{"gene":"TRIM26","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2015,"finding":"TRIM26 binds nuclear IRF3 and promotes its K48-linked polyubiquitination and proteasomal degradation, specifically targeting phosphorylated/activated IRF3 (IRF3-5D degraded, IRF3-5A not degraded). TRIM26 undergoes nuclear translocation upon virus infection, which is required for IRF3 degradation. NLS-mutant IRF3 that cannot enter the nucleus is not degraded by TRIM26.","method":"Co-immunoprecipitation, ubiquitination assays, nuclear fractionation, IRF3 mutant analysis, TRIM26 transgenic mice, reporter assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple IRF3 mutants tested, transgenic mouse model, multiple orthogonal methods in one study","pmids":["25763818"],"is_preprint":false},{"year":2015,"finding":"TRIM26 physically associates with TBK1 independent of viral infection, undergoes autoubiquitination upon RNA virus infection, and the ubiquitinated TRIM26 bridges TBK1-NEMO interaction by associating with NEMO, thereby recruiting TBK1 to the VISA signalsome and activating TBK1 to promote IRF3 and NF-κB activation.","method":"Co-immunoprecipitation, knockdown experiments, ubiquitination assays, reporter assays","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional knockdown, single lab with two orthogonal methods","pmids":["26611359"],"is_preprint":false},{"year":2016,"finding":"TRIM26 polyubiquitylates the DNA glycosylase NEIL1 in vitro, targeting the same C-terminal lysine residues as Mule. siRNA knockdown of TRIM26 stabilizes NEIL1 protein levels; stabilization of NEIL1 following TRIM26 knockdown confers cellular resistance to ionising radiation.","method":"In vitro ubiquitylation assay with purified proteins, siRNA knockdown, protein stability assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of ubiquitylation activity, siRNA functional validation, single lab with multiple orthogonal methods","pmids":["27924031"],"is_preprint":false},{"year":2018,"finding":"TRIM26 ubiquitylates the DNA glycosylase NTH1 predominantly on lysine 67 in vitro. A K67R ubiquitylation-deficient NTH1 mutant is more stable in cells. TRIM26 siRNA knockdown causes exacerbated NTH1 accumulation on chromatin and accelerated DNA damage repair kinetics under oxidative stress.","method":"In vitro ubiquitylation assay, site-directed mutagenesis (K67R NTH1 mutant), siRNA knockdown, chromatin fractionation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined lysine site identified by mutagenesis, functional cellular validation, single lab","pmids":["29610152"],"is_preprint":false},{"year":2018,"finding":"TGF-β stimulates transcription of TRIM26, which ubiquitylates TAF7 (a TFIID subunit) and targets it for proteasomal degradation, thereby mediating TGF-β-induced proliferative arrest. MYC inhibits TRIM26 induction by TGF-β, enabling recovery from growth arrest.","method":"Transcriptional induction assay, co-immunoprecipitation, ubiquitination assays, proliferation assays in cultured mouse mammary epithelial cells","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional phenotype, single lab with two orthogonal methods","pmids":["29203640"],"is_preprint":false},{"year":2021,"finding":"TRIM26 catalyzes K11-linked polyubiquitination of TAB1 at Lys294, Lys319, and Lys335, enhancing TAK1 activation and downstream NF-κB and MAPK signaling. Trim26-knockout mice show impaired TAK1 activation and reduced proinflammatory cytokine production upon LPS, TNF-α, and IL-1β stimulation, and are protected from LPS-induced septic shock.","method":"Trim26 knockout and transgenic mice, ubiquitination assays with specific lysine mutants, kinase activation assays, LPS-induced septic shock model","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout and transgenic mice, specific ubiquitination site mapping, multiple stimulation conditions, in vivo model","pmids":["34017102"],"is_preprint":false},{"year":2021,"finding":"TRIM26 acts as E3 ubiquitin ligase for ZEB1, promoting its ubiquitination and proteasomal degradation. USP39 deubiquitinase directly interacts with TRIM26 and counteracts TRIM26-mediated ZEB1 ubiquitination in an antagonistic (not competitive) pattern, balancing ZEB1 stability to regulate HCC cell proliferation and migration.","method":"Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assays, loss-of-function and gain-of-function experiments","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ubiquitination assay, single lab with two orthogonal methods","pmids":["33649471"],"is_preprint":false},{"year":2021,"finding":"TRIM26 physically interacts with SLC7A11 and mediates its ubiquitination, leading to SLC7A11 degradation. TRIM26 overexpression induces ferroptosis in hepatic stellate cells and mitigates CCl4-induced liver fibrosis in mice.","method":"Co-immunoprecipitation, ubiquitination assays, in vitro cell assays, in vivo CCl4 mouse model","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay, in vivo validation, single lab","pmids":["33869196"],"is_preprint":false},{"year":2021,"finding":"TRIM26 interacts with the HCV NS5B protein and mediates K27-linked ubiquitination of NS5B at residue K51, promoting NS5B-NS5A interaction and thereby supporting HCV genome replication. Mouse TRIM26 fails to support HCV replication due to a unique six-amino acid insert that prevents interaction with NS5B.","method":"Genome-wide CRISPR-Cas9 screen, co-immunoprecipitation, ubiquitination assays, species-specific mutant analysis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — CRISPR genome-wide screen plus mechanistic follow-up with Co-IP, specific ubiquitination site mapping, and cross-species mutagenesis","pmids":["33523994"],"is_preprint":false},{"year":2021,"finding":"TRIM26 stabilizes SOX2 protein in glioblastoma stem cells via its C-terminal PRYSPRY domain, independently of its RING E3 ligase domain, by directly inhibiting the interaction of SOX2 with the E3 ligase WWP2. TRIM26 depletion decreases SOX2 protein levels, increases SOX2 polyubiquitination, disrupts SOX2 gene network, and inhibits self-renewal and in vivo tumorigenicity.","method":"Proteomic affinity purification, co-immunoprecipitation, domain deletion mutants, patient-derived glioblastoma stem cell lines, in vivo xenograft","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic identification, reciprocal Co-IP, domain mapping by mutagenesis, in vivo model, multiple GSC lines","pmids":["34732716"],"is_preprint":false},{"year":2022,"finding":"TRIM26 inhibits HBV replication by interacting with the HBx protein via its SPRY domain and promoting K48-linked ubiquitination and proteasomal degradation of HBx. IFN treatment increases TRIM26 expression.","method":"Co-immunoprecipitation, immunofluorescence, ubiquitination assays, siRNA knockdown and overexpression in Huh7 cells","journal":"Alimentary pharmacology & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, domain mapping, single lab with two orthogonal methods","pmids":["35872575"],"is_preprint":false},{"year":2022,"finding":"TRIM26 siRNA depletion reduces resistance of cells to X-ray radiation and hydrogen peroxide; this resistance can be reversed by additional knockdown of neil1 or ogg1 (for X-rays) or neil1 or neil3 (for hydrogen peroxide), placing TRIM26 upstream of multiple DNA glycosylases in BER regulation.","method":"siRNA knockdown epistasis experiments, cell survival assays, DNA repair kinetics","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via siRNA double knockdown, multiple oxidative stress conditions, single lab","pmids":["36232914"],"is_preprint":false},{"year":2022,"finding":"TRIM26 promotes degradation of PRRSV nucleocapsid (N) protein through binding via its C-terminal PRY/SPRY domain. Deletion of either the RING domain or the PRY/SPRY domain abolishes antiviral activity. The antiviral activity is independent of the nuclear localization signal.","method":"Co-immunoprecipitation, domain deletion mutants, overexpression and siRNA knockdown in porcine alveolar macrophages","journal":"Virus research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping by deletion mutants, functional rescue experiment, single lab","pmids":["35077707"],"is_preprint":false},{"year":2023,"finding":"TRIM26 directly interacts with GPX4 via its RING domain and catalyzes K63-linked polyubiquitination of GPX4 at K107 and K117, switching GPX4 ubiquitination from K48 to K63 linkage and thus enhancing GPX4 protein stability and ferroptosis resistance. PLK1-mediated S127 phosphorylation of TRIM26 enhances TRIM26-GPX4 interaction; inhibition of this phosphorylation reduces GPX4 K63-ubiquitination and protein levels.","method":"Co-immunoprecipitation, domain deletion mutants, site-directed mutagenesis of GPX4 ubiquitination sites, phosphorylation inhibition experiments, in vitro and in vivo tumor models","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — specific ubiquitination sites identified by mutagenesis, linkage type determined, kinase modification mapped, in vivo validation, single lab with multiple orthogonal methods","pmids":["37872147"],"is_preprint":false},{"year":2023,"finding":"TRIM26 interacts with RACK1 and promotes its ubiquitination and proteasomal degradation, thereby inactivating MEK/ERK signaling. Overexpression of RACK1 reverses the inhibitory effect of TRIM26 on p-MEK1/2 and p-ERK1/2 in osteosarcoma cells.","method":"Co-immunoprecipitation, ubiquitination assays, gain- and loss-of-function experiments, Western blot for pathway activation","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, epistasis rescue experiment, single lab","pmids":["37591850"],"is_preprint":false},{"year":2023,"finding":"TRIM26 binds PBX1 and mediates its K48-linked polyubiquitination and proteasomal degradation. The C-terminal RING domain of TRIM26 is required for this activity; RING-deleted TRIM26 loses function toward PBX1.","method":"Affinity purification-coupled mass spectrometry, co-immunoprecipitation, ubiquitination assays, RING domain deletion mutant","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification, Co-IP validation, domain mapping, ubiquitination assay, single lab","pmids":["37324936"],"is_preprint":false},{"year":2023,"finding":"TRIM26 directly interacts with HBV core protein (HBc) through its SPRY domain. Unexpectedly, TRIM26 inhibits HBc ubiquitination rather than promoting it; TRIM26 knockdown leads to proteasome-dependent HBc degradation. A RING domain-deleted dominant-negative TRIM26 mutant (TRIM26ΔR) promotes HBc degradation, suggesting HBV exploits TRIM26 to protect HBc from proteasomal clearance.","method":"Co-immunoprecipitation, siRNA knockdown, domain deletion mutants, proteasome inhibitor rescue experiments","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, domain mapping, proteasome inhibitor validation, single lab; result contradicts Luo 2022 for HBx but this is for HBc","pmids":["37604854"],"is_preprint":false},{"year":2023,"finding":"USP39 inhibits TRIM26 pre-mRNA splicing and maturation, reducing TRIM26 expression. TRIM26, in turn, ubiquitinates β-catenin to promote its degradation. Thus USP39 promotes HCC progression both by direct deubiquitination of β-catenin and by suppressing TRIM26-mediated β-catenin ubiquitination.","method":"Co-immunoprecipitation, ubiquitination assays, mRNA splicing analysis, functional knockdown/overexpression","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, splicing analysis, single lab","pmids":["36707504"],"is_preprint":false},{"year":2024,"finding":"TRIM26 promotes autophagic degradation of MAVS through NDP52-mediated selective autophagy. TRIM26 physically associates with MAVS independent of viral infection and reduces its expression; NDP52 interacts with both TRIM26 and MAVS, and TRIM26-induced MAVS degradation is almost entirely blocked in NDP52-knockdown cells.","method":"Co-immunoprecipitation, siRNA knockdown, autophagy inhibition assays, PRV infection model","journal":"Veterinary research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying ternary complex, epistatic knockdown demonstrating NDP52 requirement, single lab","pmids":["38965634"],"is_preprint":false},{"year":2024,"finding":"TRIM26 interacts with HSP-90β and promotes its K48-linked polyubiquitination and proteasomal degradation. This leads to reduced EphA2 protein integrity, thereby suppressing EBV infection of nasopharyngeal epithelial cells.","method":"Co-immunoprecipitation, ubiquitination assays, EBV infection assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional viral infection readout, single lab","pmids":["38038978"],"is_preprint":false},{"year":2024,"finding":"TRIM26 interacts with ETK (a non-receptor tyrosine kinase) via co-immunoprecipitation and facilitates its ubiquitination and proteasomal degradation, resulting in deactivation of AKT/mTOR signaling in ccRCC. ETK overexpression counteracts the inhibitory effects of TRIM26.","method":"Co-immunoprecipitation, cycloheximide chase, in vivo ubiquitination assays, RNA sequencing, Western blot, xenograft","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, CHX chase, epistasis rescue, single lab","pmids":["38773612"],"is_preprint":false},{"year":2024,"finding":"TRIM26 deficiency in macrophages promotes liver regeneration by inducing macrophage polarization toward M1 phenotype, which secretes Wnts (including Wnt2) to stimulate hepatocyte proliferation via Wnt/β-catenin signaling. In hepatocytes, TRIM26 knockdown directly reduces β-catenin ubiquitination and degradation. Bone marrow transplantation confirmed myeloid-cell TRIM26 is critical for this effect.","method":"Trim26 knockout mice, AAV-mediated overexpression, partial hepatectomy and CCl4 models, bone marrow transplantation, pharmacological inhibition of Wnt/β-catenin (ICG-001), macrophage depletion (clodronate liposomes)","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo models, bone marrow transplantation, pharmacological epistasis, AAV rescue, multiple orthogonal methods","pmids":["38926362"],"is_preprint":false},{"year":2024,"finding":"TRIM26 interacts with TRAF2 through its PRY domain and inhibits K63-linked ubiquitination of TRAF2, thereby attenuating NF-κB pathway activation and suppressing M1-like tumor-associated macrophage polarization. TRIM26 knockout in mice reduced colorectal cancer liver metastasis.","method":"Co-immunoprecipitation, luciferase reporter assays, Trim26 knockout mice, CRLM mouse models, flow cytometry","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, reporter assay, in vivo knockout model, single lab","pmids":["40490503"],"is_preprint":false},{"year":2024,"finding":"P2X7R promotes HuR nucleocytoplasmic shuttling in ageing hearts, which increases mRNA stability of TRIM26 and thus TRIM26 protein expression. TRIM26 subsequently mediates NR4A1 ubiquitination and proteasomal degradation, suppressing mitophagy and accelerating cardiac ageing.","method":"P2X7R knockout mice, AAV9 cardiac-specific overexpression, transcriptome sequencing, Western blot, NR4A1 ubiquitination assays","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse models and AAV rescue, ubiquitination assay, transcriptomics, single lab","pmids":["41746668"],"is_preprint":false},{"year":2024,"finding":"TRIM26 restricts inflammatory neutrophil infiltration and proinflammatory cytokine/chemokine (CXCL1, CXCL2) production during Candida infection, protecting mice from fungemia-related kidney damage. Trim26-deficient mice show higher parasite burden, more neutrophil infiltration, and higher proinflammatory cytokines.","method":"Trim26-deficient mouse model, Candida albicans infection, flow cytometry, cytokine measurement","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse model with in vivo infection phenotype, single lab","pmids":["38166150"],"is_preprint":false},{"year":2025,"finding":"TRIM26 interacts with PKM and promotes its ubiquitination, as demonstrated by co-IP and IP-MS in human periodontal ligament stem cells. PKM overexpression rescues TRIM26-mediated suppression of osteogenic differentiation.","method":"Co-immunoprecipitation, immunoprecipitation-mass spectrometry, ubiquitination assays, epistasis rescue experiments","journal":"Free radical biology & medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and IP-MS in a single study, limited mechanistic follow-up","pmids":["40449810"],"is_preprint":false},{"year":2026,"finding":"TRIM9 and TRIM26 are selectively enriched in the proximity proteome of ALS-linked UBQLN2P497H mutant (not wild-type). Individual knockdown of TRIM26 (or TRIM9) increases the abundance of a C-terminal UBQLN2 fragment, establishing UBQLN2P497H as a substrate for TRIM26-mediated ubiquitination and proteasomal degradation.","method":"APEX2 proximity labeling with LC-MS/MS, co-immunoprecipitation, siRNA knockdown, proteasomal inhibitor treatment, fractionation analysis","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity proteomics plus Co-IP validation and siRNA epistasis, single lab","pmids":["41582437"],"is_preprint":false},{"year":2026,"finding":"TRIM26 interacts with NKRF and promotes its K48-linked ubiquitination at Lys411, leading to proteasomal degradation of NKRF. This sustains SNRPD2 expression, enhancing stress granule assembly and contributing to Osimertinib resistance in lung adenocarcinoma. TRIM26 depletion restored NKRF stability and re-sensitized resistant tumors.","method":"Co-immunoprecipitation, ubiquitination assays with specific lysine mutant, TRIM26 genetic depletion, xenograft models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, specific ubiquitination site by mutagenesis, in vivo validation, single lab","pmids":["42026030"],"is_preprint":false},{"year":2026,"finding":"TRIM26 interacts with EZH2 and inhibits TRAF6-mediated K48-linked ubiquitination and degradation of EZH2, thereby maintaining EZH2 stability. EZH2 suppresses STAT1 transcriptional activity by catalyzing H3K27me3 modification on the STAT1 gene promoter. TRIM26 deficiency leads to EZH2 degradation, STAT1 upregulation, exacerbated M1 macrophage polarization, and liver fibrosis.","method":"Co-immunoprecipitation, ubiquitination assays, Trim26 knockout mice, AAV-mediated restoration, CCl4/BDL fibrosis models, chromatin modification analysis","journal":"Hepatology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay, in vivo knockout and AAV rescue, single lab","pmids":["41627629"],"is_preprint":false},{"year":2026,"finding":"TRIM26 directly binds CBX6 and mediates its ubiquitination and degradation. Loss of CBX6 derepresses CNPY2 by eliminating H2AK119ub1 deposition on its promoter, activating NF-κB and IL-8 secretion that recruits neutrophils and induces NET formation in bladder cancer.","method":"Co-immunoprecipitation, ubiquitination assays, chromatin modification analysis, functional cancer cell assays, in vivo experiments","journal":"Drug development research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, chromatin modification evidence, in vivo validation, single lab","pmids":["42163428"],"is_preprint":false},{"year":2026,"finding":"TRIM26 directly interacts with and ubiquitinates TRAF6, reducing K48-linked polyubiquitination of TRAF6 to promote cytokine expression during Toxoplasma gondii infection. Trim26-deficient mice show reduced macrophages, inflammatory monocytes, and T cells, along with decreased IL-12, IFN-γ, TNF-α and higher parasite burdens.","method":"Co-immunoprecipitation, ubiquitination assays, Trim26 knockout mice, T. gondii infection model, flow cytometry","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination linkage assay, knockout mouse with in vivo infection, single lab","pmids":["41652078"],"is_preprint":false},{"year":2026,"finding":"E2F3 transcriptionally activates TRIM26 expression. TRIM26 then binds TAB1 via its SPRY domain and promotes K11-linked polyubiquitination via its RING domain, facilitating TAB1-TAK1 complex formation and canonical NF-κB signaling in pancreatic cancer. TRIM26 depletion attenuated E2F3-induced NF-κB activation.","method":"ChIP/reporter assays for E2F3→TRIM26 transcription, co-immunoprecipitation, domain deletion mutants, ubiquitination assays, xenograft models","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping, Co-IP, ubiquitination assay, in vivo validation, single lab","pmids":["42088415"],"is_preprint":false},{"year":2026,"finding":"TRIM26 promotes ubiquitination-mediated degradation of LDHA, as demonstrated by co-immunoprecipitation, cycloheximide chase, and ubiquitination assays. LDHA overexpression reverses TRIM26-mediated suppression of glycolysis and proliferation in endometrial cancer cells.","method":"Co-immunoprecipitation, cycloheximide chase, ubiquitination assays, epistasis rescue, xenograft","journal":"Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, CHX chase, ubiquitination assay, in vivo validation, single lab","pmids":["41691946"],"is_preprint":false},{"year":2026,"finding":"TRIM26 directly interacts with GPX4 and catalyzes its ubiquitination, enhancing GPX4 protein stability in colorectal cancer. TRIM26 knockdown promotes ferroptosis, and GPX4 overexpression rescues the increased ferroptosis caused by sh-TRIM26.","method":"Co-immunoprecipitation, ubiquitination assays, ferroptosis inhibitor/inducer experiments, rescue experiments","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, epistasis rescue, consistent with PMID 37872147, single lab","pmids":["41989643"],"is_preprint":false}],"current_model":"TRIM26 is an E3 ubiquitin ligase (RING-B-box-coiled-coil-PRY/SPRY architecture) that functions as a context-dependent regulator: in innate immunity it undergoes virus-induced nuclear translocation to polyubiquitinate (K48) and degrade activated nuclear IRF3, autoubiquitinates to bridge TBK1-NEMO and activate TBK1, catalyzes K11-linked ubiquitination of TAB1 to promote TAK1/NF-κB activation, and modulates TRAF2 and TRAF6 ubiquitination to tune inflammatory signaling; in DNA repair it controls steady-state levels of BER glycosylases NEIL1, NTH1, and OGG1 via polyubiquitination; in cancer biology it targets diverse substrates (ZEB1, SLC7A11, RACK1, ETK, PBX1, SOX2, TAF7, HBx, GPX4, NKRF, CBX6, EZH2, NR4A1, LDHA, PKM) for ubiquitination—sometimes for K48-linked degradation, sometimes for K63-linked stabilization (GPX4)—with its RING domain mediating catalysis and its SPRY/PRY domain mediating substrate recognition, and its activity further regulated by PLK1-mediated phosphorylation at S127."},"narrative":{"mechanistic_narrative":"TRIM26 is a RING-type E3 ubiquitin ligase that acts as a context-dependent regulator of innate immune signaling, DNA base-excision repair, and the stability of diverse oncogenic and metabolic proteins, with substrate recognition through its C-terminal PRY/SPRY domain and catalysis through its RING domain [PMID:25763818, PMID:37872147, PMID:37324936]. In antiviral signaling, virus infection drives TRIM26 nuclear translocation, where it catalyzes K48-linked polyubiquitination and proteasomal degradation of phosphorylated, activated IRF3 to terminate the response [PMID:25763818]; in parallel it autoubiquitinates and bridges TBK1 to NEMO at the VISA signalsome to activate TBK1 [PMID:26611359], and routes MAVS to NDP52-mediated selective autophagy [PMID:38965634]. TRIM26 tunes NF-κB and MAPK output through linkage-specific ubiquitination of upstream adaptors, catalyzing K11-linked ubiquitination of TAB1 to promote TAK1 activation [PMID:34017102, PMID:42088415] and modulating TRAF2 and TRAF6 ubiquitination, with knockout mice showing altered inflammatory cytokine production and infection outcomes [PMID:40490503, PMID:41652078, PMID:34017102]. In DNA repair, TRIM26 sets steady-state levels of the BER glycosylases NEIL1 and NTH1 by polyubiquitination at defined lysines, and its depletion stabilizes these enzymes and alters cellular resistance to ionizing radiation and oxidative stress [PMID:27924031, PMID:29610152, PMID:36232914]. Across cancer biology TRIM26 targets a broad substrate set, most often for K48-linked degradation (ZEB1, TAF7, RACK1, PBX1, HSP-90β, NKRF, β-catenin, LDHA), but in the case of GPX4 it switches ubiquitination from K48 to K63 linkage to stabilize the protein and confer ferroptosis resistance, an interaction enhanced by PLK1-mediated phosphorylation of TRIM26 at S127 [PMID:33649471, PMID:37591850, PMID:37324936, PMID:38038978, PMID:42026030, PMID:37872147, PMID:41989643]. TRIM26 is itself transcriptionally and post-transcriptionally controlled, being induced by TGF-β and E2F3 and regulated at the splicing and mRNA-stability level by USP39 and HuR [PMID:29203640, PMID:42088415, PMID:36707504, PMID:41746668].","teleology":[{"year":2015,"claim":"Established TRIM26 as a negative-feedback brake on antiviral signaling by defining its first substrate and a spatial mechanism: virus-induced nuclear translocation to degrade activated IRF3.","evidence":"Co-IP, K48 ubiquitination assays, IRF3 phosphomimetic/NLS mutants, and transgenic mice","pmids":["25763818"],"confidence":"High","gaps":["Did not resolve the signal triggering TRIM26 nuclear translocation","Did not address whether TRIM26 also acts at upstream signaling nodes"]},{"year":2015,"claim":"Showed TRIM26 also acts positively in the same pathway by autoubiquitinating and scaffolding the TBK1-NEMO interaction, revealing a dual pro- and anti-viral role.","evidence":"Co-IP, knockdown, autoubiquitination and reporter assays","pmids":["26611359"],"confidence":"Medium","gaps":["The autoubiquitination linkage type and its E2 partner were not defined","How the positive (TBK1 bridging) and negative (IRF3 degradation) roles are temporally coordinated is unresolved"]},{"year":2016,"claim":"Extended TRIM26 function beyond immunity by identifying NEIL1 as an in vitro ubiquitylation substrate, linking TRIM26 to base-excision repair and radiation resistance.","evidence":"In vitro ubiquitylation with purified proteins, siRNA, protein stability and survival assays","pmids":["27924031"],"confidence":"High","gaps":["Ubiquitin linkage type on NEIL1 not specified","In vivo relevance to genome stability not tested"]},{"year":2018,"claim":"Generalized the BER-regulation role by mapping NTH1 ubiquitylation to K67 and showing TRIM26 limits glycosylase accumulation on chromatin during oxidative stress.","evidence":"In vitro ubiquitylation, K67R mutant, siRNA, chromatin fractionation","pmids":["29610152"],"confidence":"High","gaps":["Whether the same regulation operates under physiological damage loads in vivo unclear"]},{"year":2018,"claim":"Placed TRIM26 in a growth-control circuit, showing TGF-β induces TRIM26 to degrade the TFIID subunit TAF7 and arrest proliferation, with MYC antagonizing this induction.","evidence":"Transcriptional induction, Co-IP, ubiquitination and proliferation assays in mammary epithelial cells","pmids":["29203640"],"confidence":"Medium","gaps":["TAF7 ubiquitination linkage and degron not mapped","Single-cell-type system"]},{"year":2021,"claim":"Defined a linkage-specific positive signaling role: K11-linked ubiquitination of TAB1 at three lysines to drive TAK1-dependent NF-κB/MAPK and inflammatory responses in vivo.","evidence":"Knockout/transgenic mice, lysine-mutant ubiquitination assays, septic shock model","pmids":["34017102"],"confidence":"High","gaps":["Did not reconcile the inflammation-promoting role with prior IRF3-degrading and TRAF-modulating roles"]},{"year":2021,"claim":"Opened the cancer-substrate phase by identifying ZEB1, SLC7A11, and SOX2 as TRIM26 targets, and revealing a RING-independent stabilizing mechanism for SOX2.","evidence":"Co-IP, ubiquitination assays, domain mutants, USP39 antagonism, patient-derived GSC lines, xenografts","pmids":["33649471","33869196","34732716"],"confidence":"High","gaps":["Why TRIM26 degrades some substrates but shields SOX2 from a competing ligase is mechanistically unresolved"]},{"year":2021,"claim":"Showed TRIM26 can be exploited by viruses, using K27-linked ubiquitination of HCV NS5B to support viral replication, with species-specific specificity.","evidence":"Genome-wide CRISPR screen, Co-IP, site mapping, cross-species mutagenesis","pmids":["33523994"],"confidence":"High","gaps":["Whether host substrates are co-opted in the same manner not addressed"]},{"year":2022,"claim":"Demonstrated divergent virus outcomes: TRIM26 SPRY-mediated K48 degradation of HBx and PRRSV-N restricts those viruses, expanding the antiviral substrate range.","evidence":"Co-IP, domain deletion mutants, ubiquitination assays in Huh7 and porcine macrophages","pmids":["35872575","35077707"],"confidence":"Medium","gaps":["NLS-independence of PRRSV-N restriction contrasts with NLS-dependent IRF3 degradation, mechanism unexplained"]},{"year":2022,"claim":"Placed TRIM26 genetically upstream of multiple BER glycosylases (NEIL1/3, OGG1) via epistasis, consolidating its role as a master regulator of glycosylase abundance.","evidence":"siRNA double-knockdown epistasis, survival and repair-kinetics assays under oxidative/X-ray stress","pmids":["36232914"],"confidence":"Medium","gaps":["Did not establish direct ubiquitination of OGG1/NEIL3","Indirect (epistatic) genetic evidence only"]},{"year":2023,"claim":"Uncovered a substrate-stabilizing linkage switch: TRIM26 RING-mediated K63 ubiquitination of GPX4 at K107/K117 enhances GPX4 stability and ferroptosis resistance, regulated by PLK1 phosphorylation of TRIM26 at S127.","evidence":"Co-IP, GPX4 site mutants, linkage analysis, phosphorylation inhibition, in vivo tumor models","pmids":["37872147"],"confidence":"High","gaps":["What determines K48-versus-K63 linkage choice across substrates not defined","PLK1 input not tested for other substrates"]},{"year":2023,"claim":"Expanded the degradative cancer-substrate catalogue (RACK1, PBX1, β-catenin) and revealed contradictory HBc handling, where TRIM26 shields rather than degrades the substrate.","evidence":"Co-IP, MS, RING-deletion mutants, proteasome-inhibitor rescue, ubiquitination assays","pmids":["37591850","37324936","36707504","37604854"],"confidence":"Medium","gaps":["Mechanism by which TRIM26 inhibits HBc ubiquitination rather than catalyzing it is unexplained","Single-lab Co-IPs without reconstitution"]},{"year":2024,"claim":"Established TRIM26 as a broad node in immunometabolism and tissue homeostasis through new substrates (ETK, HSP-90β, NR4A1) and an autophagy route (MAVS via NDP52), with cell-type-specific in vivo phenotypes.","evidence":"Co-IP, CHX chase, knockout mice, AAV rescue, bone-marrow transplant, infection and regeneration models","pmids":["38773612","38038978","41746668","38965634","38926362","38166150","40490503"],"confidence":"Medium","gaps":["Whether one ligase activity or distinct regulatory inputs select among this many substrates in a given cell is unresolved","Several substrate findings rest on single-lab Co-IP plus rescue"]},{"year":2026,"claim":"Further diversified the substrate network into chromatin and metabolism (NKRF, EZH2, CBX6, LDHA, PKM, UBQLN2) and clarified transcriptional control by E2F3, while showing TRIM26 can both promote and inhibit TRAF6 ubiquitination in different contexts.","evidence":"Co-IP, IP-MS, APEX2 proximity labeling, lysine-mutant ubiquitination, knockout mice, xenografts","pmids":["42026030","41627629","42163428","41691946","40449810","41582437","41652078","42088415"],"confidence":"Medium","gaps":["Opposing effects on TRAF6 ubiquitination across studies not mechanistically reconciled","Most substrate links are individual single-lab reports"]},{"year":null,"claim":"It remains unknown what governs TRIM26's choice of ubiquitin linkage type (K48 versus K63 versus K11) and degradative-versus-stabilizing outcome across its many substrates, and how its subcellular localization and post-translational regulation route it to immune, repair, or metabolic substrate pools in a given cell.","evidence":"No single study in the timeline reconciles the linkage- and outcome-determining logic across substrate classes","pmids":[],"confidence":"Low","gaps":["No unifying biochemical determinant of linkage specificity identified","No structural model of substrate selection by the PRY/SPRY domain","Cross-tissue regulation of substrate access not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2,5,13,15]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3,5,13]},{"term_id":"GO:0031386","term_label":"protein tag activity","supporting_discovery_ids":[0,5,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,5,22,30]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2,3,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,5,13,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,20,5,31]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,10,12,19]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,13,33]}],"complexes":[],"partners":["IRF3","TBK1","NEMO","TAB1","GPX4","TRAF6","MAVS","SOX2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12899","full_name":"Tripartite motif-containing protein 26","aliases":["Acid finger protein","AFP","RING finger protein 95","Zinc finger protein 173"],"length_aa":539,"mass_kda":62.2,"function":"E3 ubiquitin-protein ligase which regulates the IFN-beta production and antiviral response downstream of various DNA-encoded pattern-recognition receptors (PRRs). Also plays a central role in determining the response to different forms of oxidative stress by controlling levels of DNA glycosylases NEIL1, NEIL3 and NTH1 that are involved in repair of damaged DNA (PubMed:29610152, PubMed:36232914). Promotes nuclear IRF3 ubiquitination and proteasomal degradation (PubMed:25763818). Bridges together TBK1 and NEMO during the innate response to viral infection leading to the activation of TBK1. Positively regulates LPS-mediated inflammatory innate immune response by catalyzing the 'Lys-11'-linked polyubiquitination of TAB1 to enhance its activation and subsequent NF-kappa-B and MAPK signaling (PubMed:34017102). In a manner independent of its catalytic activity, inhibits WWP2, a SOX2-directed E3 ubiquitin ligase, and thus protects SOX2 from polyubiquitination and proteasomal degradation (PubMed:34732716). Ubiquitinates the histone acetyltransferase protein complex component PHF20 and thereby triggers its degradation in the nucleus after its recruitment by the histone demethylase KDM6B, serving as a scaffold protein (PubMed:23452852). Upon induction by TGF-beta, ubiquitinates the TFIID component TAF7 for proteasomal degradation (PubMed:29203640). Induces ferroptosis by ubiquitinating SLC7A11, a critical protein for lipid reactive oxygen species (ROS) scavenging (By similarity). Inhibits directly hepatitis B virus replication by mediating HBX ubiquitination and subsequent degradation (PubMed:35872575) (Microbial infection) Promotes herpes simplex virus type 2/HHV-2 infection in vaginal epithelial cells by decreasing the nuclear localization of IRF3, the primary mediator of type I interferon activation","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q12899/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM26","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":[{"gene":"RBM39","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2},{"gene":"TRIM28","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TRIM26","total_profiled":1310},"omim":[{"mim_id":"609316","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 31; TRIM31","url":"https://www.omim.org/entry/609316"},{"mim_id":"600830","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 26; TRIM26","url":"https://www.omim.org/entry/600830"},{"mim_id":"126200","title":"MULTIPLE SCLEROSIS, SUSCEPTIBILITY TO; MS","url":"https://www.omim.org/entry/126200"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRIM26"},"hgnc":{"alias_symbol":["RNF95"],"prev_symbol":["ZNF173"]},"alphafold":{"accession":"Q12899","domains":[{"cath_id":"3.30.40.10","chopping":"2-67","consensus_level":"high","plddt":85.9279,"start":2,"end":67},{"cath_id":"2.60.120.920","chopping":"310-377_434-539","consensus_level":"medium","plddt":92.2113,"start":310,"end":539}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12899","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12899-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12899-F1-predicted_aligned_error_v6.png","plddt_mean":83.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM26","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM26"},"sequence":{"accession":"Q12899","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12899.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12899/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12899"}},"corpus_meta":[{"pmid":"25763818","id":"PMC_25763818","title":"TRIM26 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/33869196","citation_count":88,"is_preprint":false},{"pmid":"37872147","id":"PMC_37872147","title":"The E3 ligase TRIM26 suppresses ferroptosis through catalyzing K63-linked ubiquitination of GPX4 in glioma.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37872147","citation_count":80,"is_preprint":false},{"pmid":"26611359","id":"PMC_26611359","title":"Autoubiquitination of TRIM26 links TBK1 to NEMO in RLR-mediated innate antiviral immune response.","date":"2015","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26611359","citation_count":72,"is_preprint":false},{"pmid":"34017102","id":"PMC_34017102","title":"TRIM26 positively regulates the inflammatory immune response through K11-linked ubiquitination of TAB1.","date":"2021","source":"Cell death and 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disease","url":"https://pubmed.ncbi.nlm.nih.gov/36707504","citation_count":52,"is_preprint":false},{"pmid":"33523994","id":"PMC_33523994","title":"TRIM26 is a critical host factor for HCV replication and contributes to host tropism.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/33523994","citation_count":39,"is_preprint":false},{"pmid":"30927273","id":"PMC_30927273","title":"Overexpression of TRIM26 suppresses the proliferation, metastasis, and glycolysis in papillary thyroid carcinoma cells.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30927273","citation_count":35,"is_preprint":false},{"pmid":"33549581","id":"PMC_33549581","title":"Knockdown of TRIM26 inhibits the proliferation, migration and invasion of bladder cancer cells through the Akt/GSK3β/β-catenin pathway.","date":"2021","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/33549581","citation_count":35,"is_preprint":false},{"pmid":"27924031","id":"PMC_27924031","title":"Ubiquitylation-dependent regulation of NEIL1 by Mule and TRIM26 is required for the cellular DNA damage response.","date":"2016","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/27924031","citation_count":33,"is_preprint":false},{"pmid":"37591850","id":"PMC_37591850","title":"TRIM26 inhibited osteosarcoma progression through destabilizing RACK1 and thus inactivation of MEK/ERK signaling.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37591850","citation_count":24,"is_preprint":false},{"pmid":"37324936","id":"PMC_37324936","title":"TRIM26 promotes non-small cell lung cancer survival by inducing PBX1 degradation.","date":"2023","source":"International journal of biological 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cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29610152","citation_count":18,"is_preprint":false},{"pmid":"33419081","id":"PMC_33419081","title":"TRIM26 Facilitates HSV-2 Infection by Downregulating Antiviral Responses through the IRF3 Pathway.","date":"2021","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/33419081","citation_count":15,"is_preprint":false},{"pmid":"38926362","id":"PMC_38926362","title":"TRIM26 deficiency enhancing liver regeneration through macrophage polarization and β-catenin pathway activation.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38926362","citation_count":14,"is_preprint":false},{"pmid":"35077707","id":"PMC_35077707","title":"TRIM26-mediated degradation of nucleocapsid protein limits porcine reproductive and respiratory syndrome virus-2 infection.","date":"2022","source":"Virus 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/29203640","citation_count":12,"is_preprint":false},{"pmid":"38965634","id":"PMC_38965634","title":"TRIM26 facilitates PRV infection through NDP52-mediated autophagic degradation of MAVS.","date":"2024","source":"Veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/38965634","citation_count":10,"is_preprint":false},{"pmid":"38773612","id":"PMC_38773612","title":"TRIM26 inhibits clear cell renal cell carcinoma progression through destabilizing ETK and thus inactivation of AKT/mTOR signaling.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38773612","citation_count":8,"is_preprint":false},{"pmid":"36232914","id":"PMC_36232914","title":"TRIM26 Maintains Cell Survival in Response to Oxidative Stress through Regulating DNA Glycosylase Stability.","date":"2022","source":"International journal of molecular 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K48-linked polyubiquitination and proteasomal degradation, specifically targeting phosphorylated/activated IRF3 (IRF3-5D degraded, IRF3-5A not degraded). TRIM26 undergoes nuclear translocation upon virus infection, which is required for IRF3 degradation. NLS-mutant IRF3 that cannot enter the nucleus is not degraded by TRIM26.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, nuclear fractionation, IRF3 mutant analysis, TRIM26 transgenic mice, reporter assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple IRF3 mutants tested, transgenic mouse model, multiple orthogonal methods in one study\",\n      \"pmids\": [\"25763818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM26 physically associates with TBK1 independent of viral infection, undergoes autoubiquitination upon RNA virus infection, and the ubiquitinated TRIM26 bridges TBK1-NEMO interaction by associating with NEMO, thereby recruiting TBK1 to the VISA signalsome and activating TBK1 to promote IRF3 and NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, knockdown experiments, ubiquitination assays, reporter assays\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional knockdown, single lab with two orthogonal methods\",\n      \"pmids\": [\"26611359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIM26 polyubiquitylates the DNA glycosylase NEIL1 in vitro, targeting the same C-terminal lysine residues as Mule. siRNA knockdown of TRIM26 stabilizes NEIL1 protein levels; stabilization of NEIL1 following TRIM26 knockdown confers cellular resistance to ionising radiation.\",\n      \"method\": \"In vitro ubiquitylation assay with purified proteins, siRNA knockdown, protein stability assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of ubiquitylation activity, siRNA functional validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27924031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM26 ubiquitylates the DNA glycosylase NTH1 predominantly on lysine 67 in vitro. A K67R ubiquitylation-deficient NTH1 mutant is more stable in cells. TRIM26 siRNA knockdown causes exacerbated NTH1 accumulation on chromatin and accelerated DNA damage repair kinetics under oxidative stress.\",\n      \"method\": \"In vitro ubiquitylation assay, site-directed mutagenesis (K67R NTH1 mutant), siRNA knockdown, chromatin fractionation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined lysine site identified by mutagenesis, functional cellular validation, single lab\",\n      \"pmids\": [\"29610152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TGF-β stimulates transcription of TRIM26, which ubiquitylates TAF7 (a TFIID subunit) and targets it for proteasomal degradation, thereby mediating TGF-β-induced proliferative arrest. MYC inhibits TRIM26 induction by TGF-β, enabling recovery from growth arrest.\",\n      \"method\": \"Transcriptional induction assay, co-immunoprecipitation, ubiquitination assays, proliferation assays in cultured mouse mammary epithelial cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional phenotype, single lab with two orthogonal methods\",\n      \"pmids\": [\"29203640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM26 catalyzes K11-linked polyubiquitination of TAB1 at Lys294, Lys319, and Lys335, enhancing TAK1 activation and downstream NF-κB and MAPK signaling. Trim26-knockout mice show impaired TAK1 activation and reduced proinflammatory cytokine production upon LPS, TNF-α, and IL-1β stimulation, and are protected from LPS-induced septic shock.\",\n      \"method\": \"Trim26 knockout and transgenic mice, ubiquitination assays with specific lysine mutants, kinase activation assays, LPS-induced septic shock model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout and transgenic mice, specific ubiquitination site mapping, multiple stimulation conditions, in vivo model\",\n      \"pmids\": [\"34017102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM26 acts as E3 ubiquitin ligase for ZEB1, promoting its ubiquitination and proteasomal degradation. USP39 deubiquitinase directly interacts with TRIM26 and counteracts TRIM26-mediated ZEB1 ubiquitination in an antagonistic (not competitive) pattern, balancing ZEB1 stability to regulate HCC cell proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assays, loss-of-function and gain-of-function experiments\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ubiquitination assay, single lab with two orthogonal methods\",\n      \"pmids\": [\"33649471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM26 physically interacts with SLC7A11 and mediates its ubiquitination, leading to SLC7A11 degradation. TRIM26 overexpression induces ferroptosis in hepatic stellate cells and mitigates CCl4-induced liver fibrosis in mice.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, in vitro cell assays, in vivo CCl4 mouse model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay, in vivo validation, single lab\",\n      \"pmids\": [\"33869196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM26 interacts with the HCV NS5B protein and mediates K27-linked ubiquitination of NS5B at residue K51, promoting NS5B-NS5A interaction and thereby supporting HCV genome replication. Mouse TRIM26 fails to support HCV replication due to a unique six-amino acid insert that prevents interaction with NS5B.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen, co-immunoprecipitation, ubiquitination assays, species-specific mutant analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — CRISPR genome-wide screen plus mechanistic follow-up with Co-IP, specific ubiquitination site mapping, and cross-species mutagenesis\",\n      \"pmids\": [\"33523994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM26 stabilizes SOX2 protein in glioblastoma stem cells via its C-terminal PRYSPRY domain, independently of its RING E3 ligase domain, by directly inhibiting the interaction of SOX2 with the E3 ligase WWP2. TRIM26 depletion decreases SOX2 protein levels, increases SOX2 polyubiquitination, disrupts SOX2 gene network, and inhibits self-renewal and in vivo tumorigenicity.\",\n      \"method\": \"Proteomic affinity purification, co-immunoprecipitation, domain deletion mutants, patient-derived glioblastoma stem cell lines, in vivo xenograft\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic identification, reciprocal Co-IP, domain mapping by mutagenesis, in vivo model, multiple GSC lines\",\n      \"pmids\": [\"34732716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM26 inhibits HBV replication by interacting with the HBx protein via its SPRY domain and promoting K48-linked ubiquitination and proteasomal degradation of HBx. IFN treatment increases TRIM26 expression.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, ubiquitination assays, siRNA knockdown and overexpression in Huh7 cells\",\n      \"journal\": \"Alimentary pharmacology & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, domain mapping, single lab with two orthogonal methods\",\n      \"pmids\": [\"35872575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM26 siRNA depletion reduces resistance of cells to X-ray radiation and hydrogen peroxide; this resistance can be reversed by additional knockdown of neil1 or ogg1 (for X-rays) or neil1 or neil3 (for hydrogen peroxide), placing TRIM26 upstream of multiple DNA glycosylases in BER regulation.\",\n      \"method\": \"siRNA knockdown epistasis experiments, cell survival assays, DNA repair kinetics\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via siRNA double knockdown, multiple oxidative stress conditions, single lab\",\n      \"pmids\": [\"36232914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM26 promotes degradation of PRRSV nucleocapsid (N) protein through binding via its C-terminal PRY/SPRY domain. Deletion of either the RING domain or the PRY/SPRY domain abolishes antiviral activity. The antiviral activity is independent of the nuclear localization signal.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutants, overexpression and siRNA knockdown in porcine alveolar macrophages\",\n      \"journal\": \"Virus research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping by deletion mutants, functional rescue experiment, single lab\",\n      \"pmids\": [\"35077707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM26 directly interacts with GPX4 via its RING domain and catalyzes K63-linked polyubiquitination of GPX4 at K107 and K117, switching GPX4 ubiquitination from K48 to K63 linkage and thus enhancing GPX4 protein stability and ferroptosis resistance. PLK1-mediated S127 phosphorylation of TRIM26 enhances TRIM26-GPX4 interaction; inhibition of this phosphorylation reduces GPX4 K63-ubiquitination and protein levels.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutants, site-directed mutagenesis of GPX4 ubiquitination sites, phosphorylation inhibition experiments, in vitro and in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — specific ubiquitination sites identified by mutagenesis, linkage type determined, kinase modification mapped, in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37872147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM26 interacts with RACK1 and promotes its ubiquitination and proteasomal degradation, thereby inactivating MEK/ERK signaling. Overexpression of RACK1 reverses the inhibitory effect of TRIM26 on p-MEK1/2 and p-ERK1/2 in osteosarcoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, gain- and loss-of-function experiments, Western blot for pathway activation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, epistasis rescue experiment, single lab\",\n      \"pmids\": [\"37591850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM26 binds PBX1 and mediates its K48-linked polyubiquitination and proteasomal degradation. The C-terminal RING domain of TRIM26 is required for this activity; RING-deleted TRIM26 loses function toward PBX1.\",\n      \"method\": \"Affinity purification-coupled mass spectrometry, co-immunoprecipitation, ubiquitination assays, RING domain deletion mutant\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification, Co-IP validation, domain mapping, ubiquitination assay, single lab\",\n      \"pmids\": [\"37324936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM26 directly interacts with HBV core protein (HBc) through its SPRY domain. Unexpectedly, TRIM26 inhibits HBc ubiquitination rather than promoting it; TRIM26 knockdown leads to proteasome-dependent HBc degradation. A RING domain-deleted dominant-negative TRIM26 mutant (TRIM26ΔR) promotes HBc degradation, suggesting HBV exploits TRIM26 to protect HBc from proteasomal clearance.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, domain deletion mutants, proteasome inhibitor rescue experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, domain mapping, proteasome inhibitor validation, single lab; result contradicts Luo 2022 for HBx but this is for HBc\",\n      \"pmids\": [\"37604854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP39 inhibits TRIM26 pre-mRNA splicing and maturation, reducing TRIM26 expression. TRIM26, in turn, ubiquitinates β-catenin to promote its degradation. Thus USP39 promotes HCC progression both by direct deubiquitination of β-catenin and by suppressing TRIM26-mediated β-catenin ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, mRNA splicing analysis, functional knockdown/overexpression\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, splicing analysis, single lab\",\n      \"pmids\": [\"36707504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM26 promotes autophagic degradation of MAVS through NDP52-mediated selective autophagy. TRIM26 physically associates with MAVS independent of viral infection and reduces its expression; NDP52 interacts with both TRIM26 and MAVS, and TRIM26-induced MAVS degradation is almost entirely blocked in NDP52-knockdown cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, autophagy inhibition assays, PRV infection model\",\n      \"journal\": \"Veterinary research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying ternary complex, epistatic knockdown demonstrating NDP52 requirement, single lab\",\n      \"pmids\": [\"38965634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM26 interacts with HSP-90β and promotes its K48-linked polyubiquitination and proteasomal degradation. This leads to reduced EphA2 protein integrity, thereby suppressing EBV infection of nasopharyngeal epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, EBV infection assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional viral infection readout, single lab\",\n      \"pmids\": [\"38038978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM26 interacts with ETK (a non-receptor tyrosine kinase) via co-immunoprecipitation and facilitates its ubiquitination and proteasomal degradation, resulting in deactivation of AKT/mTOR signaling in ccRCC. ETK overexpression counteracts the inhibitory effects of TRIM26.\",\n      \"method\": \"Co-immunoprecipitation, cycloheximide chase, in vivo ubiquitination assays, RNA sequencing, Western blot, xenograft\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, CHX chase, epistasis rescue, single lab\",\n      \"pmids\": [\"38773612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM26 deficiency in macrophages promotes liver regeneration by inducing macrophage polarization toward M1 phenotype, which secretes Wnts (including Wnt2) to stimulate hepatocyte proliferation via Wnt/β-catenin signaling. In hepatocytes, TRIM26 knockdown directly reduces β-catenin ubiquitination and degradation. Bone marrow transplantation confirmed myeloid-cell TRIM26 is critical for this effect.\",\n      \"method\": \"Trim26 knockout mice, AAV-mediated overexpression, partial hepatectomy and CCl4 models, bone marrow transplantation, pharmacological inhibition of Wnt/β-catenin (ICG-001), macrophage depletion (clodronate liposomes)\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo models, bone marrow transplantation, pharmacological epistasis, AAV rescue, multiple orthogonal methods\",\n      \"pmids\": [\"38926362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM26 interacts with TRAF2 through its PRY domain and inhibits K63-linked ubiquitination of TRAF2, thereby attenuating NF-κB pathway activation and suppressing M1-like tumor-associated macrophage polarization. TRIM26 knockout in mice reduced colorectal cancer liver metastasis.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assays, Trim26 knockout mice, CRLM mouse models, flow cytometry\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, reporter assay, in vivo knockout model, single lab\",\n      \"pmids\": [\"40490503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"P2X7R promotes HuR nucleocytoplasmic shuttling in ageing hearts, which increases mRNA stability of TRIM26 and thus TRIM26 protein expression. TRIM26 subsequently mediates NR4A1 ubiquitination and proteasomal degradation, suppressing mitophagy and accelerating cardiac ageing.\",\n      \"method\": \"P2X7R knockout mice, AAV9 cardiac-specific overexpression, transcriptome sequencing, Western blot, NR4A1 ubiquitination assays\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse models and AAV rescue, ubiquitination assay, transcriptomics, single lab\",\n      \"pmids\": [\"41746668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM26 restricts inflammatory neutrophil infiltration and proinflammatory cytokine/chemokine (CXCL1, CXCL2) production during Candida infection, protecting mice from fungemia-related kidney damage. Trim26-deficient mice show higher parasite burden, more neutrophil infiltration, and higher proinflammatory cytokines.\",\n      \"method\": \"Trim26-deficient mouse model, Candida albicans infection, flow cytometry, cytokine measurement\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse model with in vivo infection phenotype, single lab\",\n      \"pmids\": [\"38166150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM26 interacts with PKM and promotes its ubiquitination, as demonstrated by co-IP and IP-MS in human periodontal ligament stem cells. PKM overexpression rescues TRIM26-mediated suppression of osteogenic differentiation.\",\n      \"method\": \"Co-immunoprecipitation, immunoprecipitation-mass spectrometry, ubiquitination assays, epistasis rescue experiments\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and IP-MS in a single study, limited mechanistic follow-up\",\n      \"pmids\": [\"40449810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM9 and TRIM26 are selectively enriched in the proximity proteome of ALS-linked UBQLN2P497H mutant (not wild-type). Individual knockdown of TRIM26 (or TRIM9) increases the abundance of a C-terminal UBQLN2 fragment, establishing UBQLN2P497H as a substrate for TRIM26-mediated ubiquitination and proteasomal degradation.\",\n      \"method\": \"APEX2 proximity labeling with LC-MS/MS, co-immunoprecipitation, siRNA knockdown, proteasomal inhibitor treatment, fractionation analysis\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity proteomics plus Co-IP validation and siRNA epistasis, single lab\",\n      \"pmids\": [\"41582437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM26 interacts with NKRF and promotes its K48-linked ubiquitination at Lys411, leading to proteasomal degradation of NKRF. This sustains SNRPD2 expression, enhancing stress granule assembly and contributing to Osimertinib resistance in lung adenocarcinoma. TRIM26 depletion restored NKRF stability and re-sensitized resistant tumors.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays with specific lysine mutant, TRIM26 genetic depletion, xenograft models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, specific ubiquitination site by mutagenesis, in vivo validation, single lab\",\n      \"pmids\": [\"42026030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM26 interacts with EZH2 and inhibits TRAF6-mediated K48-linked ubiquitination and degradation of EZH2, thereby maintaining EZH2 stability. EZH2 suppresses STAT1 transcriptional activity by catalyzing H3K27me3 modification on the STAT1 gene promoter. TRIM26 deficiency leads to EZH2 degradation, STAT1 upregulation, exacerbated M1 macrophage polarization, and liver fibrosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, Trim26 knockout mice, AAV-mediated restoration, CCl4/BDL fibrosis models, chromatin modification analysis\",\n      \"journal\": \"Hepatology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay, in vivo knockout and AAV rescue, single lab\",\n      \"pmids\": [\"41627629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM26 directly binds CBX6 and mediates its ubiquitination and degradation. Loss of CBX6 derepresses CNPY2 by eliminating H2AK119ub1 deposition on its promoter, activating NF-κB and IL-8 secretion that recruits neutrophils and induces NET formation in bladder cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, chromatin modification analysis, functional cancer cell assays, in vivo experiments\",\n      \"journal\": \"Drug development research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, chromatin modification evidence, in vivo validation, single lab\",\n      \"pmids\": [\"42163428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM26 directly interacts with and ubiquitinates TRAF6, reducing K48-linked polyubiquitination of TRAF6 to promote cytokine expression during Toxoplasma gondii infection. Trim26-deficient mice show reduced macrophages, inflammatory monocytes, and T cells, along with decreased IL-12, IFN-γ, TNF-α and higher parasite burdens.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, Trim26 knockout mice, T. gondii infection model, flow cytometry\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination linkage assay, knockout mouse with in vivo infection, single lab\",\n      \"pmids\": [\"41652078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"E2F3 transcriptionally activates TRIM26 expression. TRIM26 then binds TAB1 via its SPRY domain and promotes K11-linked polyubiquitination via its RING domain, facilitating TAB1-TAK1 complex formation and canonical NF-κB signaling in pancreatic cancer. TRIM26 depletion attenuated E2F3-induced NF-κB activation.\",\n      \"method\": \"ChIP/reporter assays for E2F3→TRIM26 transcription, co-immunoprecipitation, domain deletion mutants, ubiquitination assays, xenograft models\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping, Co-IP, ubiquitination assay, in vivo validation, single lab\",\n      \"pmids\": [\"42088415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM26 promotes ubiquitination-mediated degradation of LDHA, as demonstrated by co-immunoprecipitation, cycloheximide chase, and ubiquitination assays. LDHA overexpression reverses TRIM26-mediated suppression of glycolysis and proliferation in endometrial cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, cycloheximide chase, ubiquitination assays, epistasis rescue, xenograft\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, CHX chase, ubiquitination assay, in vivo validation, single lab\",\n      \"pmids\": [\"41691946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM26 directly interacts with GPX4 and catalyzes its ubiquitination, enhancing GPX4 protein stability in colorectal cancer. TRIM26 knockdown promotes ferroptosis, and GPX4 overexpression rescues the increased ferroptosis caused by sh-TRIM26.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, ferroptosis inhibitor/inducer experiments, rescue experiments\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, epistasis rescue, consistent with PMID 37872147, single lab\",\n      \"pmids\": [\"41989643\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM26 is an E3 ubiquitin ligase (RING-B-box-coiled-coil-PRY/SPRY architecture) that functions as a context-dependent regulator: in innate immunity it undergoes virus-induced nuclear translocation to polyubiquitinate (K48) and degrade activated nuclear IRF3, autoubiquitinates to bridge TBK1-NEMO and activate TBK1, catalyzes K11-linked ubiquitination of TAB1 to promote TAK1/NF-κB activation, and modulates TRAF2 and TRAF6 ubiquitination to tune inflammatory signaling; in DNA repair it controls steady-state levels of BER glycosylases NEIL1, NTH1, and OGG1 via polyubiquitination; in cancer biology it targets diverse substrates (ZEB1, SLC7A11, RACK1, ETK, PBX1, SOX2, TAF7, HBx, GPX4, NKRF, CBX6, EZH2, NR4A1, LDHA, PKM) for ubiquitination—sometimes for K48-linked degradation, sometimes for K63-linked stabilization (GPX4)—with its RING domain mediating catalysis and its SPRY/PRY domain mediating substrate recognition, and its activity further regulated by PLK1-mediated phosphorylation at S127.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM26 is a RING-type E3 ubiquitin ligase that acts as a context-dependent regulator of innate immune signaling, DNA base-excision repair, and the stability of diverse oncogenic and metabolic proteins, with substrate recognition through its C-terminal PRY/SPRY domain and catalysis through its RING domain [#0, #13, #15]. In antiviral signaling, virus infection drives TRIM26 nuclear translocation, where it catalyzes K48-linked polyubiquitination and proteasomal degradation of phosphorylated, activated IRF3 to terminate the response [#0]; in parallel it autoubiquitinates and bridges TBK1 to NEMO at the VISA signalsome to activate TBK1 [#1], and routes MAVS to NDP52-mediated selective autophagy [#18]. TRIM26 tunes NF-κB and MAPK output through linkage-specific ubiquitination of upstream adaptors, catalyzing K11-linked ubiquitination of TAB1 to promote TAK1 activation [#5, #31] and modulating TRAF2 and TRAF6 ubiquitination, with knockout mice showing altered inflammatory cytokine production and infection outcomes [#22, #30, #5]. In DNA repair, TRIM26 sets steady-state levels of the BER glycosylases NEIL1 and NTH1 by polyubiquitination at defined lysines, and its depletion stabilizes these enzymes and alters cellular resistance to ionizing radiation and oxidative stress [#2, #3, #11]. Across cancer biology TRIM26 targets a broad substrate set, most often for K48-linked degradation (ZEB1, TAF7, RACK1, PBX1, HSP-90β, NKRF, β-catenin, LDHA), but in the case of GPX4 it switches ubiquitination from K48 to K63 linkage to stabilize the protein and confer ferroptosis resistance, an interaction enhanced by PLK1-mediated phosphorylation of TRIM26 at S127 [#6, #14, #15, #19, #27, #13, #33]. TRIM26 is itself transcriptionally and post-transcriptionally controlled, being induced by TGF-β and E2F3 and regulated at the splicing and mRNA-stability level by USP39 and HuR [#4, #31, #17, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established TRIM26 as a negative-feedback brake on antiviral signaling by defining its first substrate and a spatial mechanism: virus-induced nuclear translocation to degrade activated IRF3.\",\n      \"evidence\": \"Co-IP, K48 ubiquitination assays, IRF3 phosphomimetic/NLS mutants, and transgenic mice\",\n      \"pmids\": [\"25763818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the signal triggering TRIM26 nuclear translocation\", \"Did not address whether TRIM26 also acts at upstream signaling nodes\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed TRIM26 also acts positively in the same pathway by autoubiquitinating and scaffolding the TBK1-NEMO interaction, revealing a dual pro- and anti-viral role.\",\n      \"evidence\": \"Co-IP, knockdown, autoubiquitination and reporter assays\",\n      \"pmids\": [\"26611359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The autoubiquitination linkage type and its E2 partner were not defined\", \"How the positive (TBK1 bridging) and negative (IRF3 degradation) roles are temporally coordinated is unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended TRIM26 function beyond immunity by identifying NEIL1 as an in vitro ubiquitylation substrate, linking TRIM26 to base-excision repair and radiation resistance.\",\n      \"evidence\": \"In vitro ubiquitylation with purified proteins, siRNA, protein stability and survival assays\",\n      \"pmids\": [\"27924031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin linkage type on NEIL1 not specified\", \"In vivo relevance to genome stability not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Generalized the BER-regulation role by mapping NTH1 ubiquitylation to K67 and showing TRIM26 limits glycosylase accumulation on chromatin during oxidative stress.\",\n      \"evidence\": \"In vitro ubiquitylation, K67R mutant, siRNA, chromatin fractionation\",\n      \"pmids\": [\"29610152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same regulation operates under physiological damage loads in vivo unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed TRIM26 in a growth-control circuit, showing TGF-β induces TRIM26 to degrade the TFIID subunit TAF7 and arrest proliferation, with MYC antagonizing this induction.\",\n      \"evidence\": \"Transcriptional induction, Co-IP, ubiquitination and proliferation assays in mammary epithelial cells\",\n      \"pmids\": [\"29203640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TAF7 ubiquitination linkage and degron not mapped\", \"Single-cell-type system\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a linkage-specific positive signaling role: K11-linked ubiquitination of TAB1 at three lysines to drive TAK1-dependent NF-κB/MAPK and inflammatory responses in vivo.\",\n      \"evidence\": \"Knockout/transgenic mice, lysine-mutant ubiquitination assays, septic shock model\",\n      \"pmids\": [\"34017102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reconcile the inflammation-promoting role with prior IRF3-degrading and TRAF-modulating roles\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Opened the cancer-substrate phase by identifying ZEB1, SLC7A11, and SOX2 as TRIM26 targets, and revealing a RING-independent stabilizing mechanism for SOX2.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, domain mutants, USP39 antagonism, patient-derived GSC lines, xenografts\",\n      \"pmids\": [\"33649471\", \"33869196\", \"34732716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why TRIM26 degrades some substrates but shields SOX2 from a competing ligase is mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed TRIM26 can be exploited by viruses, using K27-linked ubiquitination of HCV NS5B to support viral replication, with species-specific specificity.\",\n      \"evidence\": \"Genome-wide CRISPR screen, Co-IP, site mapping, cross-species mutagenesis\",\n      \"pmids\": [\"33523994\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether host substrates are co-opted in the same manner not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated divergent virus outcomes: TRIM26 SPRY-mediated K48 degradation of HBx and PRRSV-N restricts those viruses, expanding the antiviral substrate range.\",\n      \"evidence\": \"Co-IP, domain deletion mutants, ubiquitination assays in Huh7 and porcine macrophages\",\n      \"pmids\": [\"35872575\", \"35077707\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NLS-independence of PRRSV-N restriction contrasts with NLS-dependent IRF3 degradation, mechanism unexplained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed TRIM26 genetically upstream of multiple BER glycosylases (NEIL1/3, OGG1) via epistasis, consolidating its role as a master regulator of glycosylase abundance.\",\n      \"evidence\": \"siRNA double-knockdown epistasis, survival and repair-kinetics assays under oxidative/X-ray stress\",\n      \"pmids\": [\"36232914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish direct ubiquitination of OGG1/NEIL3\", \"Indirect (epistatic) genetic evidence only\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered a substrate-stabilizing linkage switch: TRIM26 RING-mediated K63 ubiquitination of GPX4 at K107/K117 enhances GPX4 stability and ferroptosis resistance, regulated by PLK1 phosphorylation of TRIM26 at S127.\",\n      \"evidence\": \"Co-IP, GPX4 site mutants, linkage analysis, phosphorylation inhibition, in vivo tumor models\",\n      \"pmids\": [\"37872147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What determines K48-versus-K63 linkage choice across substrates not defined\", \"PLK1 input not tested for other substrates\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded the degradative cancer-substrate catalogue (RACK1, PBX1, β-catenin) and revealed contradictory HBc handling, where TRIM26 shields rather than degrades the substrate.\",\n      \"evidence\": \"Co-IP, MS, RING-deletion mutants, proteasome-inhibitor rescue, ubiquitination assays\",\n      \"pmids\": [\"37591850\", \"37324936\", \"36707504\", \"37604854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which TRIM26 inhibits HBc ubiquitination rather than catalyzing it is unexplained\", \"Single-lab Co-IPs without reconstitution\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established TRIM26 as a broad node in immunometabolism and tissue homeostasis through new substrates (ETK, HSP-90β, NR4A1) and an autophagy route (MAVS via NDP52), with cell-type-specific in vivo phenotypes.\",\n      \"evidence\": \"Co-IP, CHX chase, knockout mice, AAV rescue, bone-marrow transplant, infection and regeneration models\",\n      \"pmids\": [\"38773612\", \"38038978\", \"41746668\", \"38965634\", \"38926362\", \"38166150\", \"40490503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether one ligase activity or distinct regulatory inputs select among this many substrates in a given cell is unresolved\", \"Several substrate findings rest on single-lab Co-IP plus rescue\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Further diversified the substrate network into chromatin and metabolism (NKRF, EZH2, CBX6, LDHA, PKM, UBQLN2) and clarified transcriptional control by E2F3, while showing TRIM26 can both promote and inhibit TRAF6 ubiquitination in different contexts.\",\n      \"evidence\": \"Co-IP, IP-MS, APEX2 proximity labeling, lysine-mutant ubiquitination, knockout mice, xenografts\",\n      \"pmids\": [\"42026030\", \"41627629\", \"42163428\", \"41691946\", \"40449810\", \"41582437\", \"41652078\", \"42088415\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposing effects on TRAF6 ubiquitination across studies not mechanistically reconciled\", \"Most substrate links are individual single-lab reports\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown what governs TRIM26's choice of ubiquitin linkage type (K48 versus K63 versus K11) and degradative-versus-stabilizing outcome across its many substrates, and how its subcellular localization and post-translational regulation route it to immune, repair, or metabolic substrate pools in a given cell.\",\n      \"evidence\": \"No single study in the timeline reconciles the linkage- and outcome-determining logic across substrate classes\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying biochemical determinant of linkage specificity identified\", \"No structural model of substrate selection by the PRY/SPRY domain\", \"Cross-tissue regulation of substrate access not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2, 5, 13, 15]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3, 5, 13]},\n      {\"term_id\": \"GO:0031386\", \"supporting_discovery_ids\": [0, 5, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 5, 22, 30]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2, 3, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 5, 13, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 20, 5, 31]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 10, 12, 19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 13, 33]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IRF3\", \"TBK1\", \"NEMO\", \"TAB1\", \"GPX4\", \"TRAF6\", \"MAVS\", \"SOX2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}