice were resistant to LPS-induced acute lung injury.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K63-specific), TRIM47 knockdown/overexpression in endothelial cells, TRIM47-deficient mouse model, in vitro TNFα stimulation\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — K63-linkage-specific ubiquitination assay, reciprocal Co-IP, in vivo knockout mouse model, multiple orthogonal methods, in vitro and in vivo convergent evidence\",\n      \"pmids\": [\"35513381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM47 directly interacts with PKC-ε and PKD3 and promotes K27-linked polyubiquitination of PKC-ε, stabilizing PKC-ε and PKD3 in a ternary complex, thereby activating NF-κB signaling and conferring tamoxifen resistance in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K27-linkage specific), TRIM47 overexpression/knockdown, MCF-7 cell proliferation and resistance assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — K27-linkage-specific ubiquitination, Co-IP demonstrating ternary complex, functional drug resistance phenotype, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"34433666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM47 directly binds to FBP1 (fructose-1,6-biphosphatase) and promotes its ubiquitination and degradation, thereby promoting aerobic glycolysis (Warburg effect) in pancreatic cancer cells; FBP1 overexpression abolished TRIM47-mediated Warburg effect.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, TRIM47 knockdown/overexpression, FBP1 rescue experiment, in vitro and xenograft assays\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus rescue experiment; single lab\",\n      \"pmids\": [\"33529753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM47 interacts with P53 protein and promotes its ubiquitination and proteasomal degradation in renal cell carcinoma, as demonstrated by mass spectrometry, Western blot, and immunoprecipitation assays.\",\n      \"method\": \"Mass spectrometry, immunoprecipitation, Western blot, ubiquitination assay, TRIM47 knockdown/overexpression, xenograft\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identification of interaction plus Co-IP plus ubiquitination assay; single lab\",\n      \"pmids\": [\"33622324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM47 expression in hippocampal neurons is regulated by glutamate-induced synaptic activity requiring NMDA receptor activation. Knockdown of TRIM47 increases spine density and excitatory synapse development, identifying it as an activity-regulated E3 ligase that negatively regulates excitatory synapse formation.\",\n      \"method\": \"TRIM47 knockdown in cultured rat hippocampal neurons, object location test in vivo, spine density measurement, synapse quantification, NMDA receptor pharmacological inhibition\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (spine density, synapse number), activity-dependent regulation confirmed with pharmacological block; single lab\",\n      \"pmids\": [\"36211980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM47 knockdown in glioma cells reduced human umbilical vein endothelial cell proliferation, migration, and tube formation (angiogenesis). Mechanistically, TRIM47 negatively regulates SMAD4 expression in glioma cells, and SMAD4 knockdown rescued the anti-angiogenic effects of TRIM47 silencing.\",\n      \"method\": \"siRNA knockdown, HUVEC functional assays (proliferation, migration, tube formation), SMAD4 knockdown rescue, xenograft vessel density\",\n      \"journal\": \"In vitro cellular & developmental biology. Animal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement by co-knockdown rescue; no direct binding or ubiquitination of SMAD4 shown in this paper\",\n      \"pmids\": [\"36203070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM47 promotes endothelial permeability in brain endothelial cells; siRNA-mediated knockdown of TRIM47 in human brain endothelial cells increased endothelial permeability, identifying it as a candidate regulator of blood-brain barrier integrity relevant to cerebral small vessel disease.\",\n      \"method\": \"siRNA knockdown in human brain endothelial cells, endothelial permeability assay, immunohistochemistry for brain vessel enrichment\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single functional assay, preliminary functional evaluation noted as requiring further in vivo exploration\",\n      \"pmids\": [\"35511193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM47 directly interacts with BRCA1 and promotes ubiquitin-ligase-mediated proteasomal degradation of BRCA1 in triple-negative breast cancer cells, reducing BRCA1 protein levels and downstream p53/p27/p21 expression; this confers sensitivity to PARP inhibitor olaparib.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, TRIM47 overexpression/knockdown, BRCA1 rescue experiment, olaparib sensitivity assay in vitro and xenograft\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination, and functional rescue with BRCA1 overexpression; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36906594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM47 interacts with IκBα protein and promotes its ubiquitination and degradation; methionine restriction decreased TRIM47 expression, reduced IκBα ubiquitination, increased IκBα protein stability, and blocked nuclear p65 translocation and gastric cancer cell migration/invasion. TRIM47 overexpression reversed these effects.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein stability assay (cycloheximide chase implied), Western blot, methionine restriction model, in vivo metastasis model\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus in vivo rescue; single lab, multiple methods\",\n      \"pmids\": [\"37943731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM47 interacts with CDO1 through its B30.2 domain and promotes K48-linked ubiquitination and proteasomal degradation of CDO1 in hepatocellular carcinoma cells, thereby reducing GSH synthesis and suppressing ferroptotic cell death.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-specific), domain deletion analysis (B30.2), CDO1 rescue experiment, ferroptosis assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping Co-IP, K48-linkage-specific ubiquitination assay, functional rescue; single lab\",\n      \"pmids\": [\"38614226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM47 promotes HCC metastasis by interacting with SNAI1 and inhibiting its proteasomal degradation. Additionally, TRIM47 protein stability itself is regulated by CARM1-mediated arginine di-methylation at R210 and R582, which protects TRIM47 from ubiquitination and degradation by the E3 ubiquitin ligase complex CRL4CRBN.\",\n      \"method\": \"Co-immunoprecipitation, methylation site mutagenesis, ubiquitination assay, CARM1 knockdown/inhibition, CRL4CRBN complex interaction assay, in vitro and in vivo invasion assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific mutagenesis of methylation sites, Co-IP, ubiquitination assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39567506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM47 promotes K63-linked ubiquitination and stabilization of PLK1 (polo-like kinase 1) in liver cancer cells, activating NF-κB and MAPK pathways and driving cell cycle progression; pharmacological PLK1 inhibition abrogated TRIM47-driven tumor growth.\",\n      \"method\": \"Yeast two-hybrid screening, ubiquitination assay (K63-specific), TRIM47 knockdown/overexpression, PLK1 inhibitor rescue, xenograft model\",\n      \"journal\": \"Cellular oncology (Dordrecht, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus K63-specific ubiquitination assay plus pharmacological rescue; single lab\",\n      \"pmids\": [\"41460629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Trim47 promotes K48-linked ubiquitination and proteasomal degradation of MAVS (mitochondrial antiviral-signaling protein) in hematopoietic stem cells (HSCs), limiting excessive innate immune activation. Trim47 deficiency caused impaired HSC function and survival after 5-FU or irradiation stress.\",\n      \"method\": \"K48-linkage-specific ubiquitination assay, Co-immunoprecipitation, Trim47-knockout mouse model, HSC functional assays (5-FU treatment, irradiation), flow cytometry\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — K48-linkage-specific ubiquitination, Co-IP, in vivo knockout model with defined phenotype, multiple orthogonal methods; published in Nature Communications\",\n      \"pmids\": [\"39117713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM47 interacts with vimentin and promotes its K63-linked ubiquitination, stabilizing vimentin and thereby enhancing proliferation and metastasis of hypopharyngeal and laryngeal cancer cells in a vimentin-dependent manner.\",\n      \"method\": \"Tandem affinity chromatography, denatured Ni-NTA agarose pulldown, ubiquitination assay (K63-specific), in vitro and in vivo metastasis models\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity chromatography pulldown plus K63-specific ubiquitination assay plus in vivo rescue; single lab\",\n      \"pmids\": [\"39584529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM47 interacts with CYLD protein and promotes its K48-linked ubiquitination and proteasomal degradation in gastric cancer cells, thereby activating the NF-κB pathway.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-specific), TRIM47 knockdown/overexpression, xenograft model\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus K48-linkage-specific ubiquitination assay plus in vivo model; single lab\",\n      \"pmids\": [\"39516831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM47 interacts with XAF1 (XIAP-associated factor 1) and promotes its ubiquitination and degradation in head and neck squamous cell carcinoma cells, suppressing apoptosis and autophagy; XAF1 overexpression reversed TRIM47-mediated proliferation promotion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, XAF1 rescue experiment, apoptosis/autophagy assays, xenograft model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination, and functional rescue; single lab\",\n      \"pmids\": [\"39834862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM47 binds directly to ADAM17 and promotes its ubiquitination and degradation; a disease-causing ADAM17 variant (p.D647N) enhanced the ADAM17-TRIM47 association, increasing ADAM17 protein ubiquitination and degradation, reducing Notch signaling, and impairing hair follicle stem cell activation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Adam17(p.D647N) knockin mouse model, HFSC functional assays, Notch pathway analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding shown by Co-IP, ubiquitination assay, in vivo knockin model; single lab with multiple methods\",\n      \"pmids\": [\"38771644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM47 is an endogenous inhibitor of autophagy in brain endothelial cells; it binds LC3B at the LIR motif (shown by in silico prediction and immunocytochemistry/super-resolution microscopy). Silencing Trim47 in mouse brain endothelial cells significantly increased autophagy with ULK1 phosphorylation and vacuole formation.\",\n      \"method\": \"In silico binding simulation, immunocytochemistry, super-resolution microscopy, Trim47 siRNA knockdown, ULK1 phosphorylation assay, autophagy induction pharmacology\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple imaging methods plus functional knockdown phenotype; binding site prediction computational only, functional evidence from knockdown; single lab\",\n      \"pmids\": [\"39331575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Palmitoylation of TRIM47 at C520 (mediated by ZDHHC21) promotes ubiquitination and degradation of ATG16L1, thereby inhibiting autophagy and exacerbating sepsis-induced acute respiratory distress syndrome.\",\n      \"method\": \"Acyl-biotin exchange (ABE) assay for palmitoylation, Co-immunoprecipitation, ubiquitination assay, site-specific mutant (C520), CLP/LPS in vivo models, transmission electron microscopy\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific palmitoylation identified, Co-IP, ubiquitination assay, in vivo model; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41342563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM47 promotes K48-linked ubiquitination and proteasomal degradation of PPM1A in paclitaxel-resistant ovarian cancer cells, sustaining TGF-β signaling and chemoresistance; METTL3-mediated m6A modification enhances TRIM47 mRNA stability.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, cycloheximide chase assay, ubiquitination assay, RNA immunoprecipitation (RIP), dual-luciferase assay, xenograft model\",\n      \"journal\": \"American journal of reproductive immunology (New York, N.Y. : 1989)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, GST pulldown, CHX chase, ubiquitination assay, m6A modification assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40435048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM47 binds to MDM2 (shown by Co-IP and GST pull-down assay) and regulates MDM2/p53 signaling in prostate cancer cells; MDM2 overexpression counteracted the effects of TRIM47 knockdown on cell viability, cycle, and apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down assay, MDM2 overexpression rescue, cell viability, apoptosis assays\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and pulldown show binding to MDM2 but mechanism by which TRIM47 modulates MDM2/p53 not fully elucidated; single lab\",\n      \"pmids\": [\"38802602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM47 acts as a host restriction factor against murine norovirus (MNV) strain CR6 by promoting deubiquitination of the viral NS1/2 precursor protein (rather than ubiquitination/degradation), inhibiting an early stage of the MNV-CR6 life cycle in a strain-dependent manner; the closely related strain CW3 is not restricted.\",\n      \"method\": \"Forward genetic screen, TRIM47 overexpression in cell culture, viral titer assay, ubiquitination/deubiquitination assay of NS1/2, viral strain comparison\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — forward genetic screen plus deubiquitination assay plus viral replication assay; single lab with multiple methods\",\n      \"pmids\": [\"41251344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Endothelial TRIM47 maintains blood-brain barrier integrity by binding to KEAP1 and stabilizing NRF2 protein levels, promoting the NRF2 antioxidant pathway. Trim47-deficient mice and inducible endothelial-specific Trim47 knockout mice show cognitive impairments, increased BBB permeability, and astrogliosis; NRF2 activator treatment rescued these phenotypes.\",\n      \"method\": \"Trim47 knockout and inducible endothelial-specific knockout mouse models, BBB permeability assays, cognitive testing, KEAP1-TRIM47 Co-immunoprecipitation, NRF2 protein level analysis, pharmacological NRF2 activation rescue (tBHQ), human proteomic data analysis\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent mouse genetic models (global KO and inducible EC-specific KO), Co-IP, pharmacological rescue with NRF2 activator, multiple orthogonal functional readouts; single lab but convergent in vitro/in vivo evidence\",\n      \"pmids\": [\"41667829\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM47 (also known as GOA/RNF100) is a RING-finger B-box coiled-coil E3 ubiquitin ligase that acts in multiple cellular contexts by ubiquitinating and degrading key substrate proteins—including SMAD4, TRAF2, PKC-ε, FBP1, FOXO1, P53, BRCA1, CDO1, MAVS, ATG16L1, PPM1A, PLK1, CYLD, XAF1, vimentin, ADAM17, and IκBα—with distinct K48-linked (degradative) or K63/K27-linked (non-degradative/stabilizing) ubiquitin chain outcomes that activate NF-κB, MAPK, TGF-β, and other oncogenic or inflammatory signaling pathways; it additionally regulates autophagy in brain endothelial cells by inhibiting LC3B/ULK1-mediated autophagy and binding KEAP1 to stabilize NRF2, thereby maintaining blood-brain barrier integrity, while in hematopoietic stem cells it restrains MAVS-driven innate immune activation; its own stability is regulated by CARM1-mediated arginine methylation and ZDHHC21-mediated palmitoylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM47 is a RING-finger B-box coiled-coil (RBCC) E3 ubiquitin ligase that controls the abundance and activity of diverse substrate proteins to regulate inflammatory, oncogenic, and cytoprotective signaling [#0, #6]. Its central biochemical activity is substrate-selective polyubiquitination with distinct chain-type outcomes: it catalyzes K48-linked ubiquitination that targets substrates for proteasomal degradation\\u2014including the tumor suppressors CYLD, BRCA1, CDO1, and the antiviral adaptor MAVS\\u2014and K63- or K27-linked ubiquitination that instead stabilizes substrates such as TRAF2, PKC-\\u03b5/PKD3, PLK1, and vimentin [#6, #7, #15, #17, #18, #19, #20]. Across these substrates a recurring functional theme is amplification of NF-\\u03baB and MAPK signaling, achieved either by degrading negative regulators (I\\u03baB\\u03b1, CYLD) or by stabilizing positive effectors (TRAF2, PKC-\\u03b5, PLK1) [#6, #7, #14, #17, #20]. In cancer contexts TRIM47 acts broadly as an oncogenic ligase, degrading SMAD4, FOXO1, FBP1, P53, and BRCA1 to drive proliferation, invasion, glycolytic reprogramming, and therapy resistance [#1, #3, #8, #9, #13]. In the cerebrovascular endothelium TRIM47 maintains blood-brain barrier integrity through two activities: it inhibits autophagy by binding LC3B and restraining ULK1 activation, and it binds KEAP1 to stabilize NRF2 and sustain the antioxidant response, with endothelial-specific knockout causing BBB breakdown, astrogliosis, and cognitive impairment [#23, #28]. In hematopoietic stem cells it degrades MAVS to restrain excessive innate immune activation and preserve stem cell function under stress [#18]. TRIM47 activity is itself controlled post-translationally: CARM1-mediated arginine methylation protects it from CRL4-CRBN-driven degradation, and ZDHHC21-mediated palmitoylation at C520 licenses its degradation of ATG16L1 [#16, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established TRIM47 as a novel RBCC/RING-finger protein and first linked its overexpression to tumor tissue, framing it as a potential nuclear-acting regulator.\",\n      \"evidence\": \"SAGE profiling, Northern blot, and immunohistochemistry in astrocytoma showing nuclear localization and two LXXLL motifs\",\n      \"pmids\": [\"11511098\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No catalytic activity or substrate demonstrated\", \"Functional consequence of nuclear localization untested\", \"Relevance of LXXLL/nuclear-receptor binding never validated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated TRIM47's E3-ligase function for the first time by showing it ubiquitinates and degrades SMAD4 to drive a pro-tumor chemokine axis, defining it as a degradative ligase in cancer.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assay, knockdown/overexpression, and xenografts in colorectal cancer cells\",\n      \"pmids\": [\"30979374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin chain linkage type not defined\", \"RING-domain dependence of catalysis not formally tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Implicated TRIM47 in ischemic injury and NF-\\u03baB-driven inflammation in vivo, broadening its role beyond cancer.\",\n      \"evidence\": \"Trim47 knockdown/overexpression in rat MCAO and in vitro OGD models with Western blot readouts\",\n      \"pmids\": [\"31178138\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct substrate identified for the NF-\\u03baB effect\", \"Mechanism of pathway engagement inferred from phenotype only\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the degradative-ligase paradigm to additional tumor suppressors and a phosphatase, showing TRIM47 degrades FOXO1 and ubiquitinates PPM1A to sustain growth and fibrotic TGF-\\u03b2/Smad signaling.\",\n      \"evidence\": \"Co-IP and ubiquitination assays in glioma cells (FOXO1) and lung fibroblasts (PPM1A), with functional and Wnt/\\u03b2-catenin pathway readouts\",\n      \"pmids\": [\"33408486\", \"32502539\", \"32603762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chain-type specificity not resolved\", \"Wnt/\\u03b2-catenin placement rests on pharmacological rescue only\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined chain-type-specific, non-degradative ubiquitination as a distinct TRIM47 output, showing K63-linked TRAF2 and K27-linked PKC-\\u03b5 ubiquitination that activate NF-\\u03baB/MAPK rather than triggering degradation.\",\n      \"evidence\": \"Linkage-specific (K63, K27) ubiquitination assays, reciprocal Co-IP, ternary-complex mapping, knockout mice, and drug-resistance assays in endothelial and breast cancer cells\",\n      \"pmids\": [\"35513381\", \"34433666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for chain-linkage selectivity unknown\", \"What determines degradative vs stabilizing outcome on a given substrate not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected TRIM47 to metabolic reprogramming and p53 control, degrading FBP1 to drive the Warburg effect and degrading P53 in renal carcinoma.\",\n      \"evidence\": \"Co-IP, ubiquitination, and rescue assays in pancreatic and renal cancer cells with xenografts\",\n      \"pmids\": [\"33529753\", \"33622324\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chain linkage not specified for either substrate\", \"Direct vs indirect P53 regulation versus MDM2 axis not reconciled\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified neuronal and cerebrovascular roles, showing activity-dependent TRIM47 restrains excitatory synapse formation and regulates brain endothelial permeability.\",\n      \"evidence\": \"Knockdown in rat hippocampal neurons with NMDAR pharmacology and spine quantification; siRNA in human brain endothelial cells with permeability assays\",\n      \"pmids\": [\"36211980\", \"35511193\", \"36203070\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Synaptic substrate of TRIM47 not identified\", \"Mechanism linking TRIM47 to endothelial permeability not yet molecular in these studies\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reinforced TRIM47 as a degrader of DNA-repair and inflammatory checkpoints, degrading BRCA1 (conferring PARP-inhibitor sensitivity) and I\\u03baB\\u03b1 (activating NF-\\u03baB under methionine signaling).\",\n      \"evidence\": \"Co-IP, ubiquitination, and rescue assays in triple-negative breast and gastric cancer cells with in vivo models\",\n      \"pmids\": [\"36906594\", \"37943731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BRCA1 chain linkage not defined\", \"Upstream control of TRIM47 by methionine not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped substrate recognition and chain-type logic in detail, showing B30.2-domain-dependent K48 degradation of CDO1 (suppressing ferroptosis), K48 degradation of CYLD, and contrasting K63-linked stabilization of PLK1 and vimentin.\",\n      \"evidence\": \"Domain-deletion and linkage-specific (K48, K63) ubiquitination assays, Co-IP, yeast two-hybrid, and affinity pulldowns across hepatocellular, gastric, and head/neck cancer cells\",\n      \"pmids\": [\"38614226\", \"39516831\", \"41460629\", \"39584529\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"General rules dictating K48 vs K63 outcome per substrate remain undefined\", \"Structural model of B30.2 substrate binding absent\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established TRIM47 as a restraint on innate immunity and identified its post-translational regulation, degrading MAVS in HSCs and being itself stabilized by CARM1 methylation against CRL4-CRBN.\",\n      \"evidence\": \"K48-linkage ubiquitination assays, knockout mouse HSC functional assays, and methylation-site mutagenesis with CRL4-CRBN interaction assays\",\n      \"pmids\": [\"39117713\", \"39567506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRIM47 toggles between immune-restraint and pro-inflammatory roles in different tissues unresolved\", \"Triggers controlling CARM1 methylation of TRIM47 unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined autophagy regulation and lipid-based control of TRIM47, showing it inhibits autophagy by binding LC3B/restraining ULK1 and by ZDHHC21-mediated palmitoylation that drives ATG16L1 degradation.\",\n      \"evidence\": \"Imaging of LC3B binding and ULK1 phosphorylation assays in brain endothelial cells; acyl-biotin exchange, site-specific C520 mutant, and CLP/LPS sepsis models\",\n      \"pmids\": [\"39331575\", \"41342563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LC3B LIR binding is computationally predicted, not biochemically mapped\", \"Whether autophagy inhibition is ligase-dependent or adaptor-based unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed exceptions to the degradation paradigm and disease-variant relevance, showing TRIM47 stabilizes SNAI1, degrades XAF1, binds MDM2, and that an ADAM17 disease variant alters TRIM47-mediated ADAM17 turnover affecting Notch and hair-follicle stem cells.\",\n      \"evidence\": \"Co-IP, ubiquitination, rescue assays, and an Adam17(p.D647N) knockin mouse model across HCC, head/neck cancer, and prostate cancer\",\n      \"pmids\": [\"39567506\", \"39834862\", \"38802602\", \"38771644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of MDM2/p53 modulation by TRIM47 not elucidated\", \"How TRIM47 stabilizes some substrates while degrading others remains unexplained\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Tied TRIM47's cerebrovascular function to a defined molecular pathway, showing endothelial TRIM47 binds KEAP1 to stabilize NRF2 and maintain BBB integrity, with NRF2 activation rescuing knockout phenotypes.\",\n      \"evidence\": \"Global and inducible endothelial-specific knockout mice, KEAP1 Co-IP, NRF2 analysis, and tBHQ rescue with cognitive/permeability readouts\",\n      \"pmids\": [\"41667829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KEAP1 binding involves ubiquitination is not defined\", \"Relationship between the autophagy-inhibitory and NRF2-stabilizing endothelial functions unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered an antiviral, deubiquitination-promoting activity, showing TRIM47 restricts murine norovirus strain CR6 by promoting deubiquitination of viral NS1/2 rather than degradation.\",\n      \"evidence\": \"Forward genetic screen, overexpression, viral titer assays, and ubiquitination/deubiquitination assays of NS1/2 with strain comparison\",\n      \"pmids\": [\"41251344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a ubiquitin ligase promotes deubiquitination is not mechanistically explained\", \"Strain-specificity determinant (CR6 vs CW3) unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The decisive open question is what governs TRIM47's substrate selection and ubiquitin chain-type choice, determining whether a given target is degraded, stabilized, or deubiquitinated across tissues.\",\n      \"evidence\": \"No structural or systematic biochemical study in the corpus defines the rules linking substrate, chain linkage, and functional outcome\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of TRIM47 catalysis or B30.2 substrate engagement\", \"No unifying determinant of degradative vs stabilizing vs deubiquitinating outcome\", \"Tissue-specific cofactors directing substrate choice unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 6, 7, 15, 17, 18, 20]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 7, 15, 18, 19, 20]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 6, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [23, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 14, 17, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 18, 27]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 3, 15, 18, 20]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [23, 24]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [15, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [22, 28]}\n    ],\n    \"complexes\": [\"TRIM47-PKC\\u03b5-PKD3 ternary complex\"],\n    \"partners\": [\"SMAD4\", \"TRAF2\", \"PRKCE\", \"FBP1\", \"BRCA1\", \"CDO1\", \"MAVS\", \"KEAP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}