{"gene":"TRIM6","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2014,"finding":"TRIM6 cooperates with the E2-ubiquitin conjugase UbE2K to synthesize unanchored K48-linked polyubiquitin chains (not covalently attached to any protein substrate), which activate IKKε kinase for subsequent STAT1 phosphorylation and induction of IFN-I-stimulated genes. TRIM6 directly interacts with IKKε.","method":"Co-immunoprecipitation, in vitro ubiquitin chain synthesis assays, siRNA knockdown with downstream signaling readouts (STAT1 phosphorylation, ISG induction)","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical reconstitution of unanchored polyubiquitin chain synthesis, Co-IP of TRIM6–IKKε interaction, functional epistasis with E2 (UbE2K), multiple orthogonal methods in one study","pmids":["24882218"],"is_preprint":false},{"year":2016,"finding":"Nipah virus matrix protein (NiV-M) interacts with TRIM6 and promotes its proteasomal degradation, thereby reducing unanchored K48-linked polyubiquitin chains associated with IKKε, impairing IKKε oligomerization and autophosphorylation, and reducing IFN-mediated antiviral responses. This degradation of TRIM6 by NiV-M requires lysine K258 in the bipartite nuclear localization signal of NiV-M.","method":"Co-immunoprecipitation, confocal microscopy, measurement of IKKε oligomerization and autophosphorylation, live NiV infection with recombinant NiV lacking M protein as control","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, confocal co-localization, biochemical pathway readouts (IKKε oligomerization/phosphorylation), genetic control (recombinant NiV ΔM), multiple orthogonal methods","pmids":["27622505"],"is_preprint":false},{"year":2017,"finding":"TRIM6 physically interacts with Ebola virus VP35 protein and ubiquitinates it on lysine K309 (located in its IFN antagonist domain). VP35 noncovalently associates with TRIM6-generated unanchored polyubiquitin chains and inhibits TRIM6-mediated IFN-I induction. Separately, TRIM6 enhances EBOV polymerase activity, and TRIM6-knockout cells show reduced infectious EBOV replication.","method":"Mass spectrometry, co-immunoprecipitation, minigenome (polymerase activity) assay, TRIM6 knockout cells infected with infectious EBOV","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — MS-confirmed ubiquitination site (K309), Co-IP interaction, functional minigenome assay, TRIM6-KO infectious virus replication assay; multiple orthogonal methods","pmids":["28679761"],"is_preprint":false},{"year":2012,"finding":"TRIM6 interacts with the Myc proto-oncogene product in embryonic stem cells and attenuates Myc transcriptional activity. TRIM6 knockdown in ES cells enhances Myc transcriptional activity, represses NANOG expression, and promotes ES cell differentiation, indicating TRIM6 maintains ES cell pluripotency by regulating Myc-mediated transcription.","method":"Co-immunoprecipitation (TRIM6–Myc interaction), siRNA knockdown in ES cells, transcriptional reporter assays, expression analysis of pluripotency markers (NANOG)","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP interaction, functional KD with defined pluripotency phenotype and gene expression readouts, single lab","pmids":["22328504"],"is_preprint":false},{"year":2020,"finding":"TRIM6 ubiquitinates the anti-proliferative protein TIS21 on Lys5, promoting its degradation; this requires TRIM6 E3 catalytic activity (abolished by C15A mutant). TRIM6-mediated TIS21 degradation leads to elevated FoxM1, phospho-FoxM1, Cyclin B1, and c-Myc levels, promoting colorectal cancer cell proliferation and G2/M cell cycle progression.","method":"Co-immunoprecipitation/proteomics to identify TIS21 as TRIM6 binding partner, ubiquitination assay with catalytic mutant (C15A), rescue experiments with TIS21 overexpression, in vitro and in vivo proliferation assays","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP-based interaction, ubiquitination assay with catalytic mutant, rescue experiments, single lab","pmids":["31992359"],"is_preprint":false},{"year":2020,"finding":"TRIM6 contributes to an antiviral response against West Nile Virus through VAMP8. In TRIM6-KO cells, WNV replication is increased and IFN-I induction/signaling are impaired. VAMP8 knockdown reduces JAK1 and STAT1 phosphorylation and impairs ISG induction; VAMP8-mediated STAT1 phosphorylation requires TRIM6, placing VAMP8 downstream of TRIM6 in the IFN-I signaling axis.","method":"TRIM6 knockout cells (A549), next-generation sequencing to identify VAMP8, siRNA knockdown of VAMP8, measurement of JAK1/STAT1 phosphorylation and ISG induction, WNV replication assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TRIM6-KO with defined signaling phenotype, VAMP8 KD epistasis, multiple functional readouts, single lab","pmids":["31694946"],"is_preprint":false},{"year":2019,"finding":"TRIM6 promotes IKKε-dependent STAT1 activation in cardiomyocytes, leading to apoptosis and myocardial ischemia/reperfusion injury. A TRIM6 mutant lacking the ability to ubiquitinate IKKε fails to promote STAT1 activation or cardiomyocyte apoptosis. Pharmacological inhibition of IKKε or STAT1 abolishes TRIM6-driven injury.","method":"Mouse MI/R injury model, TRIM6 overexpression/depletion, E3 catalytic mutant (unable to ubiquitinate IKKε), pharmacological inhibition (CAY10576 for IKKε, fludarabine for STAT1), apoptosis and infarct size measurements","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with gain/loss-of-function, catalytic mutant controls, pharmacological epistasis, single lab","pmids":["31171760"],"is_preprint":false},{"year":2021,"finding":"TRIM6 promotes ubiquitination of TSC1 and TSC2 (negative regulators of mTORC1), activating the mTORC1 pathway, and thereby driving renal fibrosis-associated processes including EMT and ER stress. TRIM6 expression in renal fibrosis is upregulated by Angiotensin II-induced NF-κB (p50/p65) nuclear translocation.","method":"Co-immunoprecipitation, ubiquitination assays (TSC1/2), siRNA knockdown in HK2 cells, in vivo 5/6-nephrectomized rat model, Western blot for mTORC1 pathway activity","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and ubiquitination assays, in vivo model, multiple readouts, single lab","pmids":["33634104"],"is_preprint":false},{"year":2024,"finding":"TRIM6 directly interacts with GPX3 via its RING and B-box-CCD domains (inferred from NP binding domain mapping; for GPX3, interaction confirmed by Co-IP) and promotes K48-linked ubiquitination and proteasomal degradation of GPX3 protein without affecting its mRNA, leading to increased mitochondrial ROS, NLRP3 inflammasome activation, and pyroptosis in renal tubular epithelial cells.","method":"Co-immunoprecipitation (TRIM6–GPX3), ubiquitination assay, TRIM6 overexpression/knockdown, ROS measurements by flow cytometry, pyroptosis markers (caspase-1, GSDMD-N, IL-1β)","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP interaction, ubiquitination assay, functional gain/loss-of-function with multiple orthogonal cellular readouts, single lab","pmids":["38420829"],"is_preprint":false},{"year":2024,"finding":"TRIM6 binds the nucleocapsid protein (NP) of SARS-CoV-2 via its RING and B-box-CCD domains (interacting with NP's CTD) and catalyzes K29-type polyubiquitination of NP at K102, K347, and K361 residues. This ubiquitination increases NP binding to viral genomic RNA and promotes SARS-CoV-2 replication; TRIM6 knockout significantly inhibits viral proliferation. TRIM6 also ubiquitinates SARS-CoV NP, suggesting a conserved mechanism.","method":"Co-immunoprecipitation with domain mapping, mass spectrometry-identified ubiquitination sites, trVLP reverse genetic model, TRIM6 knockout, RNA-binding assays","journal":"Journal of medical virology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — domain-resolved Co-IP, MS-identified ubiquitination sites with site-directed mutation, functional viral replication assay in KO cells, multiple orthogonal methods in one study","pmids":["38515377"],"is_preprint":false},{"year":2025,"finding":"TRIM6 catalyzes K27-linked polyubiquitination of cGAS, targeting it for proteasomal degradation and suppressing the cGAS-STING innate immune pathway. TRIM6 ablation restores cGAS-STING activity, increases CD8+ T lymphocyte infiltration, and synergizes with anti-PD-L1 therapy in microsatellite-stable gastric tumors.","method":"TRIM6-knockout murine models, ubiquitination assays (K27-linked), immunoblotting for cGAS-STING pathway components, flow cytometry for TILs, RNA sequencing","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model, ubiquitination assay, multiple pathway and cellular readouts, single lab","pmids":["40817248"],"is_preprint":false},{"year":2024,"finding":"TRIM6 interacts with FOXO3A and promotes its ubiquitination and proteasomal degradation, suppressing FOXO3A protein levels and thereby driving glioma cell proliferation, invasion, and migration. Rescue of FOXO3A expression reverses TRIM6-driven malignant phenotypes.","method":"Co-immunoprecipitation (TRIM6–FOXO3A), Western blot for FOXO3A protein stability, loss/gain-of-function (proliferation, invasion, migration assays), rescue experiments, xenograft model","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP interaction, functional rescue experiments, in vivo xenograft, single lab","pmids":["38759605"],"is_preprint":false},{"year":2023,"finding":"TRIM6 directly interacts with and promotes ubiquitination/degradation of SLC1A5 (a glutamine transporter), inhibiting glutamine import, glutaminolysis, and lipid peroxidation, thereby suppressing ferroptosis in lung cancer cells and reducing chemosensitivity to cisplatin and paclitaxel.","method":"Co-immunoprecipitation (TRIM6–SLC1A5), ubiquitination assay, overexpression/knockdown with ferroptosis markers (lipid peroxidation, iron levels), in vivo xenograft models","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP interaction, ubiquitination assay, functional in vitro and in vivo readouts, single lab","pmids":["36654781"],"is_preprint":false},{"year":2025,"finding":"STAT3 directly binds the TRIM6 promoter and transcriptionally upregulates TRIM6 in hepatocellular carcinoma. TRIM6 in turn interacts with and ubiquitinates DDX58 (RIG-I), promoting its proteasomal degradation. DDX58 degradation relieves its inhibitory effect on Snail1 expression, facilitating EMT and HCC invasion, defining a STAT3–TRIM6–DDX58–Snail1 axis.","method":"Chromatin immunoprecipitation (STAT3 binding to TRIM6 promoter), Co-immunoprecipitation (TRIM6–DDX58), ubiquitination assay, loss/gain-of-function invasion assays, Western blot for pathway components","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for transcriptional regulation, Co-IP and ubiquitination assay for TRIM6–DDX58 axis, functional invasion readout, single lab","pmids":["40348925"],"is_preprint":false}],"current_model":"TRIM6 is a RING-domain E3 ubiquitin ligase that cooperates with the E2 enzyme UbE2K to synthesize unanchored K48-linked polyubiquitin chains that activate IKKε, driving STAT1 phosphorylation and type I interferon (IFN-I) antiviral responses; beyond this canonical role, TRIM6 ubiquitinates diverse substrates including viral proteins (EBOV VP35, SARS-CoV-2 NP), cell-cycle regulators (TIS21, FOXO3A), innate immune sensors (cGAS, DDX58), metabolic transporters (SLC1A5), and tumor suppressors (TSC1/2, GPX3) via distinct ubiquitin linkages (K29, K27, K48), thereby influencing antiviral immunity, mTORC1 signaling, ferroptosis, pyroptosis, and cancer cell proliferation and invasion."},"narrative":{"mechanistic_narrative":"TRIM6 is a RING-domain E3 ubiquitin ligase that functions at the intersection of antiviral innate immunity, cell-cycle control, and cancer biology by directing substrate-specific and unanchored polyubiquitination [PMID:24882218, PMID:31992359]. Its canonical role is in type I interferon (IFN-I) signaling: cooperating with the E2 conjugase UbE2K, TRIM6 synthesizes unanchored K48-linked polyubiquitin chains that activate the kinase IKKε, which it binds directly, driving IKKε oligomerization and autophosphorylation, STAT1 phosphorylation, and induction of interferon-stimulated genes [PMID:24882218, PMID:27622505]. This axis is targeted by viruses for evasion—Nipah virus matrix protein triggers proteasomal degradation of TRIM6 to dampen IKKε activity [PMID:27622505], and Ebola VP35 is ubiquitinated by TRIM6 on K309 while also sequestering its unanchored chains [PMID:28679761]. TRIM6 additionally restricts or supports diverse viruses through substrate ubiquitination, including K29-linked ubiquitination of SARS-CoV-2 nucleocapsid protein to enhance viral RNA binding and replication [PMID:38515377] and K27-linked ubiquitination of cGAS to suppress the cGAS-STING pathway [PMID:40817248]. Beyond immunity, TRIM6 acts as a pro-proliferative and pro-tumorigenic factor by ubiquitinating and degrading antiproliferative and tumor-suppressor substrates—TIS21 in colorectal cancer [PMID:31992359], FOXO3A in glioma [PMID:38759605], TSC1/TSC2 to activate mTORC1 in renal fibrosis [PMID:33634104], SLC1A5 to suppress ferroptosis in lung cancer [PMID:36654781], and DDX58/RIG-I to promote EMT in hepatocellular carcinoma [PMID:40348925]. In embryonic stem cells, TRIM6 restrains Myc transcriptional activity to maintain pluripotency [PMID:22328504].","teleology":[{"year":2012,"claim":"Established the first functional role of TRIM6 in a defined cellular context—restraining Myc-driven transcription to preserve stem cell identity—before its enzymatic mechanism was known.","evidence":"Co-IP of TRIM6–Myc, siRNA knockdown in ES cells with pluripotency marker and reporter readouts","pmids":["22328504"],"confidence":"Medium","gaps":["Whether the Myc regulation depends on TRIM6 E3 catalytic activity was not resolved","No ubiquitination linkage or substrate site defined"]},{"year":2014,"claim":"Defined the core enzymatic mechanism: TRIM6 partners with UbE2K to build unanchored K48-linked polyubiquitin chains that activate IKKε for STAT1-dependent IFN-I responses, distinguishing TRIM6 as a producer of non-substrate-attached chains.","evidence":"Co-IP, in vitro unanchored chain synthesis assays, siRNA knockdown with STAT1 phosphorylation and ISG readouts","pmids":["24882218"],"confidence":"High","gaps":["Structural basis of how unanchored chains activate IKKε not resolved","Whether TRIM6 also generates substrate-conjugated chains in this pathway unclear"]},{"year":2016,"claim":"Showed the TRIM6–IKKε axis is a viral evasion target, with Nipah virus M protein degrading TRIM6 to impair IKKε oligomerization and IFN signaling.","evidence":"Reciprocal Co-IP, confocal microscopy, IKKε oligomerization/autophosphorylation assays, recombinant NiV ΔM infection","pmids":["27622505"],"confidence":"High","gaps":["E3 ligase mediating NiV-M-induced TRIM6 degradation not identified","Mechanism linking TRIM6 loss to reduced unanchored chains not fully detailed"]},{"year":2017,"claim":"Demonstrated TRIM6 directly engages and ubiquitinates a viral IFN antagonist (EBOV VP35 at K309), while VP35 reciprocally counteracts TRIM6, revealing a bidirectional host–virus conflict at the ubiquitin level.","evidence":"MS-mapped ubiquitination site, Co-IP, minigenome polymerase assay, infectious EBOV in TRIM6-KO cells","pmids":["28679761"],"confidence":"High","gaps":["Ubiquitin linkage type on VP35 not specified","How TRIM6 enhances EBOV polymerase activity mechanistically unclear"]},{"year":2019,"claim":"Extended the TRIM6–IKKε–STAT1 axis to a pathological in vivo setting, showing catalytic-dependent STAT1 activation drives cardiomyocyte apoptosis and ischemia/reperfusion injury.","evidence":"Mouse MI/R model, gain/loss-of-function, E3 catalytic mutant, pharmacological IKKε/STAT1 inhibition","pmids":["31171760"],"confidence":"Medium","gaps":["Upstream signals inducing TRIM6 in cardiomyocytes not defined","Single-lab in vivo finding"]},{"year":2020,"claim":"Identified VAMP8 as a downstream effector of TRIM6 in the IFN-I signaling axis and showed TRIM6 restricts West Nile Virus replication.","evidence":"TRIM6-KO A549 cells, NGS to identify VAMP8, VAMP8 knockdown epistasis, JAK1/STAT1 phosphorylation and ISG readouts, WNV replication assays","pmids":["31694946"],"confidence":"Medium","gaps":["Whether VAMP8 is a direct TRIM6 ubiquitination substrate not established","Molecular connection between TRIM6 and VAMP8 not defined"]},{"year":2020,"claim":"Revealed TRIM6 as a pro-proliferative E3 in cancer by catalytically degrading the antiproliferative protein TIS21 (K5), linking TRIM6 to FoxM1/Cyclin B1/c-Myc-driven G2/M progression.","evidence":"Co-IP/proteomics, ubiquitination assay with C15A catalytic mutant, TIS21 rescue, in vitro/in vivo proliferation assays","pmids":["31992359"],"confidence":"Medium","gaps":["Ubiquitin linkage type on TIS21 not specified","Single-lab finding"]},{"year":2021,"claim":"Connected TRIM6 to mTORC1 signaling and renal fibrosis through ubiquitination of the TSC1/TSC2 tumor-suppressor complex, with TRIM6 itself induced by Angiotensin II–driven NF-κB.","evidence":"Co-IP, TSC1/2 ubiquitination assays, siRNA in HK2 cells, 5/6-nephrectomy rat model, mTORC1 pathway immunoblots","pmids":["33634104"],"confidence":"Medium","gaps":["Ubiquitin linkage and modification sites on TSC1/2 not defined","Single-lab finding"]},{"year":2023,"claim":"Showed TRIM6 suppresses ferroptosis by degrading the glutamine transporter SLC1A5, reducing glutaminolysis and lipid peroxidation, and lowering chemosensitivity in lung cancer.","evidence":"Co-IP, ubiquitination assay, gain/loss-of-function with ferroptosis markers, xenograft models","pmids":["36654781"],"confidence":"Medium","gaps":["Ubiquitin linkage type and SLC1A5 modification sites not defined","Single-lab finding"]},{"year":2024,"claim":"Demonstrated TRIM6 degrades FOXO3A to drive glioma malignancy, broadening its tumor-suppressor-degrading repertoire.","evidence":"Co-IP, FOXO3A stability immunoblots, loss/gain-of-function phenotypic assays, rescue, xenograft","pmids":["38759605"],"confidence":"Medium","gaps":["Ubiquitin linkage and FOXO3A sites not defined","Single-lab finding"]},{"year":2024,"claim":"Resolved a domain-specific, linkage-specific viral mechanism—TRIM6 catalyzes K29-linked ubiquitination of SARS-CoV-2 NP (K102/K347/K361) via its RING and B-box-CCD domains to enhance NP–RNA binding and viral replication.","evidence":"Domain-mapped Co-IP, MS-identified sites with mutation, trVLP reverse genetics, TRIM6-KO replication and RNA-binding assays","pmids":["38515377"],"confidence":"High","gaps":["Whether K29 chains alter NP function in authentic SARS-CoV-2 infection not fully tested","Generalizability across coronaviruses beyond SARS-CoV inferred"]},{"year":2024,"claim":"Showed TRIM6 degrades GPX3 via K48-linked ubiquitination, linking it to mitochondrial ROS, NLRP3 inflammasome activation, and pyroptosis in renal tubular cells.","evidence":"Co-IP, ubiquitination assay, gain/loss-of-function, ROS flow cytometry, pyroptosis marker readouts","pmids":["38420829"],"confidence":"Medium","gaps":["GPX3 ubiquitination sites not mapped","Single-lab finding"]},{"year":2025,"claim":"Established a STAT3→TRIM6→DDX58→Snail1 axis in which TRIM6 is transcriptionally induced by STAT3 and degrades DDX58/RIG-I to promote EMT and HCC invasion.","evidence":"ChIP (STAT3–TRIM6 promoter), Co-IP (TRIM6–DDX58), ubiquitination assay, invasion assays, pathway immunoblots","pmids":["40348925"],"confidence":"Medium","gaps":["DDX58 ubiquitin linkage and sites not defined","Single-lab finding"]},{"year":2025,"claim":"Showed TRIM6 catalyzes K27-linked ubiquitination of cGAS to suppress cGAS-STING immunity, and that its ablation enhances anti-tumor immunity and anti-PD-L1 efficacy in MSS gastric cancer.","evidence":"TRIM6-KO murine models, K27-linkage ubiquitination assays, cGAS-STING immunoblots, TIL flow cytometry, RNA-seq","pmids":["40817248"],"confidence":"Medium","gaps":["cGAS modification sites not mapped","Single-lab finding"]},{"year":null,"claim":"How TRIM6 selects among distinct ubiquitin linkage types (K27, K29, K48, unanchored) for different substrates, and what determines context-specific antiviral-restrictive versus pro-viral and pro-tumorigenic outcomes, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model explaining linkage specificity","No unified regulatory logic linking substrate choice to cellular context","Most non-immune substrate findings rest on single-lab studies"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2,4,7,8,9,10,11,12,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,4,8,9,10,11,12,13]}],"localization":[],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,5,9,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,4,7,8,11,12,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,11,12,13]}],"complexes":[],"partners":["IKBKE","UBE2K","MYC","VP35","TSC1","TSC2","SLC1A5","DDX58"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9C030","full_name":"Tripartite motif-containing protein 6","aliases":["RING finger protein 89","RING-type E3 ubiquitin transferase TRIM6"],"length_aa":488,"mass_kda":56.4,"function":"E3 ubiquitin ligase that plays a crucial role in the activation of the IKBKE-dependent branch of the type I interferon signaling pathway (PubMed:24882218, PubMed:31694946). In concert with the ubiquitin-conjugating E2 enzyme UBE2K, synthesizes unanchored 'Lys-48'-linked polyubiquitin chains that promote the oligomerization and autophosphorylation of IKBKE leading to stimulation of an antiviral response (PubMed:24882218). Also ubiquitinates MYC and inhibits its transcription activation activity, maintaining the pluripotency of embryonic stem cells (By similarity). Promotes the association of unanchored 'Lys-48'-polyubiquitin chains with DHX16 leading to enhanced RIGI-mediated innate antiviral immune response (PubMed:35263596) (Microbial infection) Ubiquitinates ebolavirus protein VP35 leading to enhanced viral transcriptase activity","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9C030/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM6","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRIM6","total_profiled":1310},"omim":[{"mim_id":"608487","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 5; TRIM5","url":"https://www.omim.org/entry/608487"},{"mim_id":"607564","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 6; TRIM6","url":"https://www.omim.org/entry/607564"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":19.5}],"url":"https://www.proteinatlas.org/search/TRIM6"},"hgnc":{"alias_symbol":["RNF89"],"prev_symbol":[]},"alphafold":{"accession":"Q9C030","domains":[{"cath_id":"3.30.40.10","chopping":"5-43_52-87","consensus_level":"high","plddt":84.5197,"start":5,"end":87},{"cath_id":"-","chopping":"175-281","consensus_level":"medium","plddt":93.1931,"start":175,"end":281},{"cath_id":"2.60.120.920","chopping":"287-328_340-377_394-484","consensus_level":"high","plddt":89.3635,"start":287,"end":484}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C030","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C030-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C030-F1-predicted_aligned_error_v6.png","plddt_mean":86.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM6","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM6"},"sequence":{"accession":"Q9C030","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9C030.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9C030/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C030"}},"corpus_meta":[{"pmid":"24882218","id":"PMC_24882218","title":"Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase TRIM6 stimulates the interferon-IKKε kinase-mediated antiviral response.","date":"2014","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/24882218","citation_count":152,"is_preprint":false},{"pmid":"27622505","id":"PMC_27622505","title":"The Matrix Protein of Nipah Virus Targets the E3-Ubiquitin Ligase TRIM6 to Inhibit the IKKε Kinase-Mediated Type-I IFN Antiviral Response.","date":"2016","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/27622505","citation_count":93,"is_preprint":false},{"pmid":"28679761","id":"PMC_28679761","title":"The Host E3-Ubiquitin Ligase TRIM6 Ubiquitinates the Ebola Virus VP35 Protein and Promotes Virus Replication.","date":"2017","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/28679761","citation_count":86,"is_preprint":false},{"pmid":"22328504","id":"PMC_22328504","title":"TRIM6 interacts with Myc and maintains the pluripotency of mouse embryonic stem cells.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22328504","citation_count":45,"is_preprint":false},{"pmid":"31992359","id":"PMC_31992359","title":"TRIM6 promotes colorectal cancer cells proliferation and response to thiostrepton by TIS21/FoxM1.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31992359","citation_count":35,"is_preprint":false},{"pmid":"31694946","id":"PMC_31694946","title":"VAMP8 Contributes to the TRIM6-Mediated Type I Interferon Antiviral Response during West Nile Virus Infection.","date":"2020","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/31694946","citation_count":34,"is_preprint":false},{"pmid":"36654781","id":"PMC_36654781","title":"TRIM6 Reduces Ferroptosis and Chemosensitivity by Targeting SLC1A5 in Lung Cancer.","date":"2023","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/36654781","citation_count":25,"is_preprint":false},{"pmid":"31171760","id":"PMC_31171760","title":"E3-ubiquitin ligase TRIM6 aggravates myocardial ischemia/reperfusion injury via promoting STAT1-dependent cardiomyocyte apoptosis.","date":"2019","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/31171760","citation_count":22,"is_preprint":false},{"pmid":"33634104","id":"PMC_33634104","title":"The Expression of TRIM6 Activates the mTORC1 Pathway by Regulating the Ubiquitination of TSC1-TSC2 to Promote Renal Fibrosis.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33634104","citation_count":16,"is_preprint":false},{"pmid":"38420829","id":"PMC_38420829","title":"TRIM6 Promotes ROS-Mediated Inflammasome Activation and Pyroptosis in Renal Tubular Epithelial Cells via Ubiquitination and Degradation of GPX3 Protein.","date":"2024","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/38420829","citation_count":12,"is_preprint":false},{"pmid":"38515377","id":"PMC_38515377","title":"TRIM6 facilitates SARS-CoV-2 proliferation by catalyzing the K29-typed ubiquitination of NP to enhance the ability to bind viral genomes.","date":"2024","source":"Journal of medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/38515377","citation_count":12,"is_preprint":false},{"pmid":"40817248","id":"PMC_40817248","title":"TRIM6 ablation reverses ICB resistance in MSS gastric cancer by unleashing cGAS-STING-dependent antitumor immunity.","date":"2025","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/40817248","citation_count":5,"is_preprint":false},{"pmid":"38759605","id":"PMC_38759605","title":"TRIM6 promotes glioma malignant progression by enhancing FOXO3A ubiquitination and degradation.","date":"2024","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38759605","citation_count":4,"is_preprint":false},{"pmid":"37236551","id":"PMC_37236551","title":"TRIM6 silencing for inhibiting growth and angiogenesis of gliomas by regulating VEGFA.","date":"2023","source":"Journal of chemical neuroanatomy","url":"https://pubmed.ncbi.nlm.nih.gov/37236551","citation_count":3,"is_preprint":false},{"pmid":"39892584","id":"PMC_39892584","title":"LINC02282 promotes DNA methylation of TRIM6 by recruiting DNMTs to inhibit the progression of Parkinson's disease.","date":"2025","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/39892584","citation_count":3,"is_preprint":false},{"pmid":"40089754","id":"PMC_40089754","title":"Altered LY6E and TRIM6 expression in PBMCs correlated with HBsAg clearance and response to Peg-IFN-α treatment in HBeAg-negative chronic hepatitis B patients.","date":"2025","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/40089754","citation_count":2,"is_preprint":false},{"pmid":"40248748","id":"PMC_40248748","title":"TRIM6 Promotes Cell Cycle and Growth by Modulating p53 Signaling Pathway in Lung Adenocarcinoma.","date":"2025","source":"International journal of general medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40248748","citation_count":1,"is_preprint":false},{"pmid":"40348925","id":"PMC_40348925","title":"STAT3-mediated upregulation of TRIM6 promotes hepatocellular carcinoma invasion through the DDX58-Snail1 axis.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40348925","citation_count":0,"is_preprint":false},{"pmid":"21906469","id":"PMC_21906469","title":"[Construction of Trim6 eukaryotic expression vector and its expression in HEK293 cells].","date":"2011","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21906469","citation_count":0,"is_preprint":false},{"pmid":"42086946","id":"PMC_42086946","title":"Early-Life DNA methylation at TRIM6 and TTC23 promoters associates with respiratory infections at one year.","date":"2026","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/42086946","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13528,"output_tokens":4176,"usd":0.051612,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12131,"output_tokens":4721,"usd":0.08934,"stage2_stop_reason":"end_turn"},"total_usd":0.140952,"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\": 2014,\n      \"finding\": \"TRIM6 cooperates with the E2-ubiquitin conjugase UbE2K to synthesize unanchored K48-linked polyubiquitin chains (not covalently attached to any protein substrate), which activate IKKε kinase for subsequent STAT1 phosphorylation and induction of IFN-I-stimulated genes. TRIM6 directly interacts with IKKε.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitin chain synthesis assays, siRNA knockdown with downstream signaling readouts (STAT1 phosphorylation, ISG induction)\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical reconstitution of unanchored polyubiquitin chain synthesis, Co-IP of TRIM6–IKKε interaction, functional epistasis with E2 (UbE2K), multiple orthogonal methods in one study\",\n      \"pmids\": [\"24882218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Nipah virus matrix protein (NiV-M) interacts with TRIM6 and promotes its proteasomal degradation, thereby reducing unanchored K48-linked polyubiquitin chains associated with IKKε, impairing IKKε oligomerization and autophosphorylation, and reducing IFN-mediated antiviral responses. This degradation of TRIM6 by NiV-M requires lysine K258 in the bipartite nuclear localization signal of NiV-M.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, measurement of IKKε oligomerization and autophosphorylation, live NiV infection with recombinant NiV lacking M protein as control\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, confocal co-localization, biochemical pathway readouts (IKKε oligomerization/phosphorylation), genetic control (recombinant NiV ΔM), multiple orthogonal methods\",\n      \"pmids\": [\"27622505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIM6 physically interacts with Ebola virus VP35 protein and ubiquitinates it on lysine K309 (located in its IFN antagonist domain). VP35 noncovalently associates with TRIM6-generated unanchored polyubiquitin chains and inhibits TRIM6-mediated IFN-I induction. Separately, TRIM6 enhances EBOV polymerase activity, and TRIM6-knockout cells show reduced infectious EBOV replication.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, minigenome (polymerase activity) assay, TRIM6 knockout cells infected with infectious EBOV\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — MS-confirmed ubiquitination site (K309), Co-IP interaction, functional minigenome assay, TRIM6-KO infectious virus replication assay; multiple orthogonal methods\",\n      \"pmids\": [\"28679761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM6 interacts with the Myc proto-oncogene product in embryonic stem cells and attenuates Myc transcriptional activity. TRIM6 knockdown in ES cells enhances Myc transcriptional activity, represses NANOG expression, and promotes ES cell differentiation, indicating TRIM6 maintains ES cell pluripotency by regulating Myc-mediated transcription.\",\n      \"method\": \"Co-immunoprecipitation (TRIM6–Myc interaction), siRNA knockdown in ES cells, transcriptional reporter assays, expression analysis of pluripotency markers (NANOG)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP interaction, functional KD with defined pluripotency phenotype and gene expression readouts, single lab\",\n      \"pmids\": [\"22328504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM6 ubiquitinates the anti-proliferative protein TIS21 on Lys5, promoting its degradation; this requires TRIM6 E3 catalytic activity (abolished by C15A mutant). TRIM6-mediated TIS21 degradation leads to elevated FoxM1, phospho-FoxM1, Cyclin B1, and c-Myc levels, promoting colorectal cancer cell proliferation and G2/M cell cycle progression.\",\n      \"method\": \"Co-immunoprecipitation/proteomics to identify TIS21 as TRIM6 binding partner, ubiquitination assay with catalytic mutant (C15A), rescue experiments with TIS21 overexpression, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP-based interaction, ubiquitination assay with catalytic mutant, rescue experiments, single lab\",\n      \"pmids\": [\"31992359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM6 contributes to an antiviral response against West Nile Virus through VAMP8. In TRIM6-KO cells, WNV replication is increased and IFN-I induction/signaling are impaired. VAMP8 knockdown reduces JAK1 and STAT1 phosphorylation and impairs ISG induction; VAMP8-mediated STAT1 phosphorylation requires TRIM6, placing VAMP8 downstream of TRIM6 in the IFN-I signaling axis.\",\n      \"method\": \"TRIM6 knockout cells (A549), next-generation sequencing to identify VAMP8, siRNA knockdown of VAMP8, measurement of JAK1/STAT1 phosphorylation and ISG induction, WNV replication assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TRIM6-KO with defined signaling phenotype, VAMP8 KD epistasis, multiple functional readouts, single lab\",\n      \"pmids\": [\"31694946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM6 promotes IKKε-dependent STAT1 activation in cardiomyocytes, leading to apoptosis and myocardial ischemia/reperfusion injury. A TRIM6 mutant lacking the ability to ubiquitinate IKKε fails to promote STAT1 activation or cardiomyocyte apoptosis. Pharmacological inhibition of IKKε or STAT1 abolishes TRIM6-driven injury.\",\n      \"method\": \"Mouse MI/R injury model, TRIM6 overexpression/depletion, E3 catalytic mutant (unable to ubiquitinate IKKε), pharmacological inhibition (CAY10576 for IKKε, fludarabine for STAT1), apoptosis and infarct size measurements\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with gain/loss-of-function, catalytic mutant controls, pharmacological epistasis, single lab\",\n      \"pmids\": [\"31171760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM6 promotes ubiquitination of TSC1 and TSC2 (negative regulators of mTORC1), activating the mTORC1 pathway, and thereby driving renal fibrosis-associated processes including EMT and ER stress. TRIM6 expression in renal fibrosis is upregulated by Angiotensin II-induced NF-κB (p50/p65) nuclear translocation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays (TSC1/2), siRNA knockdown in HK2 cells, in vivo 5/6-nephrectomized rat model, Western blot for mTORC1 pathway activity\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and ubiquitination assays, in vivo model, multiple readouts, single lab\",\n      \"pmids\": [\"33634104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM6 directly interacts with GPX3 via its RING and B-box-CCD domains (inferred from NP binding domain mapping; for GPX3, interaction confirmed by Co-IP) and promotes K48-linked ubiquitination and proteasomal degradation of GPX3 protein without affecting its mRNA, leading to increased mitochondrial ROS, NLRP3 inflammasome activation, and pyroptosis in renal tubular epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation (TRIM6–GPX3), ubiquitination assay, TRIM6 overexpression/knockdown, ROS measurements by flow cytometry, pyroptosis markers (caspase-1, GSDMD-N, IL-1β)\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP interaction, ubiquitination assay, functional gain/loss-of-function with multiple orthogonal cellular readouts, single lab\",\n      \"pmids\": [\"38420829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM6 binds the nucleocapsid protein (NP) of SARS-CoV-2 via its RING and B-box-CCD domains (interacting with NP's CTD) and catalyzes K29-type polyubiquitination of NP at K102, K347, and K361 residues. This ubiquitination increases NP binding to viral genomic RNA and promotes SARS-CoV-2 replication; TRIM6 knockout significantly inhibits viral proliferation. TRIM6 also ubiquitinates SARS-CoV NP, suggesting a conserved mechanism.\",\n      \"method\": \"Co-immunoprecipitation with domain mapping, mass spectrometry-identified ubiquitination sites, trVLP reverse genetic model, TRIM6 knockout, RNA-binding assays\",\n      \"journal\": \"Journal of medical virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — domain-resolved Co-IP, MS-identified ubiquitination sites with site-directed mutation, functional viral replication assay in KO cells, multiple orthogonal methods in one study\",\n      \"pmids\": [\"38515377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM6 catalyzes K27-linked polyubiquitination of cGAS, targeting it for proteasomal degradation and suppressing the cGAS-STING innate immune pathway. TRIM6 ablation restores cGAS-STING activity, increases CD8+ T lymphocyte infiltration, and synergizes with anti-PD-L1 therapy in microsatellite-stable gastric tumors.\",\n      \"method\": \"TRIM6-knockout murine models, ubiquitination assays (K27-linked), immunoblotting for cGAS-STING pathway components, flow cytometry for TILs, RNA sequencing\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model, ubiquitination assay, multiple pathway and cellular readouts, single lab\",\n      \"pmids\": [\"40817248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM6 interacts with FOXO3A and promotes its ubiquitination and proteasomal degradation, suppressing FOXO3A protein levels and thereby driving glioma cell proliferation, invasion, and migration. Rescue of FOXO3A expression reverses TRIM6-driven malignant phenotypes.\",\n      \"method\": \"Co-immunoprecipitation (TRIM6–FOXO3A), Western blot for FOXO3A protein stability, loss/gain-of-function (proliferation, invasion, migration assays), rescue experiments, xenograft model\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP interaction, functional rescue experiments, in vivo xenograft, single lab\",\n      \"pmids\": [\"38759605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM6 directly interacts with and promotes ubiquitination/degradation of SLC1A5 (a glutamine transporter), inhibiting glutamine import, glutaminolysis, and lipid peroxidation, thereby suppressing ferroptosis in lung cancer cells and reducing chemosensitivity to cisplatin and paclitaxel.\",\n      \"method\": \"Co-immunoprecipitation (TRIM6–SLC1A5), ubiquitination assay, overexpression/knockdown with ferroptosis markers (lipid peroxidation, iron levels), in vivo xenograft models\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP interaction, ubiquitination assay, functional in vitro and in vivo readouts, single lab\",\n      \"pmids\": [\"36654781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STAT3 directly binds the TRIM6 promoter and transcriptionally upregulates TRIM6 in hepatocellular carcinoma. TRIM6 in turn interacts with and ubiquitinates DDX58 (RIG-I), promoting its proteasomal degradation. DDX58 degradation relieves its inhibitory effect on Snail1 expression, facilitating EMT and HCC invasion, defining a STAT3–TRIM6–DDX58–Snail1 axis.\",\n      \"method\": \"Chromatin immunoprecipitation (STAT3 binding to TRIM6 promoter), Co-immunoprecipitation (TRIM6–DDX58), ubiquitination assay, loss/gain-of-function invasion assays, Western blot for pathway components\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for transcriptional regulation, Co-IP and ubiquitination assay for TRIM6–DDX58 axis, functional invasion readout, single lab\",\n      \"pmids\": [\"40348925\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM6 is a RING-domain E3 ubiquitin ligase that cooperates with the E2 enzyme UbE2K to synthesize unanchored K48-linked polyubiquitin chains that activate IKKε, driving STAT1 phosphorylation and type I interferon (IFN-I) antiviral responses; beyond this canonical role, TRIM6 ubiquitinates diverse substrates including viral proteins (EBOV VP35, SARS-CoV-2 NP), cell-cycle regulators (TIS21, FOXO3A), innate immune sensors (cGAS, DDX58), metabolic transporters (SLC1A5), and tumor suppressors (TSC1/2, GPX3) via distinct ubiquitin linkages (K29, K27, K48), thereby influencing antiviral immunity, mTORC1 signaling, ferroptosis, pyroptosis, and cancer cell proliferation and invasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM6 is a RING-domain E3 ubiquitin ligase that functions at the intersection of antiviral innate immunity, cell-cycle control, and cancer biology by directing substrate-specific and unanchored polyubiquitination [#0, #4]. Its canonical role is in type I interferon (IFN-I) signaling: cooperating with the E2 conjugase UbE2K, TRIM6 synthesizes unanchored K48-linked polyubiquitin chains that activate the kinase IKKε, which it binds directly, driving IKKε oligomerization and autophosphorylation, STAT1 phosphorylation, and induction of interferon-stimulated genes [#0, #1]. This axis is targeted by viruses for evasion—Nipah virus matrix protein triggers proteasomal degradation of TRIM6 to dampen IKKε activity [#1], and Ebola VP35 is ubiquitinated by TRIM6 on K309 while also sequestering its unanchored chains [#2]. TRIM6 additionally restricts or supports diverse viruses through substrate ubiquitination, including K29-linked ubiquitination of SARS-CoV-2 nucleocapsid protein to enhance viral RNA binding and replication [#9] and K27-linked ubiquitination of cGAS to suppress the cGAS-STING pathway [#10]. Beyond immunity, TRIM6 acts as a pro-proliferative and pro-tumorigenic factor by ubiquitinating and degrading antiproliferative and tumor-suppressor substrates—TIS21 in colorectal cancer [#4], FOXO3A in glioma [#11], TSC1/TSC2 to activate mTORC1 in renal fibrosis [#7], SLC1A5 to suppress ferroptosis in lung cancer [#12], and DDX58/RIG-I to promote EMT in hepatocellular carcinoma [#13]. In embryonic stem cells, TRIM6 restrains Myc transcriptional activity to maintain pluripotency [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the first functional role of TRIM6 in a defined cellular context—restraining Myc-driven transcription to preserve stem cell identity—before its enzymatic mechanism was known.\",\n      \"evidence\": \"Co-IP of TRIM6–Myc, siRNA knockdown in ES cells with pluripotency marker and reporter readouts\",\n      \"pmids\": [\"22328504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the Myc regulation depends on TRIM6 E3 catalytic activity was not resolved\", \"No ubiquitination linkage or substrate site defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the core enzymatic mechanism: TRIM6 partners with UbE2K to build unanchored K48-linked polyubiquitin chains that activate IKKε for STAT1-dependent IFN-I responses, distinguishing TRIM6 as a producer of non-substrate-attached chains.\",\n      \"evidence\": \"Co-IP, in vitro unanchored chain synthesis assays, siRNA knockdown with STAT1 phosphorylation and ISG readouts\",\n      \"pmids\": [\"24882218\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how unanchored chains activate IKKε not resolved\", \"Whether TRIM6 also generates substrate-conjugated chains in this pathway unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed the TRIM6–IKKε axis is a viral evasion target, with Nipah virus M protein degrading TRIM6 to impair IKKε oligomerization and IFN signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, confocal microscopy, IKKε oligomerization/autophosphorylation assays, recombinant NiV ΔM infection\",\n      \"pmids\": [\"27622505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating NiV-M-induced TRIM6 degradation not identified\", \"Mechanism linking TRIM6 loss to reduced unanchored chains not fully detailed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated TRIM6 directly engages and ubiquitinates a viral IFN antagonist (EBOV VP35 at K309), while VP35 reciprocally counteracts TRIM6, revealing a bidirectional host–virus conflict at the ubiquitin level.\",\n      \"evidence\": \"MS-mapped ubiquitination site, Co-IP, minigenome polymerase assay, infectious EBOV in TRIM6-KO cells\",\n      \"pmids\": [\"28679761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin linkage type on VP35 not specified\", \"How TRIM6 enhances EBOV polymerase activity mechanistically unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the TRIM6–IKKε–STAT1 axis to a pathological in vivo setting, showing catalytic-dependent STAT1 activation drives cardiomyocyte apoptosis and ischemia/reperfusion injury.\",\n      \"evidence\": \"Mouse MI/R model, gain/loss-of-function, E3 catalytic mutant, pharmacological IKKε/STAT1 inhibition\",\n      \"pmids\": [\"31171760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signals inducing TRIM6 in cardiomyocytes not defined\", \"Single-lab in vivo finding\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified VAMP8 as a downstream effector of TRIM6 in the IFN-I signaling axis and showed TRIM6 restricts West Nile Virus replication.\",\n      \"evidence\": \"TRIM6-KO A549 cells, NGS to identify VAMP8, VAMP8 knockdown epistasis, JAK1/STAT1 phosphorylation and ISG readouts, WNV replication assays\",\n      \"pmids\": [\"31694946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether VAMP8 is a direct TRIM6 ubiquitination substrate not established\", \"Molecular connection between TRIM6 and VAMP8 not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed TRIM6 as a pro-proliferative E3 in cancer by catalytically degrading the antiproliferative protein TIS21 (K5), linking TRIM6 to FoxM1/Cyclin B1/c-Myc-driven G2/M progression.\",\n      \"evidence\": \"Co-IP/proteomics, ubiquitination assay with C15A catalytic mutant, TIS21 rescue, in vitro/in vivo proliferation assays\",\n      \"pmids\": [\"31992359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage type on TIS21 not specified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected TRIM6 to mTORC1 signaling and renal fibrosis through ubiquitination of the TSC1/TSC2 tumor-suppressor complex, with TRIM6 itself induced by Angiotensin II–driven NF-κB.\",\n      \"evidence\": \"Co-IP, TSC1/2 ubiquitination assays, siRNA in HK2 cells, 5/6-nephrectomy rat model, mTORC1 pathway immunoblots\",\n      \"pmids\": [\"33634104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage and modification sites on TSC1/2 not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed TRIM6 suppresses ferroptosis by degrading the glutamine transporter SLC1A5, reducing glutaminolysis and lipid peroxidation, and lowering chemosensitivity in lung cancer.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, gain/loss-of-function with ferroptosis markers, xenograft models\",\n      \"pmids\": [\"36654781\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage type and SLC1A5 modification sites not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated TRIM6 degrades FOXO3A to drive glioma malignancy, broadening its tumor-suppressor-degrading repertoire.\",\n      \"evidence\": \"Co-IP, FOXO3A stability immunoblots, loss/gain-of-function phenotypic assays, rescue, xenograft\",\n      \"pmids\": [\"38759605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage and FOXO3A sites not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved a domain-specific, linkage-specific viral mechanism—TRIM6 catalyzes K29-linked ubiquitination of SARS-CoV-2 NP (K102/K347/K361) via its RING and B-box-CCD domains to enhance NP–RNA binding and viral replication.\",\n      \"evidence\": \"Domain-mapped Co-IP, MS-identified sites with mutation, trVLP reverse genetics, TRIM6-KO replication and RNA-binding assays\",\n      \"pmids\": [\"38515377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether K29 chains alter NP function in authentic SARS-CoV-2 infection not fully tested\", \"Generalizability across coronaviruses beyond SARS-CoV inferred\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed TRIM6 degrades GPX3 via K48-linked ubiquitination, linking it to mitochondrial ROS, NLRP3 inflammasome activation, and pyroptosis in renal tubular cells.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, gain/loss-of-function, ROS flow cytometry, pyroptosis marker readouts\",\n      \"pmids\": [\"38420829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GPX3 ubiquitination sites not mapped\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a STAT3→TRIM6→DDX58→Snail1 axis in which TRIM6 is transcriptionally induced by STAT3 and degrades DDX58/RIG-I to promote EMT and HCC invasion.\",\n      \"evidence\": \"ChIP (STAT3–TRIM6 promoter), Co-IP (TRIM6–DDX58), ubiquitination assay, invasion assays, pathway immunoblots\",\n      \"pmids\": [\"40348925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DDX58 ubiquitin linkage and sites not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed TRIM6 catalyzes K27-linked ubiquitination of cGAS to suppress cGAS-STING immunity, and that its ablation enhances anti-tumor immunity and anti-PD-L1 efficacy in MSS gastric cancer.\",\n      \"evidence\": \"TRIM6-KO murine models, K27-linkage ubiquitination assays, cGAS-STING immunoblots, TIL flow cytometry, RNA-seq\",\n      \"pmids\": [\"40817248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"cGAS modification sites not mapped\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRIM6 selects among distinct ubiquitin linkage types (K27, K29, K48, unanchored) for different substrates, and what determines context-specific antiviral-restrictive versus pro-viral and pro-tumorigenic outcomes, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model explaining linkage specificity\", \"No unified regulatory logic linking substrate choice to cellular context\", \"Most non-immune substrate findings rest on single-lab studies\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2, 4, 7, 8, 9, 10, 11, 12, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 4, 8, 9, 10, 11, 12, 13]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 5, 9, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 4, 7, 8, 11, 12, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 11, 12, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IKBKE\", \"UBE2K\", \"MYC\", \"VP35\", \"TSC1\", \"TSC2\", \"SLC1A5\", \"DDX58\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}