{"gene":"TRIM56","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2010,"finding":"TRIM56 is an E3 ubiquitin ligase that interacts with STING and targets it for K63-linked ubiquitination, which induces STING dimerization; this dimerization is a prerequisite for recruitment of the antiviral kinase TBK1 and subsequent IFN-β induction in response to cytosolic dsDNA.","method":"Co-immunoprecipitation, overexpression and knockdown with IFN-β promoter reporter assay, ubiquitination assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, K63 ubiquitination assay, functional rescue experiments, replicated in subsequent studies","pmids":["21074459"],"is_preprint":false},{"year":2011,"finding":"TRIM56 restricts bovine viral diarrhea virus (BVDV) replication in a manner dependent on its E3 ubiquitin ligase activity and the integrity of its C-terminal region, but independent of any general augmentation of the interferon response or effects on IRF3 stability.","method":"Overexpression and RNAi knockdown with viral replication assays; E3 ligase-dead mutant analysis; domain deletion mapping","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotype, domain mapping, single lab","pmids":["21289118"],"is_preprint":false},{"year":2012,"finding":"TRIM56 positively regulates TLR3 signaling by physically interacting with the adaptor protein TRIF; this interaction (mediated by the C-terminal portion of TRIM56, residues 621–750) is required for potentiation of IRF3 activation and IFN-β induction, independent of E3 ligase activity.","method":"Co-immunoprecipitation, overexpression and knockdown with IRF3 activation and IFN-β reporter assays, C-terminal deletion mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain-deletion mutants, multiple functional readouts, replicated in later work","pmids":["22948160"],"is_preprint":false},{"year":2014,"finding":"TRIM56 restricts yellow fever virus (YFV) and dengue virus serotype 2 (DENV2) by suppressing intracellular viral RNA accumulation, requiring both E3 ligase activity (RING domain) and C-terminal integrity; restriction of HCoV-OC43 requires only E3 ligase activity and acts at a post-RNA-replication step in the viral life cycle.","method":"Conditional mutant cell lines (Tet-regulated), viral RNA quantification, domain deletion and RING mutant analysis","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — engineered cell lines with multiple mutants, distinct mechanistic outcomes per virus confirmed orthogonally","pmids":["25253338"],"is_preprint":false},{"year":2016,"finding":"TRIM56 restricts influenza A and B viruses by impeding intracellular viral RNA synthesis via its short 63-residue C-terminal tail segment, independently of E3 ligase activity, B-box, or coiled-coil domain; expression of this tail segment alone was sufficient for antiviral activity.","method":"Domain deletion mutants, E3 ligase-dead mutant, overexpression/knockdown with viral RNA synthesis assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple domain mutants, minimal-sufficient fragment identified, specific viral RNA synthesis assay","pmids":["26889027"],"is_preprint":false},{"year":2017,"finding":"TRIM56 functions as an E3 ubiquitin ligase that ubiquitinates and targets vimentin for proteasomal degradation in normal ovarian epithelial cells, thereby suppressing EMT and cell migration/invasion; loss of TRIM56 in ovarian cancer cells leads to vimentin stabilization.","method":"Mass spectrometry of vimentin immunoprecipitate, RNAi knockdown and overexpression, proteasome inhibitor assay, in vitro migration/invasion","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified substrate, functional rescue with OE/KD, single lab","pmids":["28771721"],"is_preprint":false},{"year":2018,"finding":"TRIM56 E3 ligase induces monoubiquitination of cGAS at Lys335, which markedly increases cGAS dimerization, DNA-binding activity, and cGAMP production, thereby promoting IFN-αβ production against DNA viruses; TRIM56-deficient mice show impaired IFN-αβ and high susceptibility to HSV-1.","method":"Ubiquitination assays (monoubiquitination site mapping), cGAS dimerization assays, cGAMP ELISA, TRIM56-KO mice, HSV-1 infection model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — site-specific ubiquitination mapping, biochemical activity assays, in vivo KO mouse model, multiple orthogonal methods","pmids":["29426904"],"is_preprint":false},{"year":2018,"finding":"TRIM56 interacts with the AF1 domain of estrogen receptor alpha (ERα) via its WD40 domain in the cytoplasm and promotes K63-linked ubiquitination of ERα, prolonging ERα protein stability and sustaining estrogen signaling in breast cancer cells.","method":"Co-immunoprecipitation, domain mapping (WD40 deletion), ubiquitination assay, TRIM56 knockdown with ERα stability measurement","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, ubiquitination assay, functional readouts, single lab","pmids":["31000690"],"is_preprint":false},{"year":2019,"finding":"TRIM56 is an RNA-binding protein; its C-terminal 392 residues directly bind ZIKV RNA in cell-free reactions, and deletion of a short C-terminal tail abrogates both ZIKV RNA binding and antiviral activity; miRNA pathway (Dicer) was not required for TRIM56-mediated ZIKV restriction.","method":"RNA immunoprecipitation, cell-free RNA binding assay with recombinant TRIM56 fragment, Dicer-KO cells, ZIKV RNA replication assays, C-terminal deletion mutants","journal":"PLoS neglected tropical diseases","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct cell-free RNA binding with recombinant protein, KO genetic control, domain mapping, multiple orthogonal methods","pmids":["31251739"],"is_preprint":false},{"year":2019,"finding":"KSHV vFLIP recruits TRIM56 E3 ubiquitin ligase to degrade SAP18 via the ubiquitin-proteasome pathway, disrupting the SAP18-HDAC1 complex, leading to enhanced p65 acetylation and NF-κB activation that promotes cell invasion and angiogenesis.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor rescue, overexpression/knockdown functional assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, proteasome rescue, single lab","pmids":["30670829"],"is_preprint":false},{"year":2022,"finding":"TRIM56 promotes TNFα-induced NF-κB signaling by interacting with TAK1 and enhancing its M1-linked polyubiquitination, which strengthens TAK1-IKKα complex formation; the C-terminal domain of TRIM56 mediates TAK1 binding and the RING domain provides E3 activity.","method":"Co-immunoprecipitation, ubiquitination assay (M1-linkage specific), overexpression/knockdown with NF-κB reporter assays, domain mapping","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination, functional assays, single lab","pmids":["35952808"],"is_preprint":false},{"year":2022,"finding":"TRIM56 deubiquitinates and stabilizes cIAP1 mainly through its zinc-finger domain (residues 21–205), protecting cIAP1 from degradation and thereby promoting glioma cell survival and progression.","method":"Co-immunoprecipitation, Human Ubiquitin Array, domain deletion mutants, overexpression/knockdown with cIAP1 stability assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitin array, domain mapping, single lab","pmids":["36471347"],"is_preprint":false},{"year":2022,"finding":"TRIM56 stabilizes FOXM1 protein through deubiquitination, enhancing DNA damage repair in glioblastoma cells and reducing radiosensitivity; interaction between TRIM56 and FOXM1 was confirmed by Co-IP.","method":"Co-immunoprecipitation, ubiquitination assay, TRIM56 knockdown/overexpression with DNA repair and radiosensitivity assays, xenograft model","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional phenotype, single lab","pmids":["35696011"],"is_preprint":false},{"year":2022,"finding":"TRIM56 inhibits HBV replication by translocating from cytoplasm to nucleus (requiring C-terminal domain) during HBV infection, where its RING domain targets IκBα for ubiquitination, leading to p65 phosphorylation and NF-κB-mediated suppression of HBV core promoter activity.","method":"Subcellular fractionation/localization, domain deletion mutants, ubiquitination assay, NF-κB reporter, HBV replication assay in HepG2-NTCP and primary human hepatocytes","journal":"Antiviral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping, ubiquitination assay, reporter assay, two cell models, single lab","pmids":["36084850"],"is_preprint":false},{"year":2022,"finding":"TRIM56 knockout in HeLa cells severely impairs ISG upregulation in response to extracellular dsRNA (TLR3 pathway) and weakens cytosolic dsDNA (cGAS-STING pathway) responses, but does not compromise IFN-α-induced ISG induction or ISGylation, establishing TRIM56 as specifically required upstream of IFN production rather than in downstream IFN signaling.","method":"CRISPR/Cas9 gene editing (TRIM56 null cell lines), ISG expression assays, VSV antiviral bioactivity assay","journal":"Viruses","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout cell lines, multiple pathway assays, clear pathway placement with negative control","pmids":["35062293"],"is_preprint":false},{"year":2023,"finding":"The crystal structure of the TRIM56 coiled-coil domain reveals two anti-parallel dimers forming a tetramer, which positions two RING domains on each side to form an active homodimer that facilitates ubiquitin transfer from E2 to substrate.","method":"X-ray crystallography of coiled-coil domain, structural analysis of tetramer architecture","journal":"Computational and structural biotechnology journal","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure of isolated domain, single lab, no mutagenesis validation of structural model","pmids":["37168870"],"is_preprint":false},{"year":2023,"finding":"TRIM56 promotes glioma cell migration and invasion by interacting with IQGAP1 and promoting a K48-to-K63-linked polyubiquitination transition of IQGAP1 at Lys1230, which activates CDC42 downstream; TRIM56 is transcriptionally regulated by SP1.","method":"Co-immunoprecipitation, ubiquitination assay (K48/K63 linkage-specific), CDC42 activation assay, in vitro/in vivo migration/invasion assays, SP1 knockdown","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, site-specific ubiquitination, downstream activation assay, single lab","pmids":["36870986"],"is_preprint":false},{"year":2024,"finding":"TRIM56 directly interacts with and induces K48-linked ubiquitination-dependent proteasomal degradation of fatty acid synthase (FASN) in hepatocytes, limiting lipogenesis; loss of hepatic TRIM56 exacerbates NAFLD while overexpression suppresses it.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linkage), hepatocyte-specific KO and OE mouse models, interactome and transcriptome profiling, AI-based virtual screening of FASN inhibitor","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, K48-linkage ubiquitination, conditional KO and OE mouse models, orthogonal interactome/transcriptome data","pmids":["38206764"],"is_preprint":false},{"year":2024,"finding":"TRIM56 phosphorylation at Ser471 and Ser475 (occurring biphasically early after TLR3 stimulation, prior to IRF3 phosphorylation) and at Ser710 is required for augmentation of TLR3 signaling; the Coiled-coil domain and residues ~434-610 are also required; Ser710Ala mutation specifically disrupts the TRIM56-TRIF interaction.","method":"Phospho-specific antibody detection, alanine-substitution mutants, Tet-regulated cell lines, TRIM56-TRIF Co-IP, IFN-β reporter assay, antiviral state assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — phospho-specific antibodies, multiple site-specific mutants, regulated expression system, mechanistic link to TRIF binding","pmids":["38556084"],"is_preprint":false},{"year":2024,"finding":"TRIM56 is part of an ATR-TRIM56 complex in nucleus pulposus cells; disassembly of this complex during senescence frees USP5 and TRIM25, causing ATR ubiquitination to switch from K63- to K48-linked modification, thereby promoting proteasomal degradation of ATR, leading to cytosolic DNA accumulation and cGAS/STING-dependent inflammatory senescence.","method":"Co-immunoprecipitation, ubiquitination assay (K63/K48 linkage), ATR conditional KO, cGAS/STING pathway activation assays, extracellular vesicle delivery of ATR plasmid","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination, KO model, single lab","pmids":["38488012"],"is_preprint":false},{"year":2024,"finding":"TRIM56 restricts Coxsackievirus B3 (CVB3) by interacting with the viral RNA-dependent RNA polymerase 3D protein and mediating its K48-linked polyubiquitination at K220, promoting proteasomal degradation; the viral 3C protease cleaves TRIM56 to counter this restriction.","method":"Pulldown and Co-immunoprecipitation, immunofluorescence colocalization, proteasome inhibitor assay, ubiquitination assay (K48 site mapping), viral yield assay","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulldown, Co-IP, site-specific ubiquitination, colocalization, viral yield assay, single lab","pmids":["39348396"],"is_preprint":false},{"year":2024,"finding":"HDAC6 deacetylates TRIM56 at K110 (in mice), impairing TRIM56-mediated monoubiquitination of cGAS and reducing cGAS DNA-binding ability, thereby suppressing type I IFN production; the HSV-1 viral protein US3 phosphorylates HDAC6 to exploit this mechanism.","method":"HDAC6 knockout (in vitro and in vivo), acetylation site mapping (K110), monoubiquitination assay of cGAS, DNA-binding assay, HSV-1 infection model, US3-HDAC6 phosphorylation assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — KO model, acetylation site mapping, biochemical assays, in vivo validation, viral mechanism identified","pmids":["39747662"],"is_preprint":false},{"year":2024,"finding":"TRIM56 binds to YBX1 and promotes its K48-linked ubiquitination and proteasomal degradation, reducing YBX1-mediated stabilization of Zbp1 mRNA and thereby limiting ZBP1-mediated PANoptosis in neurons after spinal cord injury.","method":"Molecular docking, IP/MS, Co-immunoprecipitation, ubiquitination assay, RIP-seq, TRIM56 knockdown/overexpression with PANoptosis readouts","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP/MS, Co-IP, ubiquitination assay, RIP-seq validation, single lab","pmids":["39291396"],"is_preprint":false},{"year":2024,"finding":"LncRNA PVT1 interacts with TRIM56 post-transcriptionally to modulate the ubiquitination of AMPKα, leading to aberrant mitochondrial biogenesis and fission in podocytes; podocyte-specific Trim56 KO mice phenocopied PVT1 KO mice, confirming TRIM56 mediates PVT1's mitochondrial effects.","method":"Co-immunoprecipitation, ubiquitination assay, conditional KO mice (Nphs2-Cre/Trim56flox/flox and Nphs2-Cre/Pvt1flox/flox), mitochondrial function assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mice, ubiquitination assay, genetic phenocopy, single lab","pmids":["39349450"],"is_preprint":false},{"year":2025,"finding":"TRIM56 promotes K48-linked ubiquitination and proteasomal degradation of TLE3 in adipocytes in response to cold stimuli, activating thermogenic gene programs in subcutaneous white adipose tissue to promote beige adipogenesis and protect against diet-induced obesity.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linkage), adipocyte-specific TRIM56 OE mice, cold challenge, metabolic phenotyping","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, K48 ubiquitination, in vivo OE model, single lab","pmids":["39928840"],"is_preprint":false},{"year":2025,"finding":"TRIM56 directly interacts with the SH3 domain of Src via its B-box1 domain and catalyzes K63-linked polyubiquitination of Src at Lys184, promoting Src aggregation and intermolecular autophosphorylation-driven activation, thereby promoting HCC progression.","method":"Co-immunoprecipitation, domain mapping (B-box1), ubiquitination assay (K63-linkage, site K184), Src activation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, site-specific ubiquitination, Src activation assay, single lab","pmids":["41102183"],"is_preprint":false},{"year":2025,"finding":"TRIM56 directly interacts with KLF4 and promotes its K48-linked ubiquitination-dependent proteasomal degradation, leading to neuronal ferroptosis; TRIM56 knockout mice show reduced neurological deficits and inflammation after cerebral ischemia-reperfusion injury.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linkage), TRIM56 KO mice with I/R model, ferroptosis markers, compound screening for TRIM56 inhibitor (farudodstat)","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, KO mouse model, single lab","pmids":["41214892"],"is_preprint":false},{"year":2025,"finding":"TRIM56 stabilizes the adenoviral E1A protein and enhances viral genome transcription during HAdV-C5 infection; TRIM56 also assists E1A in antagonizing STING, thereby promoting adenoviral replication.","method":"Overexpression/knockdown with E1A stability assays, viral replication assays, recombinant OAV-TRIM56 construction and in vitro/in vivo efficacy testing","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein stability assay, viral replication, functional recombinant virus, single lab","pmids":["40459263"],"is_preprint":false},{"year":2026,"finding":"TRIM56 promotes K48-linked ubiquitination and proteasomal degradation of GCN2 at K619, thereby inhibiting the GCN2/EIF2α/ATG12 axis; CD147 suppresses TRIM56 expression to stabilize GCN2 and drive secretory autophagy-mediated exosome release and NSCLC metastasis.","method":"Proteomics (E3 ligase identification), Co-immunoprecipitation, ubiquitination assay (K48, site K619), TRIM56 knockdown/overexpression, in vitro and in vivo metastasis models","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics-identified E3 ligase, site-specific ubiquitination, in vivo model, single lab","pmids":["41413248"],"is_preprint":false},{"year":2026,"finding":"ZC3H15 recruits TRIM56 to ubiquitinate PTEN, promoting its degradation and activating AKT-mTOR signaling in NSCLC; ZC3H15 binds PTEN through its DFRP domain.","method":"Co-immunoprecipitation, ubiquitination assay, domain mapping (DFRP), overexpression/knockdown with AKT-mTOR pathway assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, domain mapping, single lab","pmids":["41513632"],"is_preprint":false},{"year":2026,"finding":"TRIM56 directly binds to STING in the cytoplasm and promotes its K48-linked ubiquitination and proteasomal degradation, thereby inhibiting M1 macrophage polarization and reducing sepsis-induced acute lung injury; this is distinct from TRIM56's previously described K63-linked activation of STING.","method":"Immunofluorescence co-localization, Co-immunoprecipitation, ubiquitination assay (K48-linkage), MG132 proteasome inhibitor rescue, TRIM56 OE/KD in vitro and in vivo (LPS-induced ALI model)","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, K48 ubiquitination, proteasome inhibitor rescue, in vivo model, single lab; note contradiction with K63-STING finding in PMID 21074459","pmids":["42155789"],"is_preprint":false},{"year":2024,"finding":"TRIM56 was identified by mass spectrometry as the E3 ligase targeting AHR for ubiquitination in NSCLC; PGRMC1 overexpression inhibits the TRIM56-AHR interaction, stabilizing AHR and maintaining cancer stem cell phenotypes.","method":"Mass spectrometry screening, Co-immunoprecipitation, TRIM56-AHR interaction assay, overexpression/knockdown functional assays","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification, Co-IP, functional rescue, single lab","pmids":["39059592"],"is_preprint":false}],"current_model":"TRIM56 is a multifunctional RING-type E3 ubiquitin ligase (and RNA-binding protein) that regulates innate antiviral immunity and diverse cellular processes through substrate-specific ubiquitination: it activates cGAS-STING signaling by monoubiquitinating cGAS (K335) to enhance dimerization and cGAMP production, and in another context promotes K63-linked ubiquitination of STING to drive TBK1 recruitment and IFN-β induction in response to cytosolic dsDNA; it also positively regulates TLR3-TRIF signaling via phosphorylation-dependent physical interaction with TRIF (requiring Ser471, Ser475, Ser710 and the coiled-coil domain), and restricts various RNA viruses through E3-ligase-independent RNA binding via its C-terminal tail; beyond immunity, TRIM56 ubiquitinates and degrades substrates including FASN (K48, lipid metabolism), vimentin (EMT suppression), TLE3 (adipocyte browning), PTEN, KLF4, YBX1, and GCN2, while also catalyzing non-degradative K63-linked modifications of IQGAP1 and Src to activate downstream signaling, and can deubiquitinate substrates such as cIAP1 and FOXM1 to stabilize them; HDAC6 deacetylates TRIM56 at K110 to suppress its cGAS-activating function, and its tetramer structure (revealed by crystallography) positions RING domains for efficient ubiquitin transfer."},"narrative":{"mechanistic_narrative":"TRIM56 is a RING-type E3 ubiquitin ligase that operates as a central node in innate antiviral immunity and, through substrate-specific ubiquitination, in a wide range of cellular processes [PMID:21074459, PMID:29426904, PMID:35062293]. In DNA-sensing immunity it monoubiquitinates cGAS at Lys335 to enhance cGAS dimerization, DNA binding, and cGAMP production, with TRIM56-deficient mice showing impaired type I interferon and heightened HSV-1 susceptibility [PMID:29426904]; this cGAS-activating function is restrained by HDAC6-mediated deacetylation of TRIM56 at K110, a circuit exploited by the HSV-1 US3 protein [PMID:39747662]. TRIM56 also catalyzes K63-linked ubiquitination of STING to induce dimerization and TBK1 recruitment for IFN-β induction against cytosolic dsDNA [PMID:21074459], and potentiates TLR3-TRIF signaling through a phosphorylation-dependent interaction with TRIF that requires Ser471/Ser475/Ser710 and the coiled-coil domain rather than ligase activity [PMID:22948160, PMID:38556084]; genetic ablation places TRIM56 upstream of IFN production in both the dsRNA/TLR3 and cGAS-STING arms [PMID:35062293]. Independently of its ligase activity, TRIM56 acts as an RNA-binding protein whose short C-terminal tail directly binds viral RNA and restricts flaviviruses, influenza, and other RNA viruses [PMID:25253338, PMID:26889027, PMID:31251739]. Beyond immunity, TRIM56 governs diverse physiology by degrading or modifying defined substrates: it drives K48-linked degradation of FASN to limit hepatic lipogenesis [PMID:38206764], of TLE3 to promote beige adipogenesis [PMID:39928840], of vimentin to suppress EMT [PMID:28771721], and of KLF4, YBX1, and GCN2 in neuronal and tumor contexts [PMID:39291396, PMID:41214892, PMID:41413248], while catalyzing non-degradative K63-linked modification of IQGAP1 and Src to activate downstream CDC42 and Src signaling [PMID:36870986, PMID:41102183]. The coiled-coil domain assembles an anti-parallel tetramer that juxtaposes RING domains for efficient ubiquitin transfer [PMID:37168870].","teleology":[{"year":2010,"claim":"Established the first mechanistic role for TRIM56 in innate immunity by showing it ubiquitinates STING to enable antiviral signaling, answering how cytosolic DNA sensing engages an E3 ligase.","evidence":"Co-IP, K63-ubiquitination assays, and IFN-β reporter with knockdown in dsDNA response","pmids":["21074459"],"confidence":"High","gaps":["Did not resolve which E2 partners with TRIM56 on STING","Physiological requirement not yet tested in knockout animals"]},{"year":2011,"claim":"Showed TRIM56 directly restricts a virus (BVDV) in a ligase- and C-terminus-dependent manner separable from general IFN induction, indicating intrinsic antiviral activity beyond signaling amplification.","evidence":"Overexpression/RNAi viral replication assays with ligase-dead and deletion mutants","pmids":["21289118"],"confidence":"Medium","gaps":["Direct viral or host substrate not identified","Mechanism by which the C-terminus contributes was unresolved"]},{"year":2012,"claim":"Defined a ligase-independent function in which TRIM56 binds the adaptor TRIF to potentiate TLR3 signaling, distinguishing scaffolding from catalytic roles.","evidence":"Reciprocal Co-IP, C-terminal deletion mutants, IRF3/IFN-β reporter assays","pmids":["22948160"],"confidence":"High","gaps":["How TRIM56 binding alters TRIF complex assembly was not defined","Did not address whether the interaction is constitutive or stimulus-induced"]},{"year":2014,"claim":"Demonstrated virus-specific restriction mechanisms, requiring ligase activity plus C-terminal integrity for flaviviruses but ligase alone for a coronavirus, showing TRIM56 uses distinct modes against different viruses.","evidence":"Tet-regulated conditional mutant cell lines, viral RNA quantification, RING and deletion mutants","pmids":["25253338"],"confidence":"High","gaps":["The molecular target restricting flavivirus RNA accumulation was unknown at this stage","Step in coronavirus life cycle beyond 'post-replication' undefined"]},{"year":2016,"claim":"Localized RNA-virus restriction to a minimal 63-residue C-terminal tail sufficient on its own, separating antiviral function from the RING, B-box, and coiled-coil domains.","evidence":"Domain deletion and minimal-fragment expression with influenza RNA synthesis assays","pmids":["26889027"],"confidence":"High","gaps":["Biochemical activity of the tail not yet defined as RNA binding","Did not establish whether the tail acts directly on viral or host machinery"]},{"year":2018,"claim":"Identified cGAS as a direct activating substrate via monoubiquitination at K335 and confirmed in vivo requirement, providing a defined biochemical mechanism for TRIM56's pro-IFN role against DNA viruses.","evidence":"Site-specific ubiquitination mapping, cGAS dimerization/cGAMP assays, TRIM56-KO mice, HSV-1 model","pmids":["29426904"],"confidence":"High","gaps":["Relationship between cGAS monoubiquitination and the earlier STING K63 model not reconciled","E2 enzyme for cGAS modification not identified"]},{"year":2019,"claim":"Demonstrated that TRIM56 is a bona fide RNA-binding protein whose C-terminal region directly binds viral RNA, explaining the ligase-independent restriction defined earlier.","evidence":"Cell-free RNA binding with recombinant fragment, RIP, Dicer-KO controls, ZIKV replication assays","pmids":["31251739"],"confidence":"High","gaps":["RNA sequence/structure specificity of binding not defined","How RNA binding mechanistically blocks replication unresolved"]},{"year":2017,"claim":"Extended TRIM56 function beyond immunity by identifying vimentin as a degradative substrate, linking the ligase to EMT suppression in epithelial cells.","evidence":"MS of vimentin IP, proteasome inhibitor rescue, OE/KD migration/invasion assays","pmids":["28771721"],"confidence":"Medium","gaps":["Ubiquitination site and linkage on vimentin not mapped","Single-lab finding without in vivo validation"]},{"year":2022,"claim":"Clarified pathway placement by showing TRIM56 is required upstream of IFN production (dsRNA/TLR3 and cGAS-STING) but not in downstream IFN signaling, defining the boundary of its requirement.","evidence":"CRISPR TRIM56-null HeLa cells, ISG assays across pathways with negative controls, VSV bioassay","pmids":["35062293"],"confidence":"High","gaps":["Did not dissect relative contributions of cGAS vs STING modification","Cell-type generality beyond HeLa not addressed"]},{"year":2023,"claim":"Provided a structural basis for catalysis by showing the coiled-coil forms an anti-parallel tetramer positioning RING domains for ubiquitin transfer.","evidence":"X-ray crystallography of isolated coiled-coil domain and tetramer modeling","pmids":["37168870"],"confidence":"Medium","gaps":["No mutagenesis validation of the proposed tetramer interface","Structure of full-length protein and RING-substrate engagement not determined"]},{"year":2024,"claim":"Defined the regulatory layer controlling TRIM56's cGAS function, showing HDAC6 deacetylates TRIM56 at K110 to suppress cGAS monoubiquitination, a node hijacked by HSV-1 US3.","evidence":"HDAC6 KO in vitro/in vivo, K110 acetylation mapping, cGAS monoubiquitination and DNA-binding assays, HSV-1 model","pmids":["39747662"],"confidence":"High","gaps":["The acetyltransferase opposing HDAC6 on TRIM56 not identified","Whether K110 acetylation affects non-cGAS substrates unknown"]},{"year":2024,"claim":"Established TRIM56's metabolic role by identifying FASN as a K48-linked degradative substrate that restrains hepatic lipogenesis, expanding its physiology to NAFLD.","evidence":"Co-IP, K48 ubiquitination, hepatocyte-specific KO/OE mice, interactome/transcriptome profiling","pmids":["38206764"],"confidence":"High","gaps":["Ubiquitination site on FASN not mapped","Upstream signals controlling hepatic TRIM56 expression not defined"]},{"year":2024,"claim":"Refined TLR3 regulation by showing site-specific TRIM56 phosphorylation (Ser471/Ser475/Ser710) governs the TRIF interaction, providing a phospho-switch for signal augmentation.","evidence":"Phospho-specific antibodies, alanine mutants, Tet-regulated cells, TRIM56-TRIF Co-IP, IFN-β reporter","pmids":["38556084"],"confidence":"High","gaps":["The kinase phosphorylating these residues not identified","How phosphorylation alters TRIM56 conformation/binding not structurally resolved"]},{"year":2022,"claim":"Broadened TRIM56's catalytic repertoire to non-canonical signaling and apparent deubiquitination, modifying TAK1 (M1-linked), IQGAP1 (K48-to-K63 switch), Src (K63), and stabilizing cIAP1 and FOXM1.","evidence":"Co-IP, linkage-specific ubiquitination, downstream activation assays across glioma/cancer models (multiple studies)","pmids":["35952808","36471347","35696011","36870986","41102183"],"confidence":"Medium","gaps":["Mechanism by which a RING E3 effects deubiquitination/stabilization not biochemically resolved","Each substrate validated in a single lab without cross-replication"]},{"year":2024,"claim":"Showed TRIM56 substrate engagement is directed by adaptors and lncRNAs, with ZC3H15 recruiting it to PTEN and PVT1 modulating AMPKα ubiquitination, indicating context-specific targeting.","evidence":"Co-IP, domain mapping, ubiquitination assays, conditional KO mice (PVT1/TRIM56 podocyte models)","pmids":["41513632","39349450"],"confidence":"Medium","gaps":["General rules determining substrate selection across tissues unknown","Whether adaptor recruitment competes with antiviral substrates not addressed"]},{"year":2025,"claim":"Documented a contradictory STING outcome, with TRIM56 driving K48-linked STING degradation to dampen inflammation, contrasting its earlier K63-linked STING activation.","evidence":"Co-IP, K48 ubiquitination, MG132 rescue, OE/KD in LPS-induced acute lung injury model","pmids":["42155789"],"confidence":"Medium","gaps":["Conditions selecting K48 versus K63 modification of STING not defined","Direct contradiction with the 2010 STING-activation model unreconciled"]},{"year":null,"claim":"How TRIM56 selects among its many substrates and switches between activating (K63/mono), degradative (K48), and stabilizing outputs in a context-dependent manner remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for linkage-type and substrate selection","Conflicting STING modifications (K63 activation vs K48 degradation) not mechanistically reconciled","No full-length structure showing RING-substrate engagement"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,6,17,16,25,24]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,6,5,17]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,6,17]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[8,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,25,30]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[13,19]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,6,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,17,24]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[17,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,25,29]}],"complexes":["ATR-TRIM56 complex"],"partners":["STING1","CGAS","TICAM1","FASN","IQGAP1","SRC","TLE3","YBX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BRZ2","full_name":"E3 ubiquitin-protein ligase TRIM56","aliases":["RING finger protein 109","Tripartite motif-containing protein 56"],"length_aa":755,"mass_kda":81.5,"function":"E3 ubiquitin-protein ligase that plays a key role in innate antiviral immunity by mediating ubiquitination of CGAS and STING1 (PubMed:21289118, PubMed:29426904). In response to pathogen- and host-derived double-stranded DNA (dsDNA), targets STING1 to 'Lys-63'-linked ubiquitination, thereby promoting its homodimerization, a step required for the production of type I interferon IFN-beta (By similarity). Also mediate monoubiquitination of CGAS, thereby promoting CGAS oligomerization and subsequent activation (PubMed:29426904). Promotes also TNFalpha-induced NF-kappa-B signaling by mediating 'Lys-63'-linked ubiquitination TAK1, leading to enhanced interaction between TAK1 and CHUK/IKKalpha (PubMed:35952808). Independently of its E3 ubiquitin ligase activity, positive regulator of TLR3 signaling. Potentiates extracellular double stranded RNA (dsRNA)-induced expression of IFNB1 and interferon-stimulated genes ISG15, IFIT1/ISG56, CXCL10, OASL and CCL5/RANTES (PubMed:22948160). Promotes establishment of an antiviral state by TLR3 ligand and TLR3-mediated chemokine induction following infection by hepatitis C virus (PubMed:22948160). Acts as a restriction factor of Zika virus through direct interaction with the viral RNA via its C-terminal region (PubMed:31251739)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9BRZ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM56","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PPM1G","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TRIM56","total_profiled":1310},"omim":[{"mim_id":"616996","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 56; TRIM56","url":"https://www.omim.org/entry/616996"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRIM56"},"hgnc":{"alias_symbol":["RNF109"],"prev_symbol":[]},"alphafold":{"accession":"Q9BRZ2","domains":[{"cath_id":"3.30.40.10","chopping":"14-91","consensus_level":"medium","plddt":84.851,"start":14,"end":91},{"cath_id":"2.120.10.30","chopping":"491-752","consensus_level":"medium","plddt":90.6031,"start":491,"end":752},{"cath_id":"3.90.20","chopping":"241-335","consensus_level":"high","plddt":89.8312,"start":241,"end":335}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRZ2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRZ2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRZ2-F1-predicted_aligned_error_v6.png","plddt_mean":76.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM56","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM56"},"sequence":{"accession":"Q9BRZ2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BRZ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BRZ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRZ2"}},"corpus_meta":[{"pmid":"21074459","id":"PMC_21074459","title":"The 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Binding Protein 1 Regulates Posttranscriptional Expression of the Ubiquitin Ligase TRIM56 in Ovarian Cancer.","date":"2018","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/30281912","citation_count":16,"is_preprint":false},{"pmid":"39349450","id":"PMC_39349450","title":"LncRNA PVT1 induces mitochondrial dysfunction of podocytes via TRIM56 in diabetic kidney disease.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39349450","citation_count":13,"is_preprint":false},{"pmid":"33577026","id":"PMC_33577026","title":"TRIM56 suppresses the malignant development of hepatocellular carcinoma via targeting RBM24 and inactivating the Wnt signaling.","date":"2021","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33577026","citation_count":13,"is_preprint":false},{"pmid":"33707970","id":"PMC_33707970","title":"Identification of TRIM56 as a Potential Biomarker for Lung 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this dimerization is a prerequisite for recruitment of the antiviral kinase TBK1 and subsequent IFN-β induction in response to cytosolic dsDNA.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown with IFN-β promoter reporter assay, ubiquitination assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, K63 ubiquitination assay, functional rescue experiments, replicated in subsequent studies\",\n      \"pmids\": [\"21074459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRIM56 restricts bovine viral diarrhea virus (BVDV) replication in a manner dependent on its E3 ubiquitin ligase activity and the integrity of its C-terminal region, but independent of any general augmentation of the interferon response or effects on IRF3 stability.\",\n      \"method\": \"Overexpression and RNAi knockdown with viral replication assays; E3 ligase-dead mutant analysis; domain deletion mapping\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotype, domain mapping, single lab\",\n      \"pmids\": [\"21289118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM56 positively regulates TLR3 signaling by physically interacting with the adaptor protein TRIF; this interaction (mediated by the C-terminal portion of TRIM56, residues 621–750) is required for potentiation of IRF3 activation and IFN-β induction, independent of E3 ligase activity.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown with IRF3 activation and IFN-β reporter assays, C-terminal deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain-deletion mutants, multiple functional readouts, replicated in later work\",\n      \"pmids\": [\"22948160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIM56 restricts yellow fever virus (YFV) and dengue virus serotype 2 (DENV2) by suppressing intracellular viral RNA accumulation, requiring both E3 ligase activity (RING domain) and C-terminal integrity; restriction of HCoV-OC43 requires only E3 ligase activity and acts at a post-RNA-replication step in the viral life cycle.\",\n      \"method\": \"Conditional mutant cell lines (Tet-regulated), viral RNA quantification, domain deletion and RING mutant analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — engineered cell lines with multiple mutants, distinct mechanistic outcomes per virus confirmed orthogonally\",\n      \"pmids\": [\"25253338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIM56 restricts influenza A and B viruses by impeding intracellular viral RNA synthesis via its short 63-residue C-terminal tail segment, independently of E3 ligase activity, B-box, or coiled-coil domain; expression of this tail segment alone was sufficient for antiviral activity.\",\n      \"method\": \"Domain deletion mutants, E3 ligase-dead mutant, overexpression/knockdown with viral RNA synthesis assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple domain mutants, minimal-sufficient fragment identified, specific viral RNA synthesis assay\",\n      \"pmids\": [\"26889027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIM56 functions as an E3 ubiquitin ligase that ubiquitinates and targets vimentin for proteasomal degradation in normal ovarian epithelial cells, thereby suppressing EMT and cell migration/invasion; loss of TRIM56 in ovarian cancer cells leads to vimentin stabilization.\",\n      \"method\": \"Mass spectrometry of vimentin immunoprecipitate, RNAi knockdown and overexpression, proteasome inhibitor assay, in vitro migration/invasion\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified substrate, functional rescue with OE/KD, single lab\",\n      \"pmids\": [\"28771721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM56 E3 ligase induces monoubiquitination of cGAS at Lys335, which markedly increases cGAS dimerization, DNA-binding activity, and cGAMP production, thereby promoting IFN-αβ production against DNA viruses; TRIM56-deficient mice show impaired IFN-αβ and high susceptibility to HSV-1.\",\n      \"method\": \"Ubiquitination assays (monoubiquitination site mapping), cGAS dimerization assays, cGAMP ELISA, TRIM56-KO mice, HSV-1 infection model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — site-specific ubiquitination mapping, biochemical activity assays, in vivo KO mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"29426904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM56 interacts with the AF1 domain of estrogen receptor alpha (ERα) via its WD40 domain in the cytoplasm and promotes K63-linked ubiquitination of ERα, prolonging ERα protein stability and sustaining estrogen signaling in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping (WD40 deletion), ubiquitination assay, TRIM56 knockdown with ERα stability measurement\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, ubiquitination assay, functional readouts, single lab\",\n      \"pmids\": [\"31000690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM56 is an RNA-binding protein; its C-terminal 392 residues directly bind ZIKV RNA in cell-free reactions, and deletion of a short C-terminal tail abrogates both ZIKV RNA binding and antiviral activity; miRNA pathway (Dicer) was not required for TRIM56-mediated ZIKV restriction.\",\n      \"method\": \"RNA immunoprecipitation, cell-free RNA binding assay with recombinant TRIM56 fragment, Dicer-KO cells, ZIKV RNA replication assays, C-terminal deletion mutants\",\n      \"journal\": \"PLoS neglected tropical diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct cell-free RNA binding with recombinant protein, KO genetic control, domain mapping, multiple orthogonal methods\",\n      \"pmids\": [\"31251739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KSHV vFLIP recruits TRIM56 E3 ubiquitin ligase to degrade SAP18 via the ubiquitin-proteasome pathway, disrupting the SAP18-HDAC1 complex, leading to enhanced p65 acetylation and NF-κB activation that promotes cell invasion and angiogenesis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor rescue, overexpression/knockdown functional assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, proteasome rescue, single lab\",\n      \"pmids\": [\"30670829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM56 promotes TNFα-induced NF-κB signaling by interacting with TAK1 and enhancing its M1-linked polyubiquitination, which strengthens TAK1-IKKα complex formation; the C-terminal domain of TRIM56 mediates TAK1 binding and the RING domain provides E3 activity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (M1-linkage specific), overexpression/knockdown with NF-κB reporter assays, domain mapping\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination, functional assays, single lab\",\n      \"pmids\": [\"35952808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM56 deubiquitinates and stabilizes cIAP1 mainly through its zinc-finger domain (residues 21–205), protecting cIAP1 from degradation and thereby promoting glioma cell survival and progression.\",\n      \"method\": \"Co-immunoprecipitation, Human Ubiquitin Array, domain deletion mutants, overexpression/knockdown with cIAP1 stability assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitin array, domain mapping, single lab\",\n      \"pmids\": [\"36471347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM56 stabilizes FOXM1 protein through deubiquitination, enhancing DNA damage repair in glioblastoma cells and reducing radiosensitivity; interaction between TRIM56 and FOXM1 was confirmed by Co-IP.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, TRIM56 knockdown/overexpression with DNA repair and radiosensitivity assays, xenograft model\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional phenotype, single lab\",\n      \"pmids\": [\"35696011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM56 inhibits HBV replication by translocating from cytoplasm to nucleus (requiring C-terminal domain) during HBV infection, where its RING domain targets IκBα for ubiquitination, leading to p65 phosphorylation and NF-κB-mediated suppression of HBV core promoter activity.\",\n      \"method\": \"Subcellular fractionation/localization, domain deletion mutants, ubiquitination assay, NF-κB reporter, HBV replication assay in HepG2-NTCP and primary human hepatocytes\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping, ubiquitination assay, reporter assay, two cell models, single lab\",\n      \"pmids\": [\"36084850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM56 knockout in HeLa cells severely impairs ISG upregulation in response to extracellular dsRNA (TLR3 pathway) and weakens cytosolic dsDNA (cGAS-STING pathway) responses, but does not compromise IFN-α-induced ISG induction or ISGylation, establishing TRIM56 as specifically required upstream of IFN production rather than in downstream IFN signaling.\",\n      \"method\": \"CRISPR/Cas9 gene editing (TRIM56 null cell lines), ISG expression assays, VSV antiviral bioactivity assay\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout cell lines, multiple pathway assays, clear pathway placement with negative control\",\n      \"pmids\": [\"35062293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The crystal structure of the TRIM56 coiled-coil domain reveals two anti-parallel dimers forming a tetramer, which positions two RING domains on each side to form an active homodimer that facilitates ubiquitin transfer from E2 to substrate.\",\n      \"method\": \"X-ray crystallography of coiled-coil domain, structural analysis of tetramer architecture\",\n      \"journal\": \"Computational and structural biotechnology journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure of isolated domain, single lab, no mutagenesis validation of structural model\",\n      \"pmids\": [\"37168870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM56 promotes glioma cell migration and invasion by interacting with IQGAP1 and promoting a K48-to-K63-linked polyubiquitination transition of IQGAP1 at Lys1230, which activates CDC42 downstream; TRIM56 is transcriptionally regulated by SP1.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48/K63 linkage-specific), CDC42 activation assay, in vitro/in vivo migration/invasion assays, SP1 knockdown\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, site-specific ubiquitination, downstream activation assay, single lab\",\n      \"pmids\": [\"36870986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM56 directly interacts with and induces K48-linked ubiquitination-dependent proteasomal degradation of fatty acid synthase (FASN) in hepatocytes, limiting lipogenesis; loss of hepatic TRIM56 exacerbates NAFLD while overexpression suppresses it.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linkage), hepatocyte-specific KO and OE mouse models, interactome and transcriptome profiling, AI-based virtual screening of FASN inhibitor\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, K48-linkage ubiquitination, conditional KO and OE mouse models, orthogonal interactome/transcriptome data\",\n      \"pmids\": [\"38206764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM56 phosphorylation at Ser471 and Ser475 (occurring biphasically early after TLR3 stimulation, prior to IRF3 phosphorylation) and at Ser710 is required for augmentation of TLR3 signaling; the Coiled-coil domain and residues ~434-610 are also required; Ser710Ala mutation specifically disrupts the TRIM56-TRIF interaction.\",\n      \"method\": \"Phospho-specific antibody detection, alanine-substitution mutants, Tet-regulated cell lines, TRIM56-TRIF Co-IP, IFN-β reporter assay, antiviral state assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phospho-specific antibodies, multiple site-specific mutants, regulated expression system, mechanistic link to TRIF binding\",\n      \"pmids\": [\"38556084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM56 is part of an ATR-TRIM56 complex in nucleus pulposus cells; disassembly of this complex during senescence frees USP5 and TRIM25, causing ATR ubiquitination to switch from K63- to K48-linked modification, thereby promoting proteasomal degradation of ATR, leading to cytosolic DNA accumulation and cGAS/STING-dependent inflammatory senescence.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K63/K48 linkage), ATR conditional KO, cGAS/STING pathway activation assays, extracellular vesicle delivery of ATR plasmid\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination, KO model, single lab\",\n      \"pmids\": [\"38488012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM56 restricts Coxsackievirus B3 (CVB3) by interacting with the viral RNA-dependent RNA polymerase 3D protein and mediating its K48-linked polyubiquitination at K220, promoting proteasomal degradation; the viral 3C protease cleaves TRIM56 to counter this restriction.\",\n      \"method\": \"Pulldown and Co-immunoprecipitation, immunofluorescence colocalization, proteasome inhibitor assay, ubiquitination assay (K48 site mapping), viral yield assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulldown, Co-IP, site-specific ubiquitination, colocalization, viral yield assay, single lab\",\n      \"pmids\": [\"39348396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HDAC6 deacetylates TRIM56 at K110 (in mice), impairing TRIM56-mediated monoubiquitination of cGAS and reducing cGAS DNA-binding ability, thereby suppressing type I IFN production; the HSV-1 viral protein US3 phosphorylates HDAC6 to exploit this mechanism.\",\n      \"method\": \"HDAC6 knockout (in vitro and in vivo), acetylation site mapping (K110), monoubiquitination assay of cGAS, DNA-binding assay, HSV-1 infection model, US3-HDAC6 phosphorylation assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — KO model, acetylation site mapping, biochemical assays, in vivo validation, viral mechanism identified\",\n      \"pmids\": [\"39747662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM56 binds to YBX1 and promotes its K48-linked ubiquitination and proteasomal degradation, reducing YBX1-mediated stabilization of Zbp1 mRNA and thereby limiting ZBP1-mediated PANoptosis in neurons after spinal cord injury.\",\n      \"method\": \"Molecular docking, IP/MS, Co-immunoprecipitation, ubiquitination assay, RIP-seq, TRIM56 knockdown/overexpression with PANoptosis readouts\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP/MS, Co-IP, ubiquitination assay, RIP-seq validation, single lab\",\n      \"pmids\": [\"39291396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LncRNA PVT1 interacts with TRIM56 post-transcriptionally to modulate the ubiquitination of AMPKα, leading to aberrant mitochondrial biogenesis and fission in podocytes; podocyte-specific Trim56 KO mice phenocopied PVT1 KO mice, confirming TRIM56 mediates PVT1's mitochondrial effects.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, conditional KO mice (Nphs2-Cre/Trim56flox/flox and Nphs2-Cre/Pvt1flox/flox), mitochondrial function assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mice, ubiquitination assay, genetic phenocopy, single lab\",\n      \"pmids\": [\"39349450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM56 promotes K48-linked ubiquitination and proteasomal degradation of TLE3 in adipocytes in response to cold stimuli, activating thermogenic gene programs in subcutaneous white adipose tissue to promote beige adipogenesis and protect against diet-induced obesity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linkage), adipocyte-specific TRIM56 OE mice, cold challenge, metabolic phenotyping\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, K48 ubiquitination, in vivo OE model, single lab\",\n      \"pmids\": [\"39928840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM56 directly interacts with the SH3 domain of Src via its B-box1 domain and catalyzes K63-linked polyubiquitination of Src at Lys184, promoting Src aggregation and intermolecular autophosphorylation-driven activation, thereby promoting HCC progression.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping (B-box1), ubiquitination assay (K63-linkage, site K184), Src activation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, site-specific ubiquitination, Src activation assay, single lab\",\n      \"pmids\": [\"41102183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM56 directly interacts with KLF4 and promotes its K48-linked ubiquitination-dependent proteasomal degradation, leading to neuronal ferroptosis; TRIM56 knockout mice show reduced neurological deficits and inflammation after cerebral ischemia-reperfusion injury.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linkage), TRIM56 KO mice with I/R model, ferroptosis markers, compound screening for TRIM56 inhibitor (farudodstat)\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, KO mouse model, single lab\",\n      \"pmids\": [\"41214892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM56 stabilizes the adenoviral E1A protein and enhances viral genome transcription during HAdV-C5 infection; TRIM56 also assists E1A in antagonizing STING, thereby promoting adenoviral replication.\",\n      \"method\": \"Overexpression/knockdown with E1A stability assays, viral replication assays, recombinant OAV-TRIM56 construction and in vitro/in vivo efficacy testing\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein stability assay, viral replication, functional recombinant virus, single lab\",\n      \"pmids\": [\"40459263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM56 promotes K48-linked ubiquitination and proteasomal degradation of GCN2 at K619, thereby inhibiting the GCN2/EIF2α/ATG12 axis; CD147 suppresses TRIM56 expression to stabilize GCN2 and drive secretory autophagy-mediated exosome release and NSCLC metastasis.\",\n      \"method\": \"Proteomics (E3 ligase identification), Co-immunoprecipitation, ubiquitination assay (K48, site K619), TRIM56 knockdown/overexpression, in vitro and in vivo metastasis models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics-identified E3 ligase, site-specific ubiquitination, in vivo model, single lab\",\n      \"pmids\": [\"41413248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZC3H15 recruits TRIM56 to ubiquitinate PTEN, promoting its degradation and activating AKT-mTOR signaling in NSCLC; ZC3H15 binds PTEN through its DFRP domain.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, domain mapping (DFRP), overexpression/knockdown with AKT-mTOR pathway assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, domain mapping, single lab\",\n      \"pmids\": [\"41513632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM56 directly binds to STING in the cytoplasm and promotes its K48-linked ubiquitination and proteasomal degradation, thereby inhibiting M1 macrophage polarization and reducing sepsis-induced acute lung injury; this is distinct from TRIM56's previously described K63-linked activation of STING.\",\n      \"method\": \"Immunofluorescence co-localization, Co-immunoprecipitation, ubiquitination assay (K48-linkage), MG132 proteasome inhibitor rescue, TRIM56 OE/KD in vitro and in vivo (LPS-induced ALI model)\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, K48 ubiquitination, proteasome inhibitor rescue, in vivo model, single lab; note contradiction with K63-STING finding in PMID 21074459\",\n      \"pmids\": [\"42155789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM56 was identified by mass spectrometry as the E3 ligase targeting AHR for ubiquitination in NSCLC; PGRMC1 overexpression inhibits the TRIM56-AHR interaction, stabilizing AHR and maintaining cancer stem cell phenotypes.\",\n      \"method\": \"Mass spectrometry screening, Co-immunoprecipitation, TRIM56-AHR interaction assay, overexpression/knockdown functional assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification, Co-IP, functional rescue, single lab\",\n      \"pmids\": [\"39059592\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM56 is a multifunctional RING-type E3 ubiquitin ligase (and RNA-binding protein) that regulates innate antiviral immunity and diverse cellular processes through substrate-specific ubiquitination: it activates cGAS-STING signaling by monoubiquitinating cGAS (K335) to enhance dimerization and cGAMP production, and in another context promotes K63-linked ubiquitination of STING to drive TBK1 recruitment and IFN-β induction in response to cytosolic dsDNA; it also positively regulates TLR3-TRIF signaling via phosphorylation-dependent physical interaction with TRIF (requiring Ser471, Ser475, Ser710 and the coiled-coil domain), and restricts various RNA viruses through E3-ligase-independent RNA binding via its C-terminal tail; beyond immunity, TRIM56 ubiquitinates and degrades substrates including FASN (K48, lipid metabolism), vimentin (EMT suppression), TLE3 (adipocyte browning), PTEN, KLF4, YBX1, and GCN2, while also catalyzing non-degradative K63-linked modifications of IQGAP1 and Src to activate downstream signaling, and can deubiquitinate substrates such as cIAP1 and FOXM1 to stabilize them; HDAC6 deacetylates TRIM56 at K110 to suppress its cGAS-activating function, and its tetramer structure (revealed by crystallography) positions RING domains for efficient ubiquitin transfer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM56 is a RING-type E3 ubiquitin ligase that operates as a central node in innate antiviral immunity and, through substrate-specific ubiquitination, in a wide range of cellular processes [#0, #6, #14]. In DNA-sensing immunity it monoubiquitinates cGAS at Lys335 to enhance cGAS dimerization, DNA binding, and cGAMP production, with TRIM56-deficient mice showing impaired type I interferon and heightened HSV-1 susceptibility [#6]; this cGAS-activating function is restrained by HDAC6-mediated deacetylation of TRIM56 at K110, a circuit exploited by the HSV-1 US3 protein [#21]. TRIM56 also catalyzes K63-linked ubiquitination of STING to induce dimerization and TBK1 recruitment for IFN-\\u03b2 induction against cytosolic dsDNA [#0], and potentiates TLR3-TRIF signaling through a phosphorylation-dependent interaction with TRIF that requires Ser471/Ser475/Ser710 and the coiled-coil domain rather than ligase activity [#2, #18]; genetic ablation places TRIM56 upstream of IFN production in both the dsRNA/TLR3 and cGAS-STING arms [#14]. Independently of its ligase activity, TRIM56 acts as an RNA-binding protein whose short C-terminal tail directly binds viral RNA and restricts flaviviruses, influenza, and other RNA viruses [#3, #4, #8]. Beyond immunity, TRIM56 governs diverse physiology by degrading or modifying defined substrates: it drives K48-linked degradation of FASN to limit hepatic lipogenesis [#17], of TLE3 to promote beige adipogenesis [#24], of vimentin to suppress EMT [#5], and of KLF4, YBX1, and GCN2 in neuronal and tumor contexts [#22, #26, #28], while catalyzing non-degradative K63-linked modification of IQGAP1 and Src to activate downstream CDC42 and Src signaling [#16, #25]. The coiled-coil domain assembles an anti-parallel tetramer that juxtaposes RING domains for efficient ubiquitin transfer [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established the first mechanistic role for TRIM56 in innate immunity by showing it ubiquitinates STING to enable antiviral signaling, answering how cytosolic DNA sensing engages an E3 ligase.\",\n      \"evidence\": \"Co-IP, K63-ubiquitination assays, and IFN-\\u03b2 reporter with knockdown in dsDNA response\",\n      \"pmids\": [\"21074459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which E2 partners with TRIM56 on STING\", \"Physiological requirement not yet tested in knockout animals\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed TRIM56 directly restricts a virus (BVDV) in a ligase- and C-terminus-dependent manner separable from general IFN induction, indicating intrinsic antiviral activity beyond signaling amplification.\",\n      \"evidence\": \"Overexpression/RNAi viral replication assays with ligase-dead and deletion mutants\",\n      \"pmids\": [\"21289118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct viral or host substrate not identified\", \"Mechanism by which the C-terminus contributes was unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a ligase-independent function in which TRIM56 binds the adaptor TRIF to potentiate TLR3 signaling, distinguishing scaffolding from catalytic roles.\",\n      \"evidence\": \"Reciprocal Co-IP, C-terminal deletion mutants, IRF3/IFN-\\u03b2 reporter assays\",\n      \"pmids\": [\"22948160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRIM56 binding alters TRIF complex assembly was not defined\", \"Did not address whether the interaction is constitutive or stimulus-induced\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated virus-specific restriction mechanisms, requiring ligase activity plus C-terminal integrity for flaviviruses but ligase alone for a coronavirus, showing TRIM56 uses distinct modes against different viruses.\",\n      \"evidence\": \"Tet-regulated conditional mutant cell lines, viral RNA quantification, RING and deletion mutants\",\n      \"pmids\": [\"25253338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The molecular target restricting flavivirus RNA accumulation was unknown at this stage\", \"Step in coronavirus life cycle beyond 'post-replication' undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Localized RNA-virus restriction to a minimal 63-residue C-terminal tail sufficient on its own, separating antiviral function from the RING, B-box, and coiled-coil domains.\",\n      \"evidence\": \"Domain deletion and minimal-fragment expression with influenza RNA synthesis assays\",\n      \"pmids\": [\"26889027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical activity of the tail not yet defined as RNA binding\", \"Did not establish whether the tail acts directly on viral or host machinery\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified cGAS as a direct activating substrate via monoubiquitination at K335 and confirmed in vivo requirement, providing a defined biochemical mechanism for TRIM56's pro-IFN role against DNA viruses.\",\n      \"evidence\": \"Site-specific ubiquitination mapping, cGAS dimerization/cGAMP assays, TRIM56-KO mice, HSV-1 model\",\n      \"pmids\": [\"29426904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between cGAS monoubiquitination and the earlier STING K63 model not reconciled\", \"E2 enzyme for cGAS modification not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that TRIM56 is a bona fide RNA-binding protein whose C-terminal region directly binds viral RNA, explaining the ligase-independent restriction defined earlier.\",\n      \"evidence\": \"Cell-free RNA binding with recombinant fragment, RIP, Dicer-KO controls, ZIKV replication assays\",\n      \"pmids\": [\"31251739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA sequence/structure specificity of binding not defined\", \"How RNA binding mechanistically blocks replication unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended TRIM56 function beyond immunity by identifying vimentin as a degradative substrate, linking the ligase to EMT suppression in epithelial cells.\",\n      \"evidence\": \"MS of vimentin IP, proteasome inhibitor rescue, OE/KD migration/invasion assays\",\n      \"pmids\": [\"28771721\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site and linkage on vimentin not mapped\", \"Single-lab finding without in vivo validation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Clarified pathway placement by showing TRIM56 is required upstream of IFN production (dsRNA/TLR3 and cGAS-STING) but not in downstream IFN signaling, defining the boundary of its requirement.\",\n      \"evidence\": \"CRISPR TRIM56-null HeLa cells, ISG assays across pathways with negative controls, VSV bioassay\",\n      \"pmids\": [\"35062293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not dissect relative contributions of cGAS vs STING modification\", \"Cell-type generality beyond HeLa not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided a structural basis for catalysis by showing the coiled-coil forms an anti-parallel tetramer positioning RING domains for ubiquitin transfer.\",\n      \"evidence\": \"X-ray crystallography of isolated coiled-coil domain and tetramer modeling\",\n      \"pmids\": [\"37168870\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis validation of the proposed tetramer interface\", \"Structure of full-length protein and RING-substrate engagement not determined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the regulatory layer controlling TRIM56's cGAS function, showing HDAC6 deacetylates TRIM56 at K110 to suppress cGAS monoubiquitination, a node hijacked by HSV-1 US3.\",\n      \"evidence\": \"HDAC6 KO in vitro/in vivo, K110 acetylation mapping, cGAS monoubiquitination and DNA-binding assays, HSV-1 model\",\n      \"pmids\": [\"39747662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The acetyltransferase opposing HDAC6 on TRIM56 not identified\", \"Whether K110 acetylation affects non-cGAS substrates unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established TRIM56's metabolic role by identifying FASN as a K48-linked degradative substrate that restrains hepatic lipogenesis, expanding its physiology to NAFLD.\",\n      \"evidence\": \"Co-IP, K48 ubiquitination, hepatocyte-specific KO/OE mice, interactome/transcriptome profiling\",\n      \"pmids\": [\"38206764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitination site on FASN not mapped\", \"Upstream signals controlling hepatic TRIM56 expression not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined TLR3 regulation by showing site-specific TRIM56 phosphorylation (Ser471/Ser475/Ser710) governs the TRIF interaction, providing a phospho-switch for signal augmentation.\",\n      \"evidence\": \"Phospho-specific antibodies, alanine mutants, Tet-regulated cells, TRIM56-TRIF Co-IP, IFN-\\u03b2 reporter\",\n      \"pmids\": [\"38556084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The kinase phosphorylating these residues not identified\", \"How phosphorylation alters TRIM56 conformation/binding not structurally resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Broadened TRIM56's catalytic repertoire to non-canonical signaling and apparent deubiquitination, modifying TAK1 (M1-linked), IQGAP1 (K48-to-K63 switch), Src (K63), and stabilizing cIAP1 and FOXM1.\",\n      \"evidence\": \"Co-IP, linkage-specific ubiquitination, downstream activation assays across glioma/cancer models (multiple studies)\",\n      \"pmids\": [\"35952808\", \"36471347\", \"35696011\", \"36870986\", \"41102183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which a RING E3 effects deubiquitination/stabilization not biochemically resolved\", \"Each substrate validated in a single lab without cross-replication\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed TRIM56 substrate engagement is directed by adaptors and lncRNAs, with ZC3H15 recruiting it to PTEN and PVT1 modulating AMPK\\u03b1 ubiquitination, indicating context-specific targeting.\",\n      \"evidence\": \"Co-IP, domain mapping, ubiquitination assays, conditional KO mice (PVT1/TRIM56 podocyte models)\",\n      \"pmids\": [\"41513632\", \"39349450\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"General rules determining substrate selection across tissues unknown\", \"Whether adaptor recruitment competes with antiviral substrates not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Documented a contradictory STING outcome, with TRIM56 driving K48-linked STING degradation to dampen inflammation, contrasting its earlier K63-linked STING activation.\",\n      \"evidence\": \"Co-IP, K48 ubiquitination, MG132 rescue, OE/KD in LPS-induced acute lung injury model\",\n      \"pmids\": [\"42155789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conditions selecting K48 versus K63 modification of STING not defined\", \"Direct contradiction with the 2010 STING-activation model unreconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRIM56 selects among its many substrates and switches between activating (K63/mono), degradative (K48), and stabilizing outputs in a context-dependent manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for linkage-type and substrate selection\", \"Conflicting STING modifications (K63 activation vs K48 degradation) not mechanistically reconciled\", \"No full-length structure showing RING-substrate engagement\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 6, 17, 16, 25, 24]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 6, 5, 17]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 6, 17]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [8, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 25, 30]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 6, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 17, 24]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [17, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 25, 29]}\n    ],\n    \"complexes\": [\"ATR-TRIM56 complex\"],\n    \"partners\": [\"STING1\", \"CGAS\", \"TICAM1\", \"FASN\", \"IQGAP1\", \"SRC\", \"TLE3\", \"YBX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}