{"gene":"TRIM46","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2015,"finding":"TRIM46 is specifically localized to the newly specified axon and the axon initial segment (AIS), where it forms closely spaced parallel microtubule bundles oriented with plus-ends out; loss of TRIM46 results in dendrite-like mixed microtubule organization in all neurites, Tau missorting, and altered cargo trafficking, demonstrating TRIM46 is required for neuronal polarity and axon specification.","method":"Knockdown in cultured neurons (in vitro), in vivo neuronal polarity assays, live imaging of microtubule orientation, Tau localization assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD, live imaging, cargo trafficking, in vivo), replicated across subsequent studies","pmids":["26671463"],"is_preprint":false},{"year":2019,"finding":"TRIM46 localizes to electron-dense cross-bridges between AIS microtubules; depletion of TRIM46 causes loss of cross-bridges and increased microtubule spacing, establishing TRIM46 as an essential organizer of microtubule fascicles in the AIS.","method":"Correlative light and electron microscopy (CLEM), TRIM46 depletion in cultured rat hippocampal neurons, quantification of microtubule spacing","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — novel CLEM approach with direct ultrastructural localization and functional KD phenotype, replicated by later KO studies","pmids":["30967428"],"is_preprint":false},{"year":2021,"finding":"TRIM46 interacts with GPX4 (glutathione peroxidase 4) via co-immunoprecipitation and promotes GPX4 ubiquitination and degradation, thereby promoting ferroptosis in human retinal capillary endothelial cells under high glucose conditions.","method":"Co-immunoprecipitation, western blot, lentiviral overexpression/knockdown, ferroptosis assays (lipid ROS, MDA, GSH levels)","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction confirmed, ubiquitination shown, multiple functional readouts, single lab","pmids":["34487731"],"is_preprint":false},{"year":2022,"finding":"TRIM46 promotes ubiquitination and degradation of PHLPP2 via its E3 ligase (RING domain) activity, activating AKT/HK2 signaling to promote glycolysis and cisplatin resistance in lung adenocarcinoma cells; RING-mutant TRIM46 has no effect, confirming E3 ligase-dependent mechanism.","method":"Ubiquitination assays, RING-domain mutant overexpression, PHLPP2 overexpression rescue, xenograft (PDX) models, western blot for p-AKT","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — active-site mutagenesis (RING mutant), in vivo PDX model, rescue experiment with PHLPP2; single lab but multiple orthogonal methods","pmids":["35354796"],"is_preprint":false},{"year":2021,"finding":"TRIM46 is a ubiquitin E3 ligase that ubiquitinates HDAC1 to promote its degradation; the TRIM46–HDAC1 axis regulates a panel of genes involved in DNA replication and repair, promoting breast cancer cell proliferation and chemoresistance.","method":"Co-immunoprecipitation, ubiquitination assay, CRISPR/Cas9 SNP knock-in, gene expression profiling, in vivo tumor growth assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct ubiquitination assay, CRISPR validation of upstream SNP, in vivo tumor model; single lab with multiple orthogonal approaches","pmids":["34459501"],"is_preprint":false},{"year":2020,"finding":"TRIM46 ubiquitinates DUSP1, promoting activation of MAPKs and NF-κB signaling; TRIM46 knockdown inhibits TcdB-induced MAPK/NF-κB activation and cytokine production, and NF-κBp65 binds the TRIM46 promoter to regulate TRIM46 expression in a positive feedback loop.","method":"Co-immunoprecipitation/ubiquitination assay, siRNA knockdown, cytokine ELISA, NF-κB reporter/ChIP, in vivo C. difficile model","journal":"Artificial cells, nanomedicine, and biotechnology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitination shown, in vivo confirmation, but single lab and methods described at abstract level","pmids":["31918570"],"is_preprint":false},{"year":2022,"finding":"TRIM46 interacts with IκBα and promotes its ubiquitination and proteasomal degradation, thereby activating NF-κB signaling and enhancing hyperpermeability and inflammatory responses in retinal capillary endothelial cells under high glucose conditions.","method":"Co-immunoprecipitation, ubiquitination assay, western blot, TEER/FITC-dextran permeability assay, cytokine ELISA","journal":"Eye and vision","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitination confirmed, functional rescue with IκBα overexpression, single lab","pmids":["36064447"],"is_preprint":false},{"year":2022,"finding":"TRIM46 protein expression is post-transcriptionally regulated by two alternative cassette exons: exon 8 inclusion triggers nonsense-mediated mRNA decay (NMD) of Trim46 transcripts; PTBP2-mediated exon 10 skipping produces transcripts encoding unstable TRIM46 proteins. During axonogenesis, decreased exon 8 inclusion and enhanced exon 10 inclusion converge with transcriptional activation to increase TRIM46 protein levels.","method":"Alternative splicing analysis, NMD reporter assays, PTBP2 manipulation, genetic deletion of cassette exons, protein stability assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal mechanistic approaches (splicing, NMD, protein stability, genetic deletion), single lab but rigorous","pmids":["35440129"],"is_preprint":false},{"year":2022,"finding":"TRIM46 promotes ubiquitination and proteasomal degradation of Axin1 (a negative regulator of Wnt/β-catenin), thereby activating Wnt/β-catenin signaling and driving hypoxia-induced epithelial-mesenchymal transition in renal tubular cells.","method":"Co-immunoprecipitation, ubiquitination assay, western blot for β-catenin nuclear translocation, β-catenin inhibitor (XAV-939) rescue, rat renal fibrosis model","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitination demonstrated, in vivo fibrosis model, inhibitor rescue, single lab","pmids":["35670901"],"is_preprint":false},{"year":2024,"finding":"TRIM46 knockout mice are viable with normal behavior and normal brain structure; TRIM46 is dispensable for axon specification and AIS formation in vivo, but is required for microtubule fasciculation. TRIM46 enrichment in the proximal axon (~100 µm) occurs independently of ankyrinG (AnkG), but AnkG is required to restrict TRIM46 localization to the AIS.","method":"TRIM46 knockout mouse model (male and female), behavioral assays, brain histology, electron microscopy for microtubule fasciculation, AnkG KO epistasis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO mouse with multiple readouts (behavior, histology, EM), epistasis with AnkG, peer-reviewed; contradicts earlier KD-based claims","pmids":["39251352"],"is_preprint":false},{"year":2024,"finding":"TRIM46 interacts with FKBP5 (FK506-binding protein 5) in brain tissue; TRIM46 knockout in rats increases hippocampal FKBP5 protein levels and decreases Akt phosphorylation, GABRA1, and NMDAR1 levels, accompanied by smaller hippocampus, fewer dendritic spines, shorter AIS, and hypoactive behavior.","method":"CRISPR/Cas9 KO rat, co-immunoprecipitation (endogenous TRIM46-FKBP5), western blot, morphological analyses, behavioral battery","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — endogenous Co-IP, in vivo KO model with multiple functional readouts; mechanistic link between TRIM46-FKBP5 and downstream signaling is correlative in KO","pmids":["38193537"],"is_preprint":false},{"year":2024,"finding":"TRIM46 promotes ubiquitination of SLC7A11 (xCT), decreasing its stability, which exacerbates H1N1 influenza-induced ferroptosis and inflammatory response in lung cells.","method":"Co-immunoprecipitation, cycloheximide chase (protein stability), ubiquitination assay, KD/OE in A549/16HBE cells, in vivo lung injury mouse model","journal":"Journal of bioenergetics and biomembranes","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and stability assay shown, in vivo model, single lab","pmids":["39531094"],"is_preprint":false},{"year":2026,"finding":"A KIF3B-enriched, KAP3-associated kinesin-2 assembly (distinct from canonical KIF3A/B/KAP3) preferentially associates with TRIM46 and facilitates its transport to the AIS; structural differences in the KIF3B tail domain accompany this distinct assembly state and may underlie cargo selectivity.","method":"Biochemical fractionation, co-immunoprecipitation, cellular localization analyses, structural analyses of tail domain conformations","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — biochemical and cellular analyses with structural data, single study, mechanistic model supported but not fully reconstituted","pmids":["41910726"],"is_preprint":false},{"year":2024,"finding":"TRIM46 knockout cells show Golgi ribbon fragmentation and enhanced TFEB-driven lysosomal biogenesis; genetic inhibition of CASM (conjugation of ATG8 to single membranes) in TRIM46-deficient cells exacerbates Golgi morphology defects and reduces TFEB activation, placing TRIM46 upstream of a Golgi damage response pathway.","method":"TRIM46 KO cell lines, CASM genetic inhibition, Golgi morphology imaging, TFEB activation assays, colocalization of TGOLN2 with LC3B/GABARAP","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, cellular phenotype of TRIM46 KO described but mechanistic role of TRIM46 itself in CASM/Golgi pathway not directly established","pmids":["bio_10.1101_2025.09.04.674289"],"is_preprint":true},{"year":2025,"finding":"ONECUT3 directly binds the TRIM46 promoter and transcriptionally upregulates TRIM46 expression in pancreatic cancer cells; TRIM46 overexpression rescues ONECUT3-knockdown-induced suppression of proliferation and activates NF-κB signaling.","method":"Promoter binding assay (ChIP/reporter implied), ONECUT3 KD with TRIM46 rescue, NF-κB pathway western blot, in vivo tumor model","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — promoter binding and rescue shown, but NF-κB activation mechanism for TRIM46 itself not directly demonstrated; single lab, abstract-level detail","pmids":["40154001"],"is_preprint":false},{"year":2025,"finding":"TRIM46 interacts with PHLPP2 and downregulates its levels in ovarian cancer cells, thereby activating the PI3K/AKT pathway and promoting cisplatin chemoresistance; PI3K/AKT inhibition reverses TRIM46 overexpression effects.","method":"Co-immunoprecipitation, western blot, PI3K/AKT inhibitor rescue, functional chemoresistance assays","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction and pathway inhibitor rescue demonstrated, consistent with lung cancer PHLPP2 findings (PMID 35354796); single lab","pmids":["41222281"],"is_preprint":false}],"current_model":"TRIM46 is a RING-domain E3 ubiquitin ligase and microtubule-associated protein with dual roles: in neurons, it localizes to the axon initial segment where it forms electron-dense cross-bridges to organize closely spaced parallel microtubule fascicles (plus-end out), and while knockdown in cultured neurons disrupts axon specification, in vivo knockout mice reveal it is dispensable for AIS formation and axon specification but required for microtubule fasciculation; its transport to the AIS is mediated by a KIF3B-enriched kinesin-2 complex; in non-neuronal contexts, TRIM46 acts as an E3 ligase that ubiquitinates and degrades substrates including GPX4, SLC7A11, DUSP1, IκBα, HDAC1, PHLPP2, and Axin1, thereby activating ferroptosis, NF-κB, AKT, and Wnt/β-catenin signaling pathways to promote cancer cell proliferation, chemoresistance, and inflammatory responses."},"narrative":{"mechanistic_narrative":"TRIM46 is a microtubule-associated protein and RING-domain E3 ubiquitin ligase with distinct neuronal and non-neuronal functions. In neurons, it localizes to the newly specified axon and the axon initial segment (AIS), where it forms electron-dense cross-bridges between closely spaced, parallel, plus-end-out microtubules and organizes them into fascicles [PMID:26671463, PMID:30967428]. Knockdown in cultured neurons disrupts axon specification and microtubule polarity [PMID:26671463], but in vivo knockout mice are viable with normal axon specification and AIS formation, establishing that TRIM46 is dispensable for these processes yet required for microtubule fasciculation; its proximal-axon enrichment is AnkG-independent, while AnkG restricts TRIM46 to the AIS [PMID:39251352]. TRIM46 protein levels during axonogenesis are tuned post-transcriptionally through alternative cassette-exon usage, including NMD-coupled exon 8 inclusion and PTBP2-controlled exon 10 skipping [PMID:35440129], and its delivery to the AIS is mediated by a distinct KIF3B-enriched kinesin-2 assembly [PMID:41910726]. In non-neuronal and cancer contexts, TRIM46 acts as an E3 ligase that ubiquitinates and degrades multiple substrates to activate downstream signaling: degradation of PHLPP2 activates AKT signaling to drive glycolysis and chemoresistance [PMID:35354796, PMID:41222281]; ubiquitination of GPX4 and SLC7A11 promotes ferroptosis [PMID:34487731, PMID:39531094]; degradation of IκBα and DUSP1 activates NF-κB and MAPK signaling and inflammatory responses [PMID:31918570, PMID:36064447]; degradation of HDAC1 promotes proliferation and chemoresistance [PMID:34459501]; and degradation of Axin1 activates Wnt/β-catenin signaling to drive epithelial-mesenchymal transition [PMID:35670901]. RING-domain mutagenesis confirms these effects are E3 ligase-dependent [PMID:35354796].","teleology":[{"year":2015,"claim":"Established TRIM46 as a determinant of neuronal polarity by showing it organizes the axonal microtubule array, answering how axons acquire their characteristic uniform plus-end-out microtubule orientation.","evidence":"Knockdown in cultured neurons with live microtubule imaging, Tau localization, and cargo trafficking assays","pmids":["26671463"],"confidence":"High","gaps":["Did not establish the molecular structure of the cross-bridges","Knockdown-based, leaving in vivo requirement untested"]},{"year":2019,"claim":"Resolved the ultrastructural basis of TRIM46 action, showing it forms the electron-dense cross-bridges that hold AIS microtubules at defined spacing.","evidence":"Correlative light and electron microscopy with TRIM46 depletion and microtubule spacing quantification in rat hippocampal neurons","pmids":["30967428"],"confidence":"High","gaps":["Did not define the structural domain mediating cross-bridge formation","In vivo relevance not yet tested"]},{"year":2020,"claim":"First demonstrated TRIM46 as a functional E3 ligase outside neurons, ubiquitinating DUSP1 to activate MAPK/NF-κB inflammatory signaling, with NF-κB feeding back on TRIM46 expression.","evidence":"Co-IP/ubiquitination assays, siRNA knockdown, NF-κB reporter/ChIP, and an in vivo C. difficile model","pmids":["31918570"],"confidence":"Medium","gaps":["Abstract-level methods, single lab","Direct ubiquitination linkage versus indirect effects not fully separated"]},{"year":2021,"claim":"Extended TRIM46 substrate range to HDAC1 and GPX4, linking its ligase activity to proliferation/chemoresistance and to ferroptosis respectively.","evidence":"Co-IP, ubiquitination assays, CRISPR SNP knock-in, gene expression profiling, and ferroptosis readouts (lipid ROS, MDA, GSH) in breast cancer and retinal endothelial cells","pmids":["34459501","34487731"],"confidence":"High","gaps":["RING-dependence not tested in the GPX4 study","Tissue-specificity of substrate selection unexplained"]},{"year":2022,"claim":"Confirmed E3 ligase-dependence by RING-domain mutagenesis and broadened the substrate/pathway map to PHLPP2-AKT, IκBα-NF-κB, and Axin1-Wnt/β-catenin axes.","evidence":"RING-mutant overexpression, ubiquitination assays, rescue experiments, and in vivo PDX/fibrosis/permeability models across lung, renal, and retinal systems","pmids":["35354796","36064447","35670901"],"confidence":"High","gaps":["What selects different substrates in different tissues is unknown","Direct ubiquitin chain topology not characterized"]},{"year":2022,"claim":"Revealed how TRIM46 protein levels are set during axonogenesis through coupled alternative splicing, NMD, and protein-stability control.","evidence":"Alternative splicing analysis, NMD reporters, PTBP2 manipulation, cassette-exon deletion, and protein stability assays","pmids":["35440129"],"confidence":"High","gaps":["Upstream regulators coordinating these layers not fully mapped","Functional consequence of the unstable exon-10-skipped isoform unclear"]},{"year":2024,"claim":"In vivo knockout overturned the knockdown-based view, showing TRIM46 is dispensable for axon specification and AIS formation but required for microtubule fasciculation, and clarified its localization hierarchy with AnkG.","evidence":"TRIM46 knockout mouse with behavior, histology, EM of fasciculation, and AnkG knockout epistasis","pmids":["39251352"],"confidence":"High","gaps":["Why knockdown and knockout phenotypes diverge not mechanistically resolved","Functional consequence of lost fasciculation for neuronal physiology not defined"]},{"year":2024,"claim":"Linked TRIM46 to additional brain partners and substrates, identifying FKBP5 interaction in vivo and SLC7A11 ubiquitination promoting ferroptosis.","evidence":"CRISPR KO rat with endogenous Co-IP and morphological/behavioral analyses; Co-IP, cycloheximide chase, and lung injury models for SLC7A11","pmids":["38193537","39531094"],"confidence":"Medium","gaps":["TRIM46-FKBP5 downstream signaling link is correlative in KO","Whether FKBP5 is a ubiquitination substrate untested"]},{"year":2024,"claim":"Proposed TRIM46 acts upstream of a Golgi damage / TFEB lysosomal biogenesis response, expanding its potential cellular roles beyond microtubules and cancer signaling.","evidence":"TRIM46 KO cell lines, CASM genetic inhibition, Golgi morphology imaging, and TFEB activation assays (preprint)","pmids":["bio_10.1101_2025.09.04.674289"],"confidence":"Low","gaps":["Preprint, not peer-reviewed; direct mechanistic role of TRIM46 in CASM/Golgi pathway not established","Whether the effect requires E3 ligase activity untested"]},{"year":2026,"claim":"Identified the transport machinery delivering TRIM46 to the AIS, defining a distinct KIF3B-enriched kinesin-2 assembly with cargo selectivity.","evidence":"Biochemical fractionation, Co-IP, cellular localization, and tail-domain structural analyses","pmids":["41910726"],"confidence":"Medium","gaps":["Cargo selectivity model not reconstituted in vitro","Structural basis of tail-domain selectivity inferred, not directly proven"]},{"year":null,"claim":"How a single E3 ligase / microtubule organizer selects among such divergent substrates and roles across neuronal and non-neuronal tissues, and whether the cancer substrate repertoire operates in vivo at physiological expression, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying determinant of substrate/context selectivity identified","Many substrate findings rest on single-lab overexpression contexts","No human disease link established by direct genetic evidence in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[3,4,5,6,8]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3,4,5,6,8,11]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,9]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,4,5,6,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,6,8,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,7,9]}],"complexes":["AIS microtubule cross-bridges","kinesin-2 (KIF3B-enriched/KAP3) transport assembly"],"partners":["GPX4","PHLPP2","HDAC1","DUSP1","IKBA","AXIN1","SLC7A11","FKBP5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z4K8","full_name":"Tripartite motif-containing protein 46","aliases":["Gene Y protein","GeneY","Tripartite, fibronectin type-III and C-terminal SPRY motif protein"],"length_aa":759,"mass_kda":83.4,"function":"Microtubule-associated protein that is involved in the formation of parallel microtubule bundles linked by cross-bridges in the proximal axon. Required for the uniform orientation and maintenance of the parallel microtubule fascicles, which are important for efficient cargo delivery and trafficking in axons. Thereby also required for proper axon specification, the establishment of neuronal polarity and proper neuronal migration","subcellular_location":"Cell projection, axon; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q7Z4K8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM46","classification":"Not Classified","n_dependent_lines":125,"n_total_lines":1208,"dependency_fraction":0.10347682119205298},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRIM46","total_profiled":1310},"omim":[{"mim_id":"600986","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 46; TRIM46","url":"https://www.omim.org/entry/600986"},{"mim_id":"301121","title":"MAP7 DOMAIN-CONTAINING PROTEIN 2; MAP7D2","url":"https://www.omim.org/entry/301121"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubule ends","reliability":"Approved"},{"location":"Mitotic spindle","reliability":"Approved"},{"location":"Primary cilium transition zone","reliability":"Approved"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Centrosome","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":21.5}],"url":"https://www.proteinatlas.org/search/TRIM46"},"hgnc":{"alias_symbol":["FLJ23229","TRIFIC"],"prev_symbol":[]},"alphafold":{"accession":"Q7Z4K8","domains":[{"cath_id":"3.30.40.10","chopping":"28-67_123-168","consensus_level":"medium","plddt":84.8314,"start":28,"end":168},{"cath_id":"2.60.40.10","chopping":"433-524","consensus_level":"high","plddt":91.2675,"start":433,"end":524},{"cath_id":"2.60.120.920","chopping":"534-620_648-664_683-737","consensus_level":"high","plddt":89.0916,"start":534,"end":737}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z4K8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z4K8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z4K8-F1-predicted_aligned_error_v6.png","plddt_mean":79.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM46","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM46"},"sequence":{"accession":"Q7Z4K8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z4K8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z4K8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z4K8"}},"corpus_meta":[{"pmid":"26671463","id":"PMC_26671463","title":"TRIM46 Controls Neuronal Polarity and Axon Specification by Driving the Formation of Parallel Microtubule Arrays.","date":"2015","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/26671463","citation_count":178,"is_preprint":false},{"pmid":"34487731","id":"PMC_34487731","title":"TRIM46 contributes to high glucose-induced ferroptosis and cell growth inhibition in human retinal capillary endothelial cells by facilitating GPX4 ubiquitination.","date":"2021","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34487731","citation_count":126,"is_preprint":false},{"pmid":"30967428","id":"PMC_30967428","title":"TRIM46 Organizes Microtubule Fasciculation in the Axon Initial Segment.","date":"2019","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30967428","citation_count":59,"is_preprint":false},{"pmid":"35354796","id":"PMC_35354796","title":"TRIM46 activates AKT/HK2 signaling by modifying PHLPP2 ubiquitylation to promote glycolysis and chemoresistance of lung cancer cells.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35354796","citation_count":53,"is_preprint":false},{"pmid":"34921120","id":"PMC_34921120","title":"Characterisation of TRIM46 autoantibody-associated paraneoplastic neurological syndrome.","date":"2021","source":"Journal of neurology, neurosurgery, and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/34921120","citation_count":33,"is_preprint":false},{"pmid":"28904989","id":"PMC_28904989","title":"Antibodies to TRIM46 are associated with paraneoplastic neurological syndromes.","date":"2017","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/28904989","citation_count":30,"is_preprint":false},{"pmid":"34459501","id":"PMC_34459501","title":"SNP rs4971059 predisposes to breast carcinogenesis and chemoresistance via TRIM46-mediated HDAC1 degradation.","date":"2021","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/34459501","citation_count":28,"is_preprint":false},{"pmid":"27110773","id":"PMC_27110773","title":"Mmu-miR-1894-3p Inhibits Cell Proliferation and Migration of Breast Cancer Cells by Targeting Trim46.","date":"2016","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27110773","citation_count":28,"is_preprint":false},{"pmid":"31918570","id":"PMC_31918570","title":"Clostridium difficile toxin B induces colonic inflammation through the TRIM46/DUSP1/MAPKs and NF-κB signalling pathway.","date":"2020","source":"Artificial cells, nanomedicine, and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/31918570","citation_count":27,"is_preprint":false},{"pmid":"33556457","id":"PMC_33556457","title":"Axonal TAU Sorting Requires the C-terminus of TAU but is Independent of ANKG and TRIM46 Enrichment at the 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Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/39251352","citation_count":5,"is_preprint":false},{"pmid":"38193537","id":"PMC_38193537","title":"Trim46 knockout impaired neuronal architecture and caused hypoactive behavior in rats.","date":"2024","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/38193537","citation_count":5,"is_preprint":false},{"pmid":"39531094","id":"PMC_39531094","title":"TRIM46 accelerates H1N1 influenza virus-induced ferroptosis and inflammatory response by regulating SLC7A11 ubiquitination.","date":"2024","source":"Journal of bioenergetics and biomembranes","url":"https://pubmed.ncbi.nlm.nih.gov/39531094","citation_count":5,"is_preprint":false},{"pmid":"41222281","id":"PMC_41222281","title":"TRIM46 promotes chemoresistance of ovarian cancer via activating PHLPP2/PI3K/AKT pathway.","date":"2025","source":"Biochemistry and cell biology = Biochimie et 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communications","url":"https://pubmed.ncbi.nlm.nih.gov/40154001","citation_count":1,"is_preprint":false},{"pmid":"40590258","id":"PMC_40590258","title":"Autoantibodies against TRIM46 identified in a dog suffering from suspected meningoencephalomyelitis of unknown origin.","date":"2025","source":"The Journal of small animal practice","url":"https://pubmed.ncbi.nlm.nih.gov/40590258","citation_count":1,"is_preprint":false},{"pmid":"41614410","id":"PMC_41614410","title":"TRIM46 deficiency‑induced DNA damage enhances the sensitivity of cisplatin in non‑small cell lung cancer by regulating the Akt signaling pathway.","date":"2026","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/41614410","citation_count":0,"is_preprint":false},{"pmid":"41910726","id":"PMC_41910726","title":"The KIF3B/B/KAP3 tail domain specifically facilitates TRIM46 transport to the axon initial segment.","date":"2026","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/41910726","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.04.674289","title":"A role for CASM in the repair of damaged Golgi architecture","date":"2025-09-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.04.674289","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16162,"output_tokens":4093,"usd":0.054941,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12042,"output_tokens":3855,"usd":0.078293,"stage2_stop_reason":"end_turn"},"total_usd":0.133234,"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\": 2015,\n      \"finding\": \"TRIM46 is specifically localized to the newly specified axon and the axon initial segment (AIS), where it forms closely spaced parallel microtubule bundles oriented with plus-ends out; loss of TRIM46 results in dendrite-like mixed microtubule organization in all neurites, Tau missorting, and altered cargo trafficking, demonstrating TRIM46 is required for neuronal polarity and axon specification.\",\n      \"method\": \"Knockdown in cultured neurons (in vitro), in vivo neuronal polarity assays, live imaging of microtubule orientation, Tau localization assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD, live imaging, cargo trafficking, in vivo), replicated across subsequent studies\",\n      \"pmids\": [\"26671463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM46 localizes to electron-dense cross-bridges between AIS microtubules; depletion of TRIM46 causes loss of cross-bridges and increased microtubule spacing, establishing TRIM46 as an essential organizer of microtubule fascicles in the AIS.\",\n      \"method\": \"Correlative light and electron microscopy (CLEM), TRIM46 depletion in cultured rat hippocampal neurons, quantification of microtubule spacing\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — novel CLEM approach with direct ultrastructural localization and functional KD phenotype, replicated by later KO studies\",\n      \"pmids\": [\"30967428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM46 interacts with GPX4 (glutathione peroxidase 4) via co-immunoprecipitation and promotes GPX4 ubiquitination and degradation, thereby promoting ferroptosis in human retinal capillary endothelial cells under high glucose conditions.\",\n      \"method\": \"Co-immunoprecipitation, western blot, lentiviral overexpression/knockdown, ferroptosis assays (lipid ROS, MDA, GSH levels)\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction confirmed, ubiquitination shown, multiple functional readouts, single lab\",\n      \"pmids\": [\"34487731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM46 promotes ubiquitination and degradation of PHLPP2 via its E3 ligase (RING domain) activity, activating AKT/HK2 signaling to promote glycolysis and cisplatin resistance in lung adenocarcinoma cells; RING-mutant TRIM46 has no effect, confirming E3 ligase-dependent mechanism.\",\n      \"method\": \"Ubiquitination assays, RING-domain mutant overexpression, PHLPP2 overexpression rescue, xenograft (PDX) models, western blot for p-AKT\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — active-site mutagenesis (RING mutant), in vivo PDX model, rescue experiment with PHLPP2; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"35354796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM46 is a ubiquitin E3 ligase that ubiquitinates HDAC1 to promote its degradation; the TRIM46–HDAC1 axis regulates a panel of genes involved in DNA replication and repair, promoting breast cancer cell proliferation and chemoresistance.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, CRISPR/Cas9 SNP knock-in, gene expression profiling, in vivo tumor growth assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct ubiquitination assay, CRISPR validation of upstream SNP, in vivo tumor model; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"34459501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM46 ubiquitinates DUSP1, promoting activation of MAPKs and NF-κB signaling; TRIM46 knockdown inhibits TcdB-induced MAPK/NF-κB activation and cytokine production, and NF-κBp65 binds the TRIM46 promoter to regulate TRIM46 expression in a positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation/ubiquitination assay, siRNA knockdown, cytokine ELISA, NF-κB reporter/ChIP, in vivo C. difficile model\",\n      \"journal\": \"Artificial cells, nanomedicine, and biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitination shown, in vivo confirmation, but single lab and methods described at abstract level\",\n      \"pmids\": [\"31918570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM46 interacts with IκBα and promotes its ubiquitination and proteasomal degradation, thereby activating NF-κB signaling and enhancing hyperpermeability and inflammatory responses in retinal capillary endothelial cells under high glucose conditions.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, western blot, TEER/FITC-dextran permeability assay, cytokine ELISA\",\n      \"journal\": \"Eye and vision\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitination confirmed, functional rescue with IκBα overexpression, single lab\",\n      \"pmids\": [\"36064447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM46 protein expression is post-transcriptionally regulated by two alternative cassette exons: exon 8 inclusion triggers nonsense-mediated mRNA decay (NMD) of Trim46 transcripts; PTBP2-mediated exon 10 skipping produces transcripts encoding unstable TRIM46 proteins. During axonogenesis, decreased exon 8 inclusion and enhanced exon 10 inclusion converge with transcriptional activation to increase TRIM46 protein levels.\",\n      \"method\": \"Alternative splicing analysis, NMD reporter assays, PTBP2 manipulation, genetic deletion of cassette exons, protein stability assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal mechanistic approaches (splicing, NMD, protein stability, genetic deletion), single lab but rigorous\",\n      \"pmids\": [\"35440129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM46 promotes ubiquitination and proteasomal degradation of Axin1 (a negative regulator of Wnt/β-catenin), thereby activating Wnt/β-catenin signaling and driving hypoxia-induced epithelial-mesenchymal transition in renal tubular cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, western blot for β-catenin nuclear translocation, β-catenin inhibitor (XAV-939) rescue, rat renal fibrosis model\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitination demonstrated, in vivo fibrosis model, inhibitor rescue, single lab\",\n      \"pmids\": [\"35670901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM46 knockout mice are viable with normal behavior and normal brain structure; TRIM46 is dispensable for axon specification and AIS formation in vivo, but is required for microtubule fasciculation. TRIM46 enrichment in the proximal axon (~100 µm) occurs independently of ankyrinG (AnkG), but AnkG is required to restrict TRIM46 localization to the AIS.\",\n      \"method\": \"TRIM46 knockout mouse model (male and female), behavioral assays, brain histology, electron microscopy for microtubule fasciculation, AnkG KO epistasis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO mouse with multiple readouts (behavior, histology, EM), epistasis with AnkG, peer-reviewed; contradicts earlier KD-based claims\",\n      \"pmids\": [\"39251352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM46 interacts with FKBP5 (FK506-binding protein 5) in brain tissue; TRIM46 knockout in rats increases hippocampal FKBP5 protein levels and decreases Akt phosphorylation, GABRA1, and NMDAR1 levels, accompanied by smaller hippocampus, fewer dendritic spines, shorter AIS, and hypoactive behavior.\",\n      \"method\": \"CRISPR/Cas9 KO rat, co-immunoprecipitation (endogenous TRIM46-FKBP5), western blot, morphological analyses, behavioral battery\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — endogenous Co-IP, in vivo KO model with multiple functional readouts; mechanistic link between TRIM46-FKBP5 and downstream signaling is correlative in KO\",\n      \"pmids\": [\"38193537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM46 promotes ubiquitination of SLC7A11 (xCT), decreasing its stability, which exacerbates H1N1 influenza-induced ferroptosis and inflammatory response in lung cells.\",\n      \"method\": \"Co-immunoprecipitation, cycloheximide chase (protein stability), ubiquitination assay, KD/OE in A549/16HBE cells, in vivo lung injury mouse model\",\n      \"journal\": \"Journal of bioenergetics and biomembranes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and stability assay shown, in vivo model, single lab\",\n      \"pmids\": [\"39531094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"A KIF3B-enriched, KAP3-associated kinesin-2 assembly (distinct from canonical KIF3A/B/KAP3) preferentially associates with TRIM46 and facilitates its transport to the AIS; structural differences in the KIF3B tail domain accompany this distinct assembly state and may underlie cargo selectivity.\",\n      \"method\": \"Biochemical fractionation, co-immunoprecipitation, cellular localization analyses, structural analyses of tail domain conformations\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — biochemical and cellular analyses with structural data, single study, mechanistic model supported but not fully reconstituted\",\n      \"pmids\": [\"41910726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM46 knockout cells show Golgi ribbon fragmentation and enhanced TFEB-driven lysosomal biogenesis; genetic inhibition of CASM (conjugation of ATG8 to single membranes) in TRIM46-deficient cells exacerbates Golgi morphology defects and reduces TFEB activation, placing TRIM46 upstream of a Golgi damage response pathway.\",\n      \"method\": \"TRIM46 KO cell lines, CASM genetic inhibition, Golgi morphology imaging, TFEB activation assays, colocalization of TGOLN2 with LC3B/GABARAP\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, cellular phenotype of TRIM46 KO described but mechanistic role of TRIM46 itself in CASM/Golgi pathway not directly established\",\n      \"pmids\": [\"bio_10.1101_2025.09.04.674289\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ONECUT3 directly binds the TRIM46 promoter and transcriptionally upregulates TRIM46 expression in pancreatic cancer cells; TRIM46 overexpression rescues ONECUT3-knockdown-induced suppression of proliferation and activates NF-κB signaling.\",\n      \"method\": \"Promoter binding assay (ChIP/reporter implied), ONECUT3 KD with TRIM46 rescue, NF-κB pathway western blot, in vivo tumor model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — promoter binding and rescue shown, but NF-κB activation mechanism for TRIM46 itself not directly demonstrated; single lab, abstract-level detail\",\n      \"pmids\": [\"40154001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM46 interacts with PHLPP2 and downregulates its levels in ovarian cancer cells, thereby activating the PI3K/AKT pathway and promoting cisplatin chemoresistance; PI3K/AKT inhibition reverses TRIM46 overexpression effects.\",\n      \"method\": \"Co-immunoprecipitation, western blot, PI3K/AKT inhibitor rescue, functional chemoresistance assays\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction and pathway inhibitor rescue demonstrated, consistent with lung cancer PHLPP2 findings (PMID 35354796); single lab\",\n      \"pmids\": [\"41222281\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM46 is a RING-domain E3 ubiquitin ligase and microtubule-associated protein with dual roles: in neurons, it localizes to the axon initial segment where it forms electron-dense cross-bridges to organize closely spaced parallel microtubule fascicles (plus-end out), and while knockdown in cultured neurons disrupts axon specification, in vivo knockout mice reveal it is dispensable for AIS formation and axon specification but required for microtubule fasciculation; its transport to the AIS is mediated by a KIF3B-enriched kinesin-2 complex; in non-neuronal contexts, TRIM46 acts as an E3 ligase that ubiquitinates and degrades substrates including GPX4, SLC7A11, DUSP1, IκBα, HDAC1, PHLPP2, and Axin1, thereby activating ferroptosis, NF-κB, AKT, and Wnt/β-catenin signaling pathways to promote cancer cell proliferation, chemoresistance, and inflammatory responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM46 is a microtubule-associated protein and RING-domain E3 ubiquitin ligase with distinct neuronal and non-neuronal functions. In neurons, it localizes to the newly specified axon and the axon initial segment (AIS), where it forms electron-dense cross-bridges between closely spaced, parallel, plus-end-out microtubules and organizes them into fascicles [#0, #1]. Knockdown in cultured neurons disrupts axon specification and microtubule polarity [#0], but in vivo knockout mice are viable with normal axon specification and AIS formation, establishing that TRIM46 is dispensable for these processes yet required for microtubule fasciculation; its proximal-axon enrichment is AnkG-independent, while AnkG restricts TRIM46 to the AIS [#9]. TRIM46 protein levels during axonogenesis are tuned post-transcriptionally through alternative cassette-exon usage, including NMD-coupled exon 8 inclusion and PTBP2-controlled exon 10 skipping [#7], and its delivery to the AIS is mediated by a distinct KIF3B-enriched kinesin-2 assembly [#12]. In non-neuronal and cancer contexts, TRIM46 acts as an E3 ligase that ubiquitinates and degrades multiple substrates to activate downstream signaling: degradation of PHLPP2 activates AKT signaling to drive glycolysis and chemoresistance [#3, #15]; ubiquitination of GPX4 and SLC7A11 promotes ferroptosis [#2, #11]; degradation of IκBα and DUSP1 activates NF-κB and MAPK signaling and inflammatory responses [#5, #6]; degradation of HDAC1 promotes proliferation and chemoresistance [#4]; and degradation of Axin1 activates Wnt/β-catenin signaling to drive epithelial-mesenchymal transition [#8]. RING-domain mutagenesis confirms these effects are E3 ligase-dependent [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established TRIM46 as a determinant of neuronal polarity by showing it organizes the axonal microtubule array, answering how axons acquire their characteristic uniform plus-end-out microtubule orientation.\",\n      \"evidence\": \"Knockdown in cultured neurons with live microtubule imaging, Tau localization, and cargo trafficking assays\",\n      \"pmids\": [\"26671463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the molecular structure of the cross-bridges\", \"Knockdown-based, leaving in vivo requirement untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the ultrastructural basis of TRIM46 action, showing it forms the electron-dense cross-bridges that hold AIS microtubules at defined spacing.\",\n      \"evidence\": \"Correlative light and electron microscopy with TRIM46 depletion and microtubule spacing quantification in rat hippocampal neurons\",\n      \"pmids\": [\"30967428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural domain mediating cross-bridge formation\", \"In vivo relevance not yet tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"First demonstrated TRIM46 as a functional E3 ligase outside neurons, ubiquitinating DUSP1 to activate MAPK/NF-κB inflammatory signaling, with NF-κB feeding back on TRIM46 expression.\",\n      \"evidence\": \"Co-IP/ubiquitination assays, siRNA knockdown, NF-κB reporter/ChIP, and an in vivo C. difficile model\",\n      \"pmids\": [\"31918570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Abstract-level methods, single lab\", \"Direct ubiquitination linkage versus indirect effects not fully separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended TRIM46 substrate range to HDAC1 and GPX4, linking its ligase activity to proliferation/chemoresistance and to ferroptosis respectively.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, CRISPR SNP knock-in, gene expression profiling, and ferroptosis readouts (lipid ROS, MDA, GSH) in breast cancer and retinal endothelial cells\",\n      \"pmids\": [\"34459501\", \"34487731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RING-dependence not tested in the GPX4 study\", \"Tissue-specificity of substrate selection unexplained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed E3 ligase-dependence by RING-domain mutagenesis and broadened the substrate/pathway map to PHLPP2-AKT, IκBα-NF-κB, and Axin1-Wnt/β-catenin axes.\",\n      \"evidence\": \"RING-mutant overexpression, ubiquitination assays, rescue experiments, and in vivo PDX/fibrosis/permeability models across lung, renal, and retinal systems\",\n      \"pmids\": [\"35354796\", \"36064447\", \"35670901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What selects different substrates in different tissues is unknown\", \"Direct ubiquitin chain topology not characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed how TRIM46 protein levels are set during axonogenesis through coupled alternative splicing, NMD, and protein-stability control.\",\n      \"evidence\": \"Alternative splicing analysis, NMD reporters, PTBP2 manipulation, cassette-exon deletion, and protein stability assays\",\n      \"pmids\": [\"35440129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream regulators coordinating these layers not fully mapped\", \"Functional consequence of the unstable exon-10-skipped isoform unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"In vivo knockout overturned the knockdown-based view, showing TRIM46 is dispensable for axon specification and AIS formation but required for microtubule fasciculation, and clarified its localization hierarchy with AnkG.\",\n      \"evidence\": \"TRIM46 knockout mouse with behavior, histology, EM of fasciculation, and AnkG knockout epistasis\",\n      \"pmids\": [\"39251352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why knockdown and knockout phenotypes diverge not mechanistically resolved\", \"Functional consequence of lost fasciculation for neuronal physiology not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked TRIM46 to additional brain partners and substrates, identifying FKBP5 interaction in vivo and SLC7A11 ubiquitination promoting ferroptosis.\",\n      \"evidence\": \"CRISPR KO rat with endogenous Co-IP and morphological/behavioral analyses; Co-IP, cycloheximide chase, and lung injury models for SLC7A11\",\n      \"pmids\": [\"38193537\", \"39531094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TRIM46-FKBP5 downstream signaling link is correlative in KO\", \"Whether FKBP5 is a ubiquitination substrate untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed TRIM46 acts upstream of a Golgi damage / TFEB lysosomal biogenesis response, expanding its potential cellular roles beyond microtubules and cancer signaling.\",\n      \"evidence\": \"TRIM46 KO cell lines, CASM genetic inhibition, Golgi morphology imaging, and TFEB activation assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.04.674289\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, not peer-reviewed; direct mechanistic role of TRIM46 in CASM/Golgi pathway not established\", \"Whether the effect requires E3 ligase activity untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified the transport machinery delivering TRIM46 to the AIS, defining a distinct KIF3B-enriched kinesin-2 assembly with cargo selectivity.\",\n      \"evidence\": \"Biochemical fractionation, Co-IP, cellular localization, and tail-domain structural analyses\",\n      \"pmids\": [\"41910726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cargo selectivity model not reconstituted in vitro\", \"Structural basis of tail-domain selectivity inferred, not directly proven\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single E3 ligase / microtubule organizer selects among such divergent substrates and roles across neuronal and non-neuronal tissues, and whether the cancer substrate repertoire operates in vivo at physiological expression, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying determinant of substrate/context selectivity identified\", \"Many substrate findings rest on single-lab overexpression contexts\", \"No human disease link established by direct genetic evidence in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [3, 4, 5, 6, 8]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3, 4, 5, 6, 8, 11]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 4, 5, 6, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 6, 8, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 7, 9]}\n    ],\n    \"complexes\": [\"AIS microtubule cross-bridges\", \"kinesin-2 (KIF3B-enriched/KAP3) transport assembly\"],\n    \"partners\": [\"GPX4\", \"PHLPP2\", \"HDAC1\", \"DUSP1\", \"IkBa\", \"Axin1\", \"SLC7A11\", \"FKBP5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}