{"gene":"TRIM14","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2013,"finding":"TRIM14 localizes to the outer membrane of mitochondria and interacts with MAVS. Upon viral infection, TRIM14 undergoes Lys-63-linked polyubiquitination at Lys-365 and recruits NF-κB essential modulator (NEMO) to the MAVS signalosome, leading to activation of both the IRF3 and NF-κB pathways. Knockdown of TRIM14 disrupts the NEMO-MAVS association and attenuates the antiviral response.","method":"Co-immunoprecipitation, subcellular fractionation/mitochondria localization, knockdown (siRNA), site-directed mutagenesis (K365 ubiquitination), reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, defined subcellular localization with functional consequence, site-specific ubiquitination mapping, KD phenotype; foundational mechanism paper replicated by multiple subsequent studies","pmids":["24379373"],"is_preprint":false},{"year":2016,"finding":"TRIM14 stabilizes cGAS by recruiting the deubiquitinase USP14, which cleaves K48-linked ubiquitin chains from cGAS at lysine 414, preventing p62-dependent selective autophagic degradation of cGAS. TRIM14 knockout impairs HSV-1-triggered antiviral responses and Trim14−/− mice are highly susceptible to lethal HSV-1 infection.","method":"Co-immunoprecipitation, knockout mice, ubiquitination assays, in vitro deubiquitination assay, autophagy flux assays, site-directed mutagenesis (K414)","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, KO mice, in vitro DUB assay, mutagenesis), in vivo validation, identifies specific ubiquitin site and enzyme","pmids":["27666593"],"is_preprint":false},{"year":2016,"finding":"TRIM14 inhibits HCV replication through its C-terminal SPRY domain, which interacts with the HCV NS5A protein (specifically the NS5A1 subdomain) and induces its K48-linked ubiquitination and degradation, independently of NF-κB or IFN pathway activation.","method":"Overexpression, knockout, domain-deletion mapping, co-immunoprecipitation, ubiquitination assays, viral replication assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, domain mapping, KO, ubiquitination assay, multiple orthogonal methods in single study; mechanism is SPRY-domain-mediated K48-ubiquitination of NS5A","pmids":["27578425"],"is_preprint":false},{"year":2017,"finding":"TRIM14 acts as a mitochondrial docking platform for assembly of a WHIP-TRIM14-PPP6C complex that promotes RIG-I mitochondrial localization and optimal activation. WHIP bridges RIG-I with MAVS via its ubiquitin-binding domain interacting with polyUb chains on RIG-I at K164, and PPP6C dephosphorylates RIG-I. The ATPase domain of WHIP stabilizes the RIG-I–dsRNA interaction.","method":"Pooled RNAi screen, yeast two-hybrid, co-immunoprecipitation, domain-deletion mapping, in vitro dephosphorylation assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid + reciprocal Co-IP + biochemical assays + domain mapping + functional readouts; defines the ternary signalosome","pmids":["29053956"],"is_preprint":false},{"year":2017,"finding":"RNF125 functions as an E3 ubiquitin ligase that interacts with TRIM14, catalyzes K48-linked polyubiquitination of TRIM14, and promotes its proteasomal degradation, thereby acting as a negative regulator of TRIM14-mediated innate antiviral signaling. RNF125-deficient MEFs retain TRIM14 protein at late time points of viral infection.","method":"Co-immunoprecipitation, ubiquitination assays, overexpression, knockdown, RNF125-deficient MEFs","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in cellulo ubiquitination assay with genetic KO validation; identifies specific E3 ligase-substrate pair with functional consequence","pmids":["28476934"],"is_preprint":false},{"year":2018,"finding":"TRIM14 inhibits HBV replication as an IFN-I-stimulated gene (ISG) whose transcription is directly activated by STAT1 (but not STAT3) binding to the TRIM14 promoter. The TRIM14 SPRY domain interacts with the C-terminal domain of HBx, potentially blocking HBx-facilitated formation of the Smc-HBx-DDB1 complex required for HBV replication.","method":"Reporter assays (ChIP-equivalent promoter binding), co-immunoprecipitation, domain mapping, overexpression, knockdown, viral replication assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for SPRY-HBx interaction, promoter-binding assay for STAT1; single lab, two orthogonal methods","pmids":["30150992"],"is_preprint":false},{"year":2019,"finding":"TRIM14 promotes noncanonical NF-κB signaling by recruiting deubiquitinase USP14 to cleave K63-linked ubiquitin chains from p100/p52 at multiple sites, thereby preventing p62-mediated selective autophagic degradation of p100/p52 and sustaining noncanonical NF-κB activation. Trim14-deficient mice show impaired noncanonical NF-κB-mediated inflammatory responses.","method":"Co-immunoprecipitation, ubiquitination assays, knockout mice, autophagy flux assays, in vivo colitis/tumor models","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, specific ubiquitin-chain type identified, KO mice in vivo, multiple orthogonal methods; extends the TRIM14-USP14 axis to noncanonical NF-κB","pmids":["31921549"],"is_preprint":false},{"year":2019,"finding":"The crystal structure of the TRIM14 PRYSPRY domain reveals a positively charged (basic) surface that mediates protein-protein interactions preferentially with acidic amino acid residues, as validated by isothermal titration calorimetry showing binding of the domain to acidic peptides.","method":"X-ray crystallography, isothermal titration calorimetry (ITC)","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus ITC binding validation; single lab but two orthogonal methods including atomic resolution structure","pmids":["30973643"],"is_preprint":false},{"year":2019,"finding":"TRIM14 interacts with the viral nucleoprotein (NP) of Influenza A virus through multiple domains: the PRYSPRY domain promotes K48-linked ubiquitination and proteasomal degradation of NP (inhibiting viral RNP formation and NP nuclear translocation), while the ΔS2 domain antagonizes this by stabilizing NP. TRIM14 restricts IAV replication in an IFN/NF-κB-independent manner.","method":"Co-immunoprecipitation, domain-deletion mapping, ubiquitination assays, viral replication assays, NP nuclear translocation imaging","journal":"Frontiers in microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mapping, ubiquitination assay, subcellular localization readout, multiple independent functional assays","pmids":["30873142"],"is_preprint":false},{"year":2019,"finding":"TRIM14 promotes NF-κB activation in vascular endothelial cells by directly binding to NEMO (IKK complex) upon TNF-α stimulation, promoting IκBα and p65 phosphorylation in a manner dependent on K63-linked ubiquitination of TRIM14. p65 in turn binds directly to the TRIM14 promoter to enhance TRIM14 transcription, forming a positive feedback loop.","method":"Co-immunoprecipitation, promoter ChIP (p65 binding to TRIM14 promoter), ubiquitination assays, overexpression, knockdown","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for NEMO interaction, ChIP for promoter binding, ubiquitination assay; single lab with multiple orthogonal methods","pmids":["31070748"],"is_preprint":false},{"year":2019,"finding":"TRIM14 inactivation in glioblastoma cells causes ubiquitination and proteasomal degradation of ZEB2, a transcription factor involved in EMT, indicating that TRIM14 stabilizes ZEB2 by preventing its ubiquitination.","method":"Knockdown (shRNA), ubiquitination assays, cycloheximide chase (stability analysis), western blot","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — ubiquitination assay and stability assay; single lab, two complementary but not fully orthogonal methods","pmids":["30728039"],"is_preprint":false},{"year":2019,"finding":"IRF-1 and IRF-2 bind to the TRIM14 promoter (at a GC box and ISRE element) and activate TRIM14 transcription; IRF-1 mediates IFN-α-induced upregulation of TRIM14, while IRF-2 is required for basal TRIM14 transcription. Knockdown of IRF-1 reduces IFN-α-stimulated TRIM14 expression.","method":"Promoter reporter assays, EMSA/ChIP (IRF binding to TRIM14 promoter), siRNA knockdown, RT-PCR","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — promoter reporter + IRF binding assay + KD functional readout; single lab","pmids":["31150153"],"is_preprint":false},{"year":2018,"finding":"TRIM14 stabilizes Dishevelled 2 (Dvl2) protein in glioma cells, activating canonical Wnt/β-catenin signaling and promoting chemoresistance to temozolomide. Inhibition of Dvl2 reverses the oncogenic effects of TRIM14 overexpression on chemoresistance.","method":"Overexpression, knockdown, western blot (Dvl2 stability), in vitro and in vivo TMZ resistance assays, pharmacological inhibition of Dvl2","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — protein stability assay plus epistasis via Dvl2 inhibition; single lab, two complementary approaches","pmids":["29867201"],"is_preprint":false},{"year":2019,"finding":"TRIM14 co-localizes with PTEN in the cytoplasm and induces PTEN ubiquitination, leading to PTEN degradation and downstream AKT pathway activation to promote colorectal cancer cell proliferation.","method":"Co-immunoprecipitation/co-localization, ubiquitination assay, western blot, overexpression/knockdown, epistasis via PTEN overexpression rescue","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization + ubiquitination assay + epistasis rescue; single lab, multiple approaches","pmids":["31296997"],"is_preprint":false},{"year":2019,"finding":"TRIM14 interacts with PPM1A and mediates its ubiquitination in human nucleus pulposus cells, promoting NF-κB p65 activation and TNF-α-induced apoptosis.","method":"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, western blot","journal":"Artificial cells, nanomedicine, and biotechnology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP plus ubiquitination assay; single lab, limited mechanistic validation","pmids":["31322007"],"is_preprint":false},{"year":2020,"finding":"In Mycobacterium tuberculosis-infected macrophages, TRIM14 acts as a negative regulator of type I IFN responses by interacting with both cGAS and TBK1, acting as a scaffold to promote STAT3 phosphorylation at Ser727 (over Ser754), thereby upregulating SOCS3 to resolve IFN signaling. Trim14 KO macrophages hyperinduce ISG expression and are better at restricting M. tuberculosis replication.","method":"Knockout macrophages, co-immunoprecipitation (cGAS and TBK1 interaction), phospho-specific western blot, cytokine/ISG measurement, bacterial colony assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO macrophages with defined molecular phenotype, Co-IP for two interacting partners, phospho-specific readout, multiple orthogonal methods","pmids":["32404352"],"is_preprint":false},{"year":2022,"finding":"TRIM14 recruits deubiquitinases USP14 and BRCC3 to form a regulatory complex that cleaves K63-linked ubiquitin chains from the histone demethylase KDM4D, thereby preventing OPTN (optineurin)-mediated selective autophagic degradation of KDM4D. This preserves KDM4D-mediated inhibition of histone H3K9 trimethylation, epigenetically promoting IL-12 and IL-23 expression in dendritic cells. TRIM14 deficiency in dendritic cells impairs proinflammatory cytokine expression and protects mice from autoimmune inflammation.","method":"Co-immunoprecipitation, ubiquitination assays, autophagy flux assays, KO dendritic cells, histone methylation assays, in vivo autoimmune model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP identifying ternary complex, specific ubiquitin chain type, selective autophagy receptor identified, KO in vivo, multiple orthogonal methods","pmids":["35145029"],"is_preprint":false},{"year":2024,"finding":"TRIM14 recruits USP14 to inhibit autophagic degradation of PD-L1 by removing K63-linked ubiquitin chains from PD-L1, impairing recognition of PD-L1 by the cargo receptor p62 for autophagic degradation. IFNα transcriptionally upregulates TRIM14, which then stabilizes PD-L1 and suppresses CD8+ T cell-mediated antitumor activity. Combining USP14 inhibitor IU1 with IFNα and anti-CTLA4 effectively suppresses tumor growth.","method":"Co-immunoprecipitation, ubiquitination assays (K63 chain type), autophagy flux assays, KO/knockdown, CD8+ T cell functional assays, in vivo tumor models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, specific ubiquitin chain characterization, autophagic flux assay, in vivo tumor model with pharmacological validation; multiple orthogonal methods","pmids":["38924473"],"is_preprint":false},{"year":2025,"finding":"TRIM14 assembles at the GPX4 locus following radiation and recruits USP14, forming a TRIM14/USP14 complex that removes K48-linked polyubiquitination from GPX4 at K48 or K118, thereby stabilizing GPX4 and suppressing radiation-induced ferroptosis. Pharmacological inhibition of USP14 sensitizes HCC to radiotherapy.","method":"CRISPR-based DUB screen, co-immunoprecipitation, ubiquitination site mapping (K48/K118 mutagenesis), in vitro ferroptosis assays, patient-derived xenograft models","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR screen plus Co-IP, site-specific mutagenesis at ubiquitination sites, PDX in vivo validation; multiple orthogonal methods","pmids":["40595451"],"is_preprint":false},{"year":2025,"finding":"TRIM14 interacts with duck TBK1 and promotes its K63-linked polyubiquitination on K30 and K401, augmenting IFN-β production during TMUV infection. Separately, TRIM14 interacts with TMUV NS1 protein, facilitating K27/K29-linked polyubiquitination of NS1 and its proteasomal degradation; K141 on NS1 is critical for this process.","method":"Co-immunoprecipitation, ubiquitination site mapping (mutagenesis of TBK1 K30/K401 and NS1 K141), in vitro viral replication assays, in vivo (duck) infection model","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific mutagenesis for multiple ubiquitination sites, Co-IP, in vivo validation; multiple orthogonal methods in single rigorous study","pmids":["40435148"],"is_preprint":false},{"year":2025,"finding":"TRIM14 promotes IκBα ubiquitination and degradation in spinal cord microglia, thereby activating NF-κB and driving M1 polarization and NLRP3-mediated pyroptosis. TRIM14 knockdown stabilizes IκBα, suppresses NF-κB/NLRP3 signaling, attenuates neuroinflammation, and improves locomotor recovery in rats after spinal cord injury.","method":"Knockdown/overexpression, ubiquitination assay (IκBα), western blot (phospho-NF-κB), AAV-CRISPR in vivo, rat SCI model","journal":"Mediators of inflammation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — ubiquitination assay plus in vivo KD; single lab with complementary in vitro and in vivo methods","pmids":["41250673"],"is_preprint":false},{"year":2024,"finding":"TRIM14 directly binds to GFAT1 (glutamine fructose-6-phosphate amidotransferase 1), a rate-limiting enzyme of the hexosamine biosynthetic pathway, and promotes its ubiquitination and degradation, reducing O-glycosylation and suppressing NSCLC cell proliferation and migration. N-acetyl-D-glucosamine supplementation rescues the inhibitory effect.","method":"Co-immunoprecipitation, ubiquitination assay, rescue experiment (N-acetyl-glucosamine), knockdown/overexpression, in vitro and in vivo tumor assays","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP identifies GFAT1 as substrate, ubiquitination assay, metabolic rescue; single lab, multiple approaches","pmids":["38267812"],"is_preprint":false},{"year":2024,"finding":"TCF19 transcriptionally promotes TRIM14 expression, and the TCF19-TRIM14 axis activates TBK1-IRF3-IFN-β signaling; enhanced IFN-β secretion facilitates CD8+ T cell exhaustion via differentiation reprogramming in MSI endometrial cancer.","method":"ChIP/promoter analysis (TCF19 binding to TRIM14 promoter), overexpression/knockdown, IFN-β ELISA, humanized mouse models, CD8+ T cell functional assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — promoter binding assay plus humanized model; single lab, multiple methods","pmids":["37566545"],"is_preprint":false},{"year":2025,"finding":"TRIM14 binds to TRAF3 and mediates its autophagic degradation via the selective autophagy receptor NDP52, activating the NF-κB pathway and driving psoriasis-associated keratinocyte proliferation and inflammation.","method":"Co-immunoprecipitation (TRIM14-TRAF3 and TRIM14-NDP52 interactions), autophagy flux assays, overexpression/knockdown, in vivo psoriatic mouse model","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for two interactions, autophagy assay, in vivo model; single lab with multiple approaches","pmids":["39933682"],"is_preprint":false},{"year":2023,"finding":"TRIM14 interacts with EBOV nucleoprotein, and this interaction enhances IFN-β and NF-κB promoter activation. TRIM14 overexpression reduces EBOV replication ~10-fold in an infectious but biologically contained system. TRIM14-deficient mice are more susceptible to mouse-adapted EBOV infection.","method":"Co-immunoprecipitation, reporter assays (IFN-β and NF-κB promoters), viral replication assay, TRIM14 KO mice","journal":"The Journal of infectious diseases","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus KO in vivo plus viral replication assay; single lab, multiple orthogonal methods","pmids":["37562033"],"is_preprint":false},{"year":2024,"finding":"Co-immunoprecipitation confirmed a direct interaction between TRIM14 and KIF1B in kidney tubular epithelial cells under high-glucose conditions, with TRIM14 positively regulating KIF1B expression; TRIM14 knockdown suppresses the TLR4/NF-κB pathway and mitigates high-glucose-induced apoptosis, oxidative stress, and inflammation.","method":"Co-immunoprecipitation, transcriptome sequencing, knockdown, western blot (TLR4/NF-κB), in vitro HK-2 cell assays","journal":"Diabetes, metabolic syndrome and obesity","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying novel interactor; single lab, limited mechanistic follow-up","pmids":["41710718"],"is_preprint":false},{"year":2025,"finding":"Co-immunoprecipitation assays revealed a potential interaction between TRIM14 and ATP7A (copper-exporting ATPase) in glioma cells, and combined TMZ and CuCl2 treatment suppresses TRIM14 expression and downregulates the TRIM14-ATP7A axis, inhibiting non-canonical NF-κB signaling and inducing cuproptosis.","method":"Co-immunoprecipitation, western blot, immunofluorescence, in vitro and in vivo xenograft models","journal":"Biomedicines","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for TRIM14-ATP7A; single lab, limited mechanistic validation of direct functional relationship","pmids":["41463095"],"is_preprint":false}],"current_model":"TRIM14 is a mitochondrial scaffold protein (lacking a RING-domain E3 ligase) that promotes innate antiviral and inflammatory signaling by (1) anchoring MAVS-associated signalosomes on mitochondria and recruiting NEMO, (2) stabilizing key immune regulators (cGAS, p100/p52, KDM4D, PD-L1, GPX4) by recruiting deubiquitinase USP14—and also BRCC3—to remove K48- or K63-linked ubiquitin chains that would otherwise target these proteins for p62- or OPTN-mediated selective autophagic degradation, (3) acting as a scaffold between TBK1 and STAT3 to resolve type I IFN responses via Ser727-STAT3 phosphorylation, (4) directly promoting K63-ubiquitination of TBK1 to enhance IFN-β production, (5) restricting viral replication through SPRY-domain-mediated K48-ubiquitination and proteasomal degradation of viral proteins (HCV NS5A, HBx, IAV NP, TMUV NS1), and (6) activating NF-κB in diverse cell types by binding NEMO and promoting IκBα degradation, with its own expression transcriptionally controlled by IRF-1/IRF-2 and STAT1 through an ISRE in its promoter."},"narrative":{"mechanistic_narrative":"TRIM14 is a mitochondrial outer-membrane scaffold protein that integrates innate antiviral and inflammatory signaling and, in cancer contexts, stabilizes a broad set of substrate proteins by controlling their ubiquitination-dependent turnover [PMID:24379373, PMID:27666593]. In RNA-virus sensing, it docks at MAVS, undergoes K63-linked polyubiquitination at Lys365, and recruits NEMO to the MAVS signalosome to drive IRF3 and NF-κB activation [PMID:24379373]; it further serves as a mitochondrial platform for a WHIP–TRIM14–PPP6C complex that optimizes RIG-I localization and activation [PMID:29053956]. A recurrent mechanism is the recruitment of the deubiquitinase USP14 (and BRCC3) to remove K48- or K63-linked ubiquitin chains from client proteins, sparing them from p62- or OPTN-mediated selective autophagic degradation: this axis stabilizes cGAS to support DNA-virus antiviral responses [PMID:27666593], sustains noncanonical NF-κB by protecting p100/p52 [PMID:31921549], preserves KDM4D to maintain H3K9 demethylation and proinflammatory IL-12/IL-23 expression in dendritic cells [PMID:35145029], and stabilizes the immune checkpoint ligand PD-L1 to suppress CD8+ T-cell antitumor activity [PMID:38924473]. Conversely, through its C-terminal PRYSPRY/SPRY domain—whose basic surface mediates interactions with acidic targets [PMID:30973643]—TRIM14 restricts viral replication by directing K48-linked ubiquitination and proteasomal degradation of viral proteins including HCV NS5A, HBx, influenza A NP, and TMUV NS1 [PMID:27578425, PMID:30150992, PMID:30873142, PMID:40435148]. TRIM14 also directly promotes K63-ubiquitination of TBK1 to enhance IFN-β production [PMID:40435148] and acts as a TBK1–STAT3 scaffold that resolves type I IFN signaling via Ser727-STAT3 phosphorylation and SOCS3 induction during M. tuberculosis infection [PMID:32404352]. TRIM14 expression is itself an interferon- and inflammation-responsive node, transcriptionally activated by IRF-1/IRF-2 and STAT1 through promoter ISRE/GC elements [PMID:30150992, PMID:31150153]. In tumor and inflammatory tissues it activates NF-κB by binding NEMO or promoting IκBα degradation [PMID:31070748, PMID:41250673] and stabilizes oncogenic effectors, while its own level is restrained by RNF125-mediated K48-ubiquitination and proteasomal degradation [PMID:28476934].","teleology":[{"year":2013,"claim":"Established the founding mechanism by placing TRIM14 on mitochondria as a MAVS-associated scaffold that recruits NEMO, defining how a RING-less TRIM links the antiviral sensor platform to downstream IRF3/NF-κB activation.","evidence":"Co-IP, mitochondrial fractionation, K365 ubiquitination mutagenesis, and siRNA knockdown with reporter readouts","pmids":["24379373"],"confidence":"High","gaps":["E3 ligase responsible for K365 K63-ubiquitination of TRIM14 not identified here","Stoichiometry and architecture of the MAVS–TRIM14–NEMO signalosome unresolved"]},{"year":2016,"claim":"Defined TRIM14's stabilizing arm by showing it recruits USP14 to deubiquitinate cGAS and block its autophagic degradation, explaining how TRIM14 supports DNA-virus sensing in vivo.","evidence":"Co-IP, Trim14 KO mice with HSV-1 challenge, in vitro DUB assay, autophagy flux, K414 mutagenesis","pmids":["27666593"],"confidence":"High","gaps":["How TRIM14 selects USP14 over other DUBs not addressed","Whether mitochondrial localization is required for cGAS stabilization unclear"]},{"year":2016,"claim":"Showed TRIM14 can act directly against viral proteins, with its SPRY domain targeting HCV NS5A for K48-ubiquitination and degradation independently of IFN/NF-κB, distinguishing a degradative restriction activity from its scaffolding role.","evidence":"Domain-deletion mapping, Co-IP, ubiquitination and viral replication assays in KO/overexpression systems","pmids":["27578425"],"confidence":"High","gaps":["TRIM14 lacks a RING domain, so the E3 ligase executing K48-ubiquitination of NS5A is not defined","Direct vs. adaptor role in NS5A ubiquitination unresolved"]},{"year":2017,"claim":"Extended the mitochondrial scaffold concept by defining a WHIP–TRIM14–PPP6C ternary complex that optimizes RIG-I activation, showing TRIM14 organizes multiple signalosome components rather than acting alone.","evidence":"Pooled RNAi screen, yeast two-hybrid, reciprocal Co-IP, domain mapping, in vitro dephosphorylation assay","pmids":["29053956"],"confidence":"High","gaps":["Direct TRIM14 contacts within the complex not atomically mapped","Relationship between this complex and the MAVS–NEMO axis not integrated"]},{"year":2017,"claim":"Identified RNF125 as the negative regulator that limits TRIM14 abundance via K48-ubiquitination and proteasomal degradation, establishing how TRIM14-driven antiviral signaling is turned down.","evidence":"Reciprocal Co-IP, in cellulo ubiquitination assay, RNF125-deficient MEFs","pmids":["28476934"],"confidence":"High","gaps":["Signal that triggers RNF125-mediated turnover of TRIM14 unknown","Whether RNF125 acts on the mitochondrial pool specifically not determined"]},{"year":2018,"claim":"Placed TRIM14 as an interferon-stimulated gene driven by STAT1 and showed SPRY-mediated targeting of HBx, broadening the viral-restriction repertoire and linking TRIM14 induction to IFN-I.","evidence":"Promoter-binding/reporter assays, Co-IP domain mapping, viral replication assays","pmids":["30150992"],"confidence":"Medium","gaps":["Direct STAT1 promoter occupancy shown by reporter-equivalent rather than full ChIP","Mechanistic detail of HBx complex disruption inferred ('potentially')"]},{"year":2019,"claim":"Generalized the TRIM14–USP14 deubiquitination axis to noncanonical NF-κB by showing it protects p100/p52 from autophagic degradation, connecting TRIM14 to inflammatory tissue responses.","evidence":"Co-IP, K63 chain characterization, Trim14 KO mice, autophagy flux, colitis/tumor models","pmids":["31921549"],"confidence":"High","gaps":["Subcellular site of p100/p52 stabilization not specified","Whether the same complex operates in non-immune cells unaddressed"]},{"year":2019,"claim":"Provided atomic-level basis for TRIM14 target selection by solving the PRYSPRY structure and showing its basic surface binds acidic peptides, rationalizing its broad protein-interaction profile.","evidence":"X-ray crystallography and isothermal titration calorimetry","pmids":["30973643"],"confidence":"High","gaps":["No co-structure with a physiological partner","Does not explain how the same surface achieves stabilizing vs. degradative outcomes"]},{"year":2019,"claim":"Demonstrated domain-dependent dual control of a viral substrate, with PRYSPRY driving influenza NP degradation and a ΔS2 region stabilizing it, showing TRIM14 outputs are tunable by its own domains.","evidence":"Co-IP, domain-deletion mapping, ubiquitination assays, NP nuclear translocation imaging","pmids":["30873142"],"confidence":"High","gaps":["E3 ligase mediating NP K48-ubiquitination not identified","Physiological balance between the two domain activities in infection unclear"]},{"year":2019,"claim":"Defined a positive feedback loop in endothelium where TRIM14 binds NEMO to drive IκBα/p65 phosphorylation and p65 in turn induces TRIM14, linking TRIM14 to TNF-α-driven NF-κB amplification.","evidence":"Co-IP, promoter ChIP, ubiquitination assays in overexpression/knockdown cells","pmids":["31070748"],"confidence":"Medium","gaps":["Single-lab evidence for the feedback loop","Direct vs. scaffold-mediated NEMO activation not separated"]},{"year":2019,"claim":"Opened the oncogenic dimension by showing TRIM14 stabilizes pro-tumor effectors (ZEB2, Dvl2) and degrades tumor suppressor PTEN to drive proliferation, EMT, chemoresistance, and AKT activation.","evidence":"Knockdown/overexpression, ubiquitination and cycloheximide-chase stability assays, epistasis rescue, in vitro/in vivo tumor models","pmids":["30728039","29867201","31296997"],"confidence":"Medium","gaps":["Whether TRIM14 directly ubiquitinates these substrates or acts via recruited enzymes unresolved","Cell-type specificity of opposing stabilizing/degradative outcomes unexplained"]},{"year":2020,"claim":"Revealed a negative-regulatory scaffolding role in which TRIM14 bridges cGAS/TBK1 to STAT3 and promotes Ser727-STAT3 phosphorylation and SOCS3 to dampen type I IFN, showing TRIM14 can resolve as well as initiate IFN responses.","evidence":"Trim14 KO macrophages, Co-IP for cGAS and TBK1, phospho-specific blots, M. tuberculosis replication assays","pmids":["32404352"],"confidence":"High","gaps":["How TRIM14 switches between IFN-promoting and IFN-resolving modes unclear","Determinants of Ser727 vs Ser754 selectivity not defined"]},{"year":2022,"claim":"Showed TRIM14 builds a USP14/BRCC3 deubiquitinase complex to protect KDM4D from OPTN-mediated autophagy, linking TRIM14 to epigenetic (H3K9) control of proinflammatory cytokine expression in dendritic cells.","evidence":"Co-IP, K63 ubiquitination assays, autophagy flux, KO dendritic cells, histone methylation assays, autoimmune model","pmids":["35145029"],"confidence":"High","gaps":["Respective contributions of USP14 vs BRCC3 not dissected","Whether KDM4D stabilization occurs at chromatin or in cytoplasm unclear"]},{"year":2023,"claim":"Extended viral targeting to filoviruses, showing TRIM14 binds EBOV nucleoprotein, enhances IFN-β/NF-κB promoter activation, and restricts replication in vivo.","evidence":"Co-IP, IFN-β/NF-κB reporter assays, viral replication assay, TRIM14 KO mice","pmids":["37562033"],"confidence":"Medium","gaps":["Whether NP is degraded or merely sensed not resolved","Direct molecular consequence of the TRIM14–NP interaction undefined"]},{"year":2024,"claim":"Connected the TRIM14–USP14 stabilization axis to tumor immune evasion by showing IFNα-induced TRIM14 protects PD-L1 from autophagy, providing a pharmacological combination (IU1 + IFNα + anti-CTLA4) rationale.","evidence":"Co-IP, K63 ubiquitination assays, autophagy flux, KO/knockdown, CD8+ T-cell assays, in vivo tumor models with USP14 inhibitor","pmids":["38924473"],"confidence":"High","gaps":["Generality across tumor types beyond models tested unknown","How IFNα simultaneously induces TRIM14 and PD-L1 not fully integrated"]},{"year":2024,"claim":"Added tumor-suppressive substrate degradation, with TRIM14 binding and degrading GFAT1 to reduce hexosamine flux and O-glycosylation in NSCLC, and revealed TCF19 as an additional transcriptional driver of the TRIM14–TBK1–IFN-β axis.","evidence":"Co-IP, ubiquitination assays, metabolic rescue with N-acetyl-glucosamine, tumor assays; separate ChIP/promoter, humanized mouse, and CD8+ T-cell exhaustion assays","pmids":["38267812","37566545"],"confidence":"Medium","gaps":["Opposing pro- and anti-tumor roles across studies not reconciled","Direct E3 activity vs adaptor function for GFAT1 degradation unresolved"]},{"year":2025,"claim":"Consolidated TRIM14 as a TBK1 K63-ubiquitin enhancer and viral-protein degrader in the duck TMUV system, mapping specific ubiquitination sites on both TBK1 and viral NS1.","evidence":"Co-IP, site-specific mutagenesis (TBK1 K30/K401, NS1 K141), viral replication assays, in vivo duck infection","pmids":["40435148"],"confidence":"High","gaps":["Whether TRIM14 directly catalyzes TBK1 K63 chains given absence of a RING domain unclear","Conservation of these sites in mammalian TBK1 not addressed"]},{"year":2025,"claim":"Broadened the stabilizing axis to redox control, showing a radiation-induced TRIM14/USP14 complex removes K48 chains from GPX4 to suppress ferroptosis, with USP14 inhibition radiosensitizing HCC.","evidence":"CRISPR DUB screen, Co-IP, K48/K118 site mutagenesis, ferroptosis assays, PDX models","pmids":["40595451"],"confidence":"High","gaps":["Mechanism recruiting TRIM14 to the GPX4 locus after radiation unclear","Whether ferroptosis control is mitochondrial or cytosolic unresolved"]},{"year":2025,"claim":"Linked TRIM14 to tissue inflammation, driving NF-κB via IκBα degradation in microglia (neuroinflammation/pyroptosis) and via TRAF3 autophagic degradation in keratinocytes (psoriasis), reinforcing its proinflammatory scaffolding role across disease contexts.","evidence":"Knockdown/overexpression, ubiquitination and autophagy assays, AAV-CRISPR rat SCI model and psoriatic mouse model","pmids":["41250673","39933682"],"confidence":"Medium","gaps":["Single-lab, single-model evidence for each disease context","Direct vs indirect control of IκBα ubiquitination not resolved"]},{"year":null,"claim":"How a RING-less TRIM14 directs both K48/K63 substrate ubiquitination and DUB recruitment — i.e., which partner E3 ligases it co-opts and how the same PRYSPRY surface produces opposite stabilizing vs degradative outcomes — remains unresolved.","evidence":"No discovery in the timeline identifies the cognate E3 ligase(s) that execute TRIM14-directed ubiquitination","pmids":[],"confidence":"Low","gaps":["No catalytic E3 partner defined for TRIM14-mediated K48/K63 ubiquitination","No structural basis for the switch between substrate stabilization and degradation","Determinants of cell-type-specific antiviral vs pro-tumor outputs unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,15,16]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,8,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,6,17,4]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,6,15,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,8,17,19,24]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,6,16,17,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,9,20]}],"complexes":["WHIP-TRIM14-PPP6C complex","MAVS signalosome","TRIM14-USP14-BRCC3 deubiquitinase complex"],"partners":["MAVS","NEMO/IKBKG","USP14","CGAS","TBK1","BRCC3","STAT3","PPP6C"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14142","full_name":"Tripartite motif-containing protein 14","aliases":[],"length_aa":442,"mass_kda":49.8,"function":"Plays an essential role in the innate immune defense against viruses and bacteria (PubMed:30150992, PubMed:32404352). Promotes the 'Lys-48'-linked ubiquitination and subsequent degradation of hepatitis C virus NS5A leading to the inhibition of viral replication (PubMed:27578425). Also plays a role in the inhibition of ebolavirus infection by enhancing IFN-beta and NF-kappa-B activation after binding to the viral protein NP (PubMed:37562033). Facilitates the type I IFN response by interacting with MAVS at the outer mitochondria membrane and thereby recruiting NF-kappa-B essential modulator IKBKG/NEMO to the MAVS signalosome, leading to the activation of both the IFN regulatory factor 3/IRF3 and NF-kappa-B pathways (PubMed:24379373). Positively regulates the CGAS-induced type I interferon signaling pathway by stabilizing CGAS and inhibiting its autophagic degradation (PubMed:27666593). Acts as a scaffold between TBK1 and STAT3 to promote phosphorylation of STAT3 and resolve interferon-stimulated gene (ISG) expression (PubMed:32404352). Inhibits the transcriptional activity of SPI1 in a dose-dependent manner (By similarity). Also inhibits OPTN-mediated selective autophagic degradation of KDM4D and thereby negatively regulates H3K9me2 and H3K9me3. Mechanistically, recruits USP14 to remove the 'Lys-63'-linked ubiquitination of KDM4D, preventing its recognition by OPTN and subsequent degradation (PubMed:35145029)","subcellular_location":"Mitochondrion outer membrane; Cytoplasmic vesicle, phagosome; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q14142/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM14","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRIM14","total_profiled":1310},"omim":[{"mim_id":"606556","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 14; TRIM14","url":"https://www.omim.org/entry/606556"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRIM14"},"hgnc":{"alias_symbol":["KIAA0129"],"prev_symbol":[]},"alphafold":{"accession":"Q14142","domains":[{"cath_id":"2.60.120.920","chopping":"257-436","consensus_level":"high","plddt":90.3282,"start":257,"end":436},{"cath_id":"1.10.287","chopping":"138-223","consensus_level":"medium","plddt":89.6958,"start":138,"end":223}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14142","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14142-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14142-F1-predicted_aligned_error_v6.png","plddt_mean":85.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM14","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM14"},"sequence":{"accession":"Q14142","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14142.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14142/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14142"}},"corpus_meta":[{"pmid":"27666593","id":"PMC_27666593","title":"TRIM14 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osteoclastogenesis and noncanonical NF-κB activation by targeting p100/p52 in chronic periodontitis.","date":"2021","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/33901321","citation_count":5,"is_preprint":false},{"pmid":"35311471","id":"PMC_35311471","title":"The TRIM14-USP14-BRCC3 complex epigenetically regulates inflammation through inhibiting OPTN-mediated autophagic degradation of KDM4D.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/35311471","citation_count":5,"is_preprint":false},{"pmid":"38267812","id":"PMC_38267812","title":"TRIM14 suppressed the progression of NSCLC via hexosamine biosynthesis pathway.","date":"2024","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/38267812","citation_count":4,"is_preprint":false},{"pmid":"40431659","id":"PMC_40431659","title":"Identification of TRIM21 and TRIM14 as Antiviral Factors Against Langat and Zika Viruses.","date":"2025","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/40431659","citation_count":3,"is_preprint":false},{"pmid":"29053952","id":"PMC_29053952","title":"Unexpected Alliance of WHIP-TRIM14-PPP6C to Combat Viruses.","date":"2017","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/29053952","citation_count":2,"is_preprint":false},{"pmid":"41250673","id":"PMC_41250673","title":"TRIM14 Inhibition Suppresses Microglial Polarization and Pyroptosis Through the NF-κB/NLRP3 Pathway to Enhance Spinal Cord Injury Repair.","date":"2025","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/41250673","citation_count":1,"is_preprint":false},{"pmid":"40200729","id":"PMC_40200729","title":"TRIM14-NF-κB pathway in the anterior cingulate cortex modulates comorbid depressive symptoms in chronic pain.","date":"2025","source":"Molecular pain","url":"https://pubmed.ncbi.nlm.nih.gov/40200729","citation_count":1,"is_preprint":false},{"pmid":"41710718","id":"PMC_41710718","title":"The TRIM14-KIF1B Axis Drives Renal Injury in Diabetic Nephropathy Through TLR4/NF-κB Pathway Modulation.","date":"2026","source":"Diabetes, metabolic syndrome and obesity : targets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41710718","citation_count":1,"is_preprint":false},{"pmid":"41463095","id":"PMC_41463095","title":"TRIM14 Regulation of Copper Homeostasis and Cuproptosis: A New Strategy to Overcome Chemoresistance in Glioblastoma.","date":"2025","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/41463095","citation_count":0,"is_preprint":false},{"pmid":"35601146","id":"PMC_35601146","title":"Corrigendum to \"miR-195-5p Suppresses the Proliferation, Migration, and Invasion of Oral Squamous Cell Carcinoma by Targeting TRIM14\".","date":"2022","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/35601146","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":36274,"output_tokens":7163,"usd":0.108133,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16425,"output_tokens":6750,"usd":0.125438,"stage2_stop_reason":"end_turn"},"total_usd":0.233571,"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\": 2013,\n      \"finding\": \"TRIM14 localizes to the outer membrane of mitochondria and interacts with MAVS. Upon viral infection, TRIM14 undergoes Lys-63-linked polyubiquitination at Lys-365 and recruits NF-κB essential modulator (NEMO) to the MAVS signalosome, leading to activation of both the IRF3 and NF-κB pathways. Knockdown of TRIM14 disrupts the NEMO-MAVS association and attenuates the antiviral response.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation/mitochondria localization, knockdown (siRNA), site-directed mutagenesis (K365 ubiquitination), reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, defined subcellular localization with functional consequence, site-specific ubiquitination mapping, KD phenotype; foundational mechanism paper replicated by multiple subsequent studies\",\n      \"pmids\": [\"24379373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIM14 stabilizes cGAS by recruiting the deubiquitinase USP14, which cleaves K48-linked ubiquitin chains from cGAS at lysine 414, preventing p62-dependent selective autophagic degradation of cGAS. TRIM14 knockout impairs HSV-1-triggered antiviral responses and Trim14−/− mice are highly susceptible to lethal HSV-1 infection.\",\n      \"method\": \"Co-immunoprecipitation, knockout mice, ubiquitination assays, in vitro deubiquitination assay, autophagy flux assays, site-directed mutagenesis (K414)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, KO mice, in vitro DUB assay, mutagenesis), in vivo validation, identifies specific ubiquitin site and enzyme\",\n      \"pmids\": [\"27666593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIM14 inhibits HCV replication through its C-terminal SPRY domain, which interacts with the HCV NS5A protein (specifically the NS5A1 subdomain) and induces its K48-linked ubiquitination and degradation, independently of NF-κB or IFN pathway activation.\",\n      \"method\": \"Overexpression, knockout, domain-deletion mapping, co-immunoprecipitation, ubiquitination assays, viral replication assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, domain mapping, KO, ubiquitination assay, multiple orthogonal methods in single study; mechanism is SPRY-domain-mediated K48-ubiquitination of NS5A\",\n      \"pmids\": [\"27578425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIM14 acts as a mitochondrial docking platform for assembly of a WHIP-TRIM14-PPP6C complex that promotes RIG-I mitochondrial localization and optimal activation. WHIP bridges RIG-I with MAVS via its ubiquitin-binding domain interacting with polyUb chains on RIG-I at K164, and PPP6C dephosphorylates RIG-I. The ATPase domain of WHIP stabilizes the RIG-I–dsRNA interaction.\",\n      \"method\": \"Pooled RNAi screen, yeast two-hybrid, co-immunoprecipitation, domain-deletion mapping, in vitro dephosphorylation assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid + reciprocal Co-IP + biochemical assays + domain mapping + functional readouts; defines the ternary signalosome\",\n      \"pmids\": [\"29053956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RNF125 functions as an E3 ubiquitin ligase that interacts with TRIM14, catalyzes K48-linked polyubiquitination of TRIM14, and promotes its proteasomal degradation, thereby acting as a negative regulator of TRIM14-mediated innate antiviral signaling. RNF125-deficient MEFs retain TRIM14 protein at late time points of viral infection.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, overexpression, knockdown, RNF125-deficient MEFs\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in cellulo ubiquitination assay with genetic KO validation; identifies specific E3 ligase-substrate pair with functional consequence\",\n      \"pmids\": [\"28476934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM14 inhibits HBV replication as an IFN-I-stimulated gene (ISG) whose transcription is directly activated by STAT1 (but not STAT3) binding to the TRIM14 promoter. The TRIM14 SPRY domain interacts with the C-terminal domain of HBx, potentially blocking HBx-facilitated formation of the Smc-HBx-DDB1 complex required for HBV replication.\",\n      \"method\": \"Reporter assays (ChIP-equivalent promoter binding), co-immunoprecipitation, domain mapping, overexpression, knockdown, viral replication assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for SPRY-HBx interaction, promoter-binding assay for STAT1; single lab, two orthogonal methods\",\n      \"pmids\": [\"30150992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM14 promotes noncanonical NF-κB signaling by recruiting deubiquitinase USP14 to cleave K63-linked ubiquitin chains from p100/p52 at multiple sites, thereby preventing p62-mediated selective autophagic degradation of p100/p52 and sustaining noncanonical NF-κB activation. Trim14-deficient mice show impaired noncanonical NF-κB-mediated inflammatory responses.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, knockout mice, autophagy flux assays, in vivo colitis/tumor models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, specific ubiquitin-chain type identified, KO mice in vivo, multiple orthogonal methods; extends the TRIM14-USP14 axis to noncanonical NF-κB\",\n      \"pmids\": [\"31921549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The crystal structure of the TRIM14 PRYSPRY domain reveals a positively charged (basic) surface that mediates protein-protein interactions preferentially with acidic amino acid residues, as validated by isothermal titration calorimetry showing binding of the domain to acidic peptides.\",\n      \"method\": \"X-ray crystallography, isothermal titration calorimetry (ITC)\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus ITC binding validation; single lab but two orthogonal methods including atomic resolution structure\",\n      \"pmids\": [\"30973643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM14 interacts with the viral nucleoprotein (NP) of Influenza A virus through multiple domains: the PRYSPRY domain promotes K48-linked ubiquitination and proteasomal degradation of NP (inhibiting viral RNP formation and NP nuclear translocation), while the ΔS2 domain antagonizes this by stabilizing NP. TRIM14 restricts IAV replication in an IFN/NF-κB-independent manner.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion mapping, ubiquitination assays, viral replication assays, NP nuclear translocation imaging\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mapping, ubiquitination assay, subcellular localization readout, multiple independent functional assays\",\n      \"pmids\": [\"30873142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM14 promotes NF-κB activation in vascular endothelial cells by directly binding to NEMO (IKK complex) upon TNF-α stimulation, promoting IκBα and p65 phosphorylation in a manner dependent on K63-linked ubiquitination of TRIM14. p65 in turn binds directly to the TRIM14 promoter to enhance TRIM14 transcription, forming a positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, promoter ChIP (p65 binding to TRIM14 promoter), ubiquitination assays, overexpression, knockdown\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for NEMO interaction, ChIP for promoter binding, ubiquitination assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31070748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM14 inactivation in glioblastoma cells causes ubiquitination and proteasomal degradation of ZEB2, a transcription factor involved in EMT, indicating that TRIM14 stabilizes ZEB2 by preventing its ubiquitination.\",\n      \"method\": \"Knockdown (shRNA), ubiquitination assays, cycloheximide chase (stability analysis), western blot\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — ubiquitination assay and stability assay; single lab, two complementary but not fully orthogonal methods\",\n      \"pmids\": [\"30728039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IRF-1 and IRF-2 bind to the TRIM14 promoter (at a GC box and ISRE element) and activate TRIM14 transcription; IRF-1 mediates IFN-α-induced upregulation of TRIM14, while IRF-2 is required for basal TRIM14 transcription. Knockdown of IRF-1 reduces IFN-α-stimulated TRIM14 expression.\",\n      \"method\": \"Promoter reporter assays, EMSA/ChIP (IRF binding to TRIM14 promoter), siRNA knockdown, RT-PCR\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — promoter reporter + IRF binding assay + KD functional readout; single lab\",\n      \"pmids\": [\"31150153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM14 stabilizes Dishevelled 2 (Dvl2) protein in glioma cells, activating canonical Wnt/β-catenin signaling and promoting chemoresistance to temozolomide. Inhibition of Dvl2 reverses the oncogenic effects of TRIM14 overexpression on chemoresistance.\",\n      \"method\": \"Overexpression, knockdown, western blot (Dvl2 stability), in vitro and in vivo TMZ resistance assays, pharmacological inhibition of Dvl2\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — protein stability assay plus epistasis via Dvl2 inhibition; single lab, two complementary approaches\",\n      \"pmids\": [\"29867201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM14 co-localizes with PTEN in the cytoplasm and induces PTEN ubiquitination, leading to PTEN degradation and downstream AKT pathway activation to promote colorectal cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation/co-localization, ubiquitination assay, western blot, overexpression/knockdown, epistasis via PTEN overexpression rescue\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization + ubiquitination assay + epistasis rescue; single lab, multiple approaches\",\n      \"pmids\": [\"31296997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM14 interacts with PPM1A and mediates its ubiquitination in human nucleus pulposus cells, promoting NF-κB p65 activation and TNF-α-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, western blot\",\n      \"journal\": \"Artificial cells, nanomedicine, and biotechnology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus ubiquitination assay; single lab, limited mechanistic validation\",\n      \"pmids\": [\"31322007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Mycobacterium tuberculosis-infected macrophages, TRIM14 acts as a negative regulator of type I IFN responses by interacting with both cGAS and TBK1, acting as a scaffold to promote STAT3 phosphorylation at Ser727 (over Ser754), thereby upregulating SOCS3 to resolve IFN signaling. Trim14 KO macrophages hyperinduce ISG expression and are better at restricting M. tuberculosis replication.\",\n      \"method\": \"Knockout macrophages, co-immunoprecipitation (cGAS and TBK1 interaction), phospho-specific western blot, cytokine/ISG measurement, bacterial colony assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO macrophages with defined molecular phenotype, Co-IP for two interacting partners, phospho-specific readout, multiple orthogonal methods\",\n      \"pmids\": [\"32404352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM14 recruits deubiquitinases USP14 and BRCC3 to form a regulatory complex that cleaves K63-linked ubiquitin chains from the histone demethylase KDM4D, thereby preventing OPTN (optineurin)-mediated selective autophagic degradation of KDM4D. This preserves KDM4D-mediated inhibition of histone H3K9 trimethylation, epigenetically promoting IL-12 and IL-23 expression in dendritic cells. TRIM14 deficiency in dendritic cells impairs proinflammatory cytokine expression and protects mice from autoimmune inflammation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, autophagy flux assays, KO dendritic cells, histone methylation assays, in vivo autoimmune model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP identifying ternary complex, specific ubiquitin chain type, selective autophagy receptor identified, KO in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"35145029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM14 recruits USP14 to inhibit autophagic degradation of PD-L1 by removing K63-linked ubiquitin chains from PD-L1, impairing recognition of PD-L1 by the cargo receptor p62 for autophagic degradation. IFNα transcriptionally upregulates TRIM14, which then stabilizes PD-L1 and suppresses CD8+ T cell-mediated antitumor activity. Combining USP14 inhibitor IU1 with IFNα and anti-CTLA4 effectively suppresses tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays (K63 chain type), autophagy flux assays, KO/knockdown, CD8+ T cell functional assays, in vivo tumor models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, specific ubiquitin chain characterization, autophagic flux assay, in vivo tumor model with pharmacological validation; multiple orthogonal methods\",\n      \"pmids\": [\"38924473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM14 assembles at the GPX4 locus following radiation and recruits USP14, forming a TRIM14/USP14 complex that removes K48-linked polyubiquitination from GPX4 at K48 or K118, thereby stabilizing GPX4 and suppressing radiation-induced ferroptosis. Pharmacological inhibition of USP14 sensitizes HCC to radiotherapy.\",\n      \"method\": \"CRISPR-based DUB screen, co-immunoprecipitation, ubiquitination site mapping (K48/K118 mutagenesis), in vitro ferroptosis assays, patient-derived xenograft models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR screen plus Co-IP, site-specific mutagenesis at ubiquitination sites, PDX in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"40595451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM14 interacts with duck TBK1 and promotes its K63-linked polyubiquitination on K30 and K401, augmenting IFN-β production during TMUV infection. Separately, TRIM14 interacts with TMUV NS1 protein, facilitating K27/K29-linked polyubiquitination of NS1 and its proteasomal degradation; K141 on NS1 is critical for this process.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination site mapping (mutagenesis of TBK1 K30/K401 and NS1 K141), in vitro viral replication assays, in vivo (duck) infection model\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific mutagenesis for multiple ubiquitination sites, Co-IP, in vivo validation; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"40435148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM14 promotes IκBα ubiquitination and degradation in spinal cord microglia, thereby activating NF-κB and driving M1 polarization and NLRP3-mediated pyroptosis. TRIM14 knockdown stabilizes IκBα, suppresses NF-κB/NLRP3 signaling, attenuates neuroinflammation, and improves locomotor recovery in rats after spinal cord injury.\",\n      \"method\": \"Knockdown/overexpression, ubiquitination assay (IκBα), western blot (phospho-NF-κB), AAV-CRISPR in vivo, rat SCI model\",\n      \"journal\": \"Mediators of inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — ubiquitination assay plus in vivo KD; single lab with complementary in vitro and in vivo methods\",\n      \"pmids\": [\"41250673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM14 directly binds to GFAT1 (glutamine fructose-6-phosphate amidotransferase 1), a rate-limiting enzyme of the hexosamine biosynthetic pathway, and promotes its ubiquitination and degradation, reducing O-glycosylation and suppressing NSCLC cell proliferation and migration. N-acetyl-D-glucosamine supplementation rescues the inhibitory effect.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, rescue experiment (N-acetyl-glucosamine), knockdown/overexpression, in vitro and in vivo tumor assays\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP identifies GFAT1 as substrate, ubiquitination assay, metabolic rescue; single lab, multiple approaches\",\n      \"pmids\": [\"38267812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TCF19 transcriptionally promotes TRIM14 expression, and the TCF19-TRIM14 axis activates TBK1-IRF3-IFN-β signaling; enhanced IFN-β secretion facilitates CD8+ T cell exhaustion via differentiation reprogramming in MSI endometrial cancer.\",\n      \"method\": \"ChIP/promoter analysis (TCF19 binding to TRIM14 promoter), overexpression/knockdown, IFN-β ELISA, humanized mouse models, CD8+ T cell functional assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — promoter binding assay plus humanized model; single lab, multiple methods\",\n      \"pmids\": [\"37566545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM14 binds to TRAF3 and mediates its autophagic degradation via the selective autophagy receptor NDP52, activating the NF-κB pathway and driving psoriasis-associated keratinocyte proliferation and inflammation.\",\n      \"method\": \"Co-immunoprecipitation (TRIM14-TRAF3 and TRIM14-NDP52 interactions), autophagy flux assays, overexpression/knockdown, in vivo psoriatic mouse model\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for two interactions, autophagy assay, in vivo model; single lab with multiple approaches\",\n      \"pmids\": [\"39933682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM14 interacts with EBOV nucleoprotein, and this interaction enhances IFN-β and NF-κB promoter activation. TRIM14 overexpression reduces EBOV replication ~10-fold in an infectious but biologically contained system. TRIM14-deficient mice are more susceptible to mouse-adapted EBOV infection.\",\n      \"method\": \"Co-immunoprecipitation, reporter assays (IFN-β and NF-κB promoters), viral replication assay, TRIM14 KO mice\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus KO in vivo plus viral replication assay; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37562033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Co-immunoprecipitation confirmed a direct interaction between TRIM14 and KIF1B in kidney tubular epithelial cells under high-glucose conditions, with TRIM14 positively regulating KIF1B expression; TRIM14 knockdown suppresses the TLR4/NF-κB pathway and mitigates high-glucose-induced apoptosis, oxidative stress, and inflammation.\",\n      \"method\": \"Co-immunoprecipitation, transcriptome sequencing, knockdown, western blot (TLR4/NF-κB), in vitro HK-2 cell assays\",\n      \"journal\": \"Diabetes, metabolic syndrome and obesity\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying novel interactor; single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"41710718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Co-immunoprecipitation assays revealed a potential interaction between TRIM14 and ATP7A (copper-exporting ATPase) in glioma cells, and combined TMZ and CuCl2 treatment suppresses TRIM14 expression and downregulates the TRIM14-ATP7A axis, inhibiting non-canonical NF-κB signaling and inducing cuproptosis.\",\n      \"method\": \"Co-immunoprecipitation, western blot, immunofluorescence, in vitro and in vivo xenograft models\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for TRIM14-ATP7A; single lab, limited mechanistic validation of direct functional relationship\",\n      \"pmids\": [\"41463095\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM14 is a mitochondrial scaffold protein (lacking a RING-domain E3 ligase) that promotes innate antiviral and inflammatory signaling by (1) anchoring MAVS-associated signalosomes on mitochondria and recruiting NEMO, (2) stabilizing key immune regulators (cGAS, p100/p52, KDM4D, PD-L1, GPX4) by recruiting deubiquitinase USP14—and also BRCC3—to remove K48- or K63-linked ubiquitin chains that would otherwise target these proteins for p62- or OPTN-mediated selective autophagic degradation, (3) acting as a scaffold between TBK1 and STAT3 to resolve type I IFN responses via Ser727-STAT3 phosphorylation, (4) directly promoting K63-ubiquitination of TBK1 to enhance IFN-β production, (5) restricting viral replication through SPRY-domain-mediated K48-ubiquitination and proteasomal degradation of viral proteins (HCV NS5A, HBx, IAV NP, TMUV NS1), and (6) activating NF-κB in diverse cell types by binding NEMO and promoting IκBα degradation, with its own expression transcriptionally controlled by IRF-1/IRF-2 and STAT1 through an ISRE in its promoter.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM14 is a mitochondrial outer-membrane scaffold protein that integrates innate antiviral and inflammatory signaling and, in cancer contexts, stabilizes a broad set of substrate proteins by controlling their ubiquitination-dependent turnover [#0, #1]. In RNA-virus sensing, it docks at MAVS, undergoes K63-linked polyubiquitination at Lys365, and recruits NEMO to the MAVS signalosome to drive IRF3 and NF-\\u03baB activation [#0]; it further serves as a mitochondrial platform for a WHIP–TRIM14–PPP6C complex that optimizes RIG-I localization and activation [#3]. A recurrent mechanism is the recruitment of the deubiquitinase USP14 (and BRCC3) to remove K48- or K63-linked ubiquitin chains from client proteins, sparing them from p62- or OPTN-mediated selective autophagic degradation: this axis stabilizes cGAS to support DNA-virus antiviral responses [#1], sustains noncanonical NF-\\u03baB by protecting p100/p52 [#6], preserves KDM4D to maintain H3K9 demethylation and proinflammatory IL-12/IL-23 expression in dendritic cells [#16], and stabilizes the immune checkpoint ligand PD-L1 to suppress CD8+ T-cell antitumor activity [#17]. Conversely, through its C-terminal PRYSPRY/SPRY domain—whose basic surface mediates interactions with acidic targets [#7]—TRIM14 restricts viral replication by directing K48-linked ubiquitination and proteasomal degradation of viral proteins including HCV NS5A, HBx, influenza A NP, and TMUV NS1 [#2, #5, #8, #19]. TRIM14 also directly promotes K63-ubiquitination of TBK1 to enhance IFN-\\u03b2 production [#19] and acts as a TBK1–STAT3 scaffold that resolves type I IFN signaling via Ser727-STAT3 phosphorylation and SOCS3 induction during M. tuberculosis infection [#15]. TRIM14 expression is itself an interferon- and inflammation-responsive node, transcriptionally activated by IRF-1/IRF-2 and STAT1 through promoter ISRE/GC elements [#5, #11]. In tumor and inflammatory tissues it activates NF-\\u03baB by binding NEMO or promoting I\\u03baB\\u03b1 degradation [#9, #20] and stabilizes oncogenic effectors, while its own level is restrained by RNF125-mediated K48-ubiquitination and proteasomal degradation [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established the founding mechanism by placing TRIM14 on mitochondria as a MAVS-associated scaffold that recruits NEMO, defining how a RING-less TRIM links the antiviral sensor platform to downstream IRF3/NF-\\u03baB activation.\",\n      \"evidence\": \"Co-IP, mitochondrial fractionation, K365 ubiquitination mutagenesis, and siRNA knockdown with reporter readouts\",\n      \"pmids\": [\"24379373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase responsible for K365 K63-ubiquitination of TRIM14 not identified here\", \"Stoichiometry and architecture of the MAVS–TRIM14–NEMO signalosome unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined TRIM14's stabilizing arm by showing it recruits USP14 to deubiquitinate cGAS and block its autophagic degradation, explaining how TRIM14 supports DNA-virus sensing in vivo.\",\n      \"evidence\": \"Co-IP, Trim14 KO mice with HSV-1 challenge, in vitro DUB assay, autophagy flux, K414 mutagenesis\",\n      \"pmids\": [\"27666593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRIM14 selects USP14 over other DUBs not addressed\", \"Whether mitochondrial localization is required for cGAS stabilization unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed TRIM14 can act directly against viral proteins, with its SPRY domain targeting HCV NS5A for K48-ubiquitination and degradation independently of IFN/NF-\\u03baB, distinguishing a degradative restriction activity from its scaffolding role.\",\n      \"evidence\": \"Domain-deletion mapping, Co-IP, ubiquitination and viral replication assays in KO/overexpression systems\",\n      \"pmids\": [\"27578425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TRIM14 lacks a RING domain, so the E3 ligase executing K48-ubiquitination of NS5A is not defined\", \"Direct vs. adaptor role in NS5A ubiquitination unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended the mitochondrial scaffold concept by defining a WHIP–TRIM14–PPP6C ternary complex that optimizes RIG-I activation, showing TRIM14 organizes multiple signalosome components rather than acting alone.\",\n      \"evidence\": \"Pooled RNAi screen, yeast two-hybrid, reciprocal Co-IP, domain mapping, in vitro dephosphorylation assay\",\n      \"pmids\": [\"29053956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct TRIM14 contacts within the complex not atomically mapped\", \"Relationship between this complex and the MAVS–NEMO axis not integrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified RNF125 as the negative regulator that limits TRIM14 abundance via K48-ubiquitination and proteasomal degradation, establishing how TRIM14-driven antiviral signaling is turned down.\",\n      \"evidence\": \"Reciprocal Co-IP, in cellulo ubiquitination assay, RNF125-deficient MEFs\",\n      \"pmids\": [\"28476934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal that triggers RNF125-mediated turnover of TRIM14 unknown\", \"Whether RNF125 acts on the mitochondrial pool specifically not determined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed TRIM14 as an interferon-stimulated gene driven by STAT1 and showed SPRY-mediated targeting of HBx, broadening the viral-restriction repertoire and linking TRIM14 induction to IFN-I.\",\n      \"evidence\": \"Promoter-binding/reporter assays, Co-IP domain mapping, viral replication assays\",\n      \"pmids\": [\"30150992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct STAT1 promoter occupancy shown by reporter-equivalent rather than full ChIP\", \"Mechanistic detail of HBx complex disruption inferred ('potentially')\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Generalized the TRIM14–USP14 deubiquitination axis to noncanonical NF-\\u03baB by showing it protects p100/p52 from autophagic degradation, connecting TRIM14 to inflammatory tissue responses.\",\n      \"evidence\": \"Co-IP, K63 chain characterization, Trim14 KO mice, autophagy flux, colitis/tumor models\",\n      \"pmids\": [\"31921549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subcellular site of p100/p52 stabilization not specified\", \"Whether the same complex operates in non-immune cells unaddressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided atomic-level basis for TRIM14 target selection by solving the PRYSPRY structure and showing its basic surface binds acidic peptides, rationalizing its broad protein-interaction profile.\",\n      \"evidence\": \"X-ray crystallography and isothermal titration calorimetry\",\n      \"pmids\": [\"30973643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-structure with a physiological partner\", \"Does not explain how the same surface achieves stabilizing vs. degradative outcomes\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated domain-dependent dual control of a viral substrate, with PRYSPRY driving influenza NP degradation and a \\u0394S2 region stabilizing it, showing TRIM14 outputs are tunable by its own domains.\",\n      \"evidence\": \"Co-IP, domain-deletion mapping, ubiquitination assays, NP nuclear translocation imaging\",\n      \"pmids\": [\"30873142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating NP K48-ubiquitination not identified\", \"Physiological balance between the two domain activities in infection unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a positive feedback loop in endothelium where TRIM14 binds NEMO to drive I\\u03baB\\u03b1/p65 phosphorylation and p65 in turn induces TRIM14, linking TRIM14 to TNF-\\u03b1-driven NF-\\u03baB amplification.\",\n      \"evidence\": \"Co-IP, promoter ChIP, ubiquitination assays in overexpression/knockdown cells\",\n      \"pmids\": [\"31070748\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab evidence for the feedback loop\", \"Direct vs. scaffold-mediated NEMO activation not separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Opened the oncogenic dimension by showing TRIM14 stabilizes pro-tumor effectors (ZEB2, Dvl2) and degrades tumor suppressor PTEN to drive proliferation, EMT, chemoresistance, and AKT activation.\",\n      \"evidence\": \"Knockdown/overexpression, ubiquitination and cycloheximide-chase stability assays, epistasis rescue, in vitro/in vivo tumor models\",\n      \"pmids\": [\"30728039\", \"29867201\", \"31296997\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TRIM14 directly ubiquitinates these substrates or acts via recruited enzymes unresolved\", \"Cell-type specificity of opposing stabilizing/degradative outcomes unexplained\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a negative-regulatory scaffolding role in which TRIM14 bridges cGAS/TBK1 to STAT3 and promotes Ser727-STAT3 phosphorylation and SOCS3 to dampen type I IFN, showing TRIM14 can resolve as well as initiate IFN responses.\",\n      \"evidence\": \"Trim14 KO macrophages, Co-IP for cGAS and TBK1, phospho-specific blots, M. tuberculosis replication assays\",\n      \"pmids\": [\"32404352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRIM14 switches between IFN-promoting and IFN-resolving modes unclear\", \"Determinants of Ser727 vs Ser754 selectivity not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed TRIM14 builds a USP14/BRCC3 deubiquitinase complex to protect KDM4D from OPTN-mediated autophagy, linking TRIM14 to epigenetic (H3K9) control of proinflammatory cytokine expression in dendritic cells.\",\n      \"evidence\": \"Co-IP, K63 ubiquitination assays, autophagy flux, KO dendritic cells, histone methylation assays, autoimmune model\",\n      \"pmids\": [\"35145029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Respective contributions of USP14 vs BRCC3 not dissected\", \"Whether KDM4D stabilization occurs at chromatin or in cytoplasm unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended viral targeting to filoviruses, showing TRIM14 binds EBOV nucleoprotein, enhances IFN-\\u03b2/NF-\\u03baB promoter activation, and restricts replication in vivo.\",\n      \"evidence\": \"Co-IP, IFN-\\u03b2/NF-\\u03baB reporter assays, viral replication assay, TRIM14 KO mice\",\n      \"pmids\": [\"37562033\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NP is degraded or merely sensed not resolved\", \"Direct molecular consequence of the TRIM14–NP interaction undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected the TRIM14–USP14 stabilization axis to tumor immune evasion by showing IFN\\u03b1-induced TRIM14 protects PD-L1 from autophagy, providing a pharmacological combination (IU1 + IFN\\u03b1 + anti-CTLA4) rationale.\",\n      \"evidence\": \"Co-IP, K63 ubiquitination assays, autophagy flux, KO/knockdown, CD8+ T-cell assays, in vivo tumor models with USP14 inhibitor\",\n      \"pmids\": [\"38924473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality across tumor types beyond models tested unknown\", \"How IFN\\u03b1 simultaneously induces TRIM14 and PD-L1 not fully integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added tumor-suppressive substrate degradation, with TRIM14 binding and degrading GFAT1 to reduce hexosamine flux and O-glycosylation in NSCLC, and revealed TCF19 as an additional transcriptional driver of the TRIM14–TBK1–IFN-\\u03b2 axis.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, metabolic rescue with N-acetyl-glucosamine, tumor assays; separate ChIP/promoter, humanized mouse, and CD8+ T-cell exhaustion assays\",\n      \"pmids\": [\"38267812\", \"37566545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposing pro- and anti-tumor roles across studies not reconciled\", \"Direct E3 activity vs adaptor function for GFAT1 degradation unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Consolidated TRIM14 as a TBK1 K63-ubiquitin enhancer and viral-protein degrader in the duck TMUV system, mapping specific ubiquitination sites on both TBK1 and viral NS1.\",\n      \"evidence\": \"Co-IP, site-specific mutagenesis (TBK1 K30/K401, NS1 K141), viral replication assays, in vivo duck infection\",\n      \"pmids\": [\"40435148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRIM14 directly catalyzes TBK1 K63 chains given absence of a RING domain unclear\", \"Conservation of these sites in mammalian TBK1 not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadened the stabilizing axis to redox control, showing a radiation-induced TRIM14/USP14 complex removes K48 chains from GPX4 to suppress ferroptosis, with USP14 inhibition radiosensitizing HCC.\",\n      \"evidence\": \"CRISPR DUB screen, Co-IP, K48/K118 site mutagenesis, ferroptosis assays, PDX models\",\n      \"pmids\": [\"40595451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism recruiting TRIM14 to the GPX4 locus after radiation unclear\", \"Whether ferroptosis control is mitochondrial or cytosolic unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked TRIM14 to tissue inflammation, driving NF-\\u03baB via I\\u03baB\\u03b1 degradation in microglia (neuroinflammation/pyroptosis) and via TRAF3 autophagic degradation in keratinocytes (psoriasis), reinforcing its proinflammatory scaffolding role across disease contexts.\",\n      \"evidence\": \"Knockdown/overexpression, ubiquitination and autophagy assays, AAV-CRISPR rat SCI model and psoriatic mouse model\",\n      \"pmids\": [\"41250673\", \"39933682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab, single-model evidence for each disease context\", \"Direct vs indirect control of I\\u03baB\\u03b1 ubiquitination not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a RING-less TRIM14 directs both K48/K63 substrate ubiquitination and DUB recruitment — i.e., which partner E3 ligases it co-opts and how the same PRYSPRY surface produces opposite stabilizing vs degradative outcomes — remains unresolved.\",\n      \"evidence\": \"No discovery in the timeline identifies the cognate E3 ligase(s) that execute TRIM14-directed ubiquitination\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No catalytic E3 partner defined for TRIM14-mediated K48/K63 ubiquitination\", \"No structural basis for the switch between substrate stabilization and degradation\", \"Determinants of cell-type-specific antiviral vs pro-tumor outputs unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 15, 16]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 8, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 6, 17, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005741\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 6, 15, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 8, 17, 19, 24]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 6, 16, 17, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 9, 20]}\n    ],\n    \"complexes\": [\n      \"WHIP-TRIM14-PPP6C complex\",\n      \"MAVS signalosome\",\n      \"TRIM14-USP14-BRCC3 deubiquitinase complex\"\n    ],\n    \"partners\": [\n      \"MAVS\",\n      \"NEMO/IKBKG\",\n      \"USP14\",\n      \"cGAS\",\n      \"TBK1\",\n      \"BRCC3\",\n      \"STAT3\",\n      \"PPP6C\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}