{"gene":"TRIM56","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2010,"finding":"TRIM56 interacts with STING and catalyzes K63-linked ubiquitination of STING, 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, ubiquitination assay","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ubiquitination assay, functional epistasis with KD/OE; foundational paper with 424 citations","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 does not affect VSV or HCV replication.","method":"TRIM56 overexpression/knockdown with viral replication assays; E3 ligase-dead mutant analysis; C-terminal deletion analysis","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — gain/loss-of-function with domain mutants and direct viral replication readout; 99 citations","pmids":["21289118"],"is_preprint":false},{"year":2012,"finding":"TRIM56 physically interacts with the TLR3 adaptor TRIF via its C-terminal residues (621–750) and positively regulates TLR3 signaling to promote IRF3 activation and IFN-β induction; this function is independent of TRIM56's E3 ligase activity.","method":"Co-immunoprecipitation, overexpression/knockdown with IRF3 activation and IFN-β reporter assays, C-terminal deletion analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with domain mapping and functional epistasis; 92 citations","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 later step in the viral life cycle.","method":"Conditional cell lines expressing TRIM56 mutants; viral replication assays; intracellular viral RNA quantification","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — engineered cell lines with domain mutants, multiple viruses, orthogonal readouts; 90 citations","pmids":["25253338"],"is_preprint":false},{"year":2016,"finding":"TRIM56 restricts influenza A and B virus replication by impairing intracellular viral RNA synthesis; this antiviral activity is independent of E3 ligase activity, B-box, or coiled-coil domain but requires a 63-residue C-terminal tail segment that is itself sufficient to inhibit influenza replication.","method":"Overexpression of TRIM56 domain mutants, viral RNA synthesis assays, C-terminal segment expression","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — domain dissection with multiple mutants, direct RNA synthesis readout; 92 citations","pmids":["26889027"],"is_preprint":false},{"year":2018,"finding":"TRIM56 induces monoubiquitination of cGAS at Lys335, which markedly increases cGAS dimerization, DNA-binding activity, and cGAMP production; TRIM56-deficient cells show impaired IFN-αβ production and mice show high susceptibility to HSV-1 infection.","method":"Monoubiquitination assay, site-directed mutagenesis (K335R), cGAS dimerization assay, DNA-binding assay, cGAMP quantification, TRIM56-knockout mice","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — in vitro ubiquitination assay with mutagenesis, biochemical activity assays, and in vivo mouse model; 190 citations","pmids":["29426904"],"is_preprint":false},{"year":2019,"finding":"TRIM56 associates 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 supporting ERα-positive breast cancer cell proliferation.","method":"Co-immunoprecipitation, domain mapping (WD40 deletion), ubiquitination assay, siRNA knockdown with proliferation assays in vitro and xenograft in vivo","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP with domain mapping, ubiquitination assay; single lab, moderate mechanistic follow-up","pmids":["31000690"],"is_preprint":false},{"year":2019,"finding":"TRIM56 restricts Zika virus (ZIKV) by directly binding ZIKV RNA via its C-terminal 392 residues; deletion of a short C-terminal tail abrogates both RNA binding and antiviral activity; this restriction is independent of Dicer/miRNA activity.","method":"TRIM56 overexpression/knockout, E3-dead mutant analysis, RNA immunoprecipitation in infected cells, cell-free RNA binding assay with recombinant C-terminal TRIM56 fragment, Dicer-knockout cells","journal":"PLoS neglected tropical diseases","confidence":"High","confidence_rationale":"Tier 1 — in vitro direct RNA binding with recombinant protein, cell-based RIP, domain mutagenesis, and Dicer-KO epistasis","pmids":["31251739"],"is_preprint":false},{"year":2019,"finding":"TRIM56 is recruited by KSHV vFLIP to ubiquitinate and degrade SAP18 via the proteasome pathway, dismantling the SAP18-HDAC1 complex, enhancing p65 acetylation, and activating NF-κB to promote cell invasion and angiogenesis.","method":"Co-immunoprecipitation, ubiquitination/degradation assay, siRNA knockdown, NF-κB reporter assay, migration/invasion assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP, proteasomal degradation assay, functional downstream readout; single lab","pmids":["30670829"],"is_preprint":false},{"year":2022,"finding":"TRIM56 deubiquitinates cIAP1 primarily through its zinc finger domain (amino acids 21–205), reducing cIAP1 degradation and stabilizing it to promote glioblastoma progression.","method":"Ubiquitin array, co-immunoprecipitation, domain deletion analysis, xenograft model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP with domain mapping and in vivo xenograft; deubiquitinase activity inferred but not directly reconstituted","pmids":["36471347"],"is_preprint":false},{"year":2022,"finding":"TRIM56 stabilizes FOXM1 by deubiquitination, enhancing FOXM1-mediated DNA damage repair and thereby reducing radiosensitivity of glioblastoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, knockdown with clonogenic/DNA repair assays, xenograft model","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP, ubiquitination assay, functional phenotype; single lab, deubiquitinase mechanism not reconstituted in vitro","pmids":["35696011"],"is_preprint":false},{"year":2022,"finding":"TRIM56 promotes K48-to-K63-linked polyubiquitination transition of IQGAP1 at Lys-1230 by physically interacting with IQGAP1, which activates CDC42 and drives glioma cell migration and invasion.","method":"Co-immunoprecipitation, ubiquitination assay with linkage-specific analysis, CDC42 activation assay, knockdown/overexpression with invasion/migration assays, in vivo glioma model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, site-specific ubiquitination analysis, downstream signaling validated, in vivo model; single lab","pmids":["36870986"],"is_preprint":false},{"year":2022,"finding":"TRIM56 Ring domain-mediated ubiquitination of IκBα promotes NF-κB p65 phosphorylation, which subsequently inhibits HBV core promoter activity; the C-terminal domain is required for TRIM56 nuclear translocation during HBV infection.","method":"TRIM56 overexpression/knockdown, domain deletion/mutation analysis, ubiquitination assay, NF-κB reporter, HBV replication assays in HepG2-NTCP and primary hepatocytes","journal":"Antiviral research","confidence":"Medium","confidence_rationale":"Tier 2/3 — domain dissection with functional viral replication readout, ubiquitination assay; single lab","pmids":["36084850"],"is_preprint":false},{"year":2022,"finding":"TRIM56 positively regulates TNFα-induced NF-κB signaling by interacting with TAK1 via its C-terminal domain and promoting M1-linked polyubiquitination of TAK1 through its RING domain, strengthening TAK1-IKKα complex interactions.","method":"Co-immunoprecipitation, ubiquitination assay with linkage-specific analysis, domain deletion constructs, knockdown/overexpression with NF-κB reporter","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP, ubiquitin linkage analysis, domain mapping; single lab, not reconstituted in vitro","pmids":["35952808"],"is_preprint":false},{"year":2022,"finding":"TRIM56 knockout in HeLa cells severely impairs ISG upregulation by extracellular dsRNA (TLR3 pathway) and weakens the response to cytosolic dsDNA (cGAS-STING pathway), but does not compromise ISG induction or antiviral state established by IFN-α treatment.","method":"CRISPR/Cas9 TRIM56 knockout HeLa cells, ISG qRT-PCR, IFN-α stimulation, VSV-based antiviral bioactivity assay","journal":"Viruses","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with multiple orthogonal assays distinguishing TLR3, cGAS-STING, and IFN-I downstream pathways","pmids":["35062293"],"is_preprint":false},{"year":2023,"finding":"The crystal structure of the TRIM56 coiled-coil domain reveals that two anti-parallel dimers form a tetramer, positioning two RING domains on each side to support active homodimerization for ubiquitin transfer from E2 to nearby substrates recruited by C-terminal domains.","method":"X-ray crystallography of coiled-coil domain, structural analysis","journal":"Computational and structural biotechnology journal","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mechanistic interpretation of E3 ligase quaternary architecture","pmids":["37168870"],"is_preprint":false},{"year":2024,"finding":"TRIM56 directly binds to and promotes K48-linked ubiquitination-dependent proteasomal degradation of fatty acid synthase (FASN), limiting lipogenesis; TRIM56 loss exacerbates NAFLD and TRIM56 overexpression suppresses it.","method":"Co-immunoprecipitation, ubiquitination assay, hepatocyte-specific TRIM56 KO and overexpression mice, NAFLD/NASH models, AI-based small-molecule screening","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1/2 — direct binding Co-IP, K48 ubiquitination assay, conditional KO and OE mouse models, replicated in disease context","pmids":["38206764"],"is_preprint":false},{"year":2024,"finding":"TRIM56 mediates K63-linked ubiquitination of ATR (via an ATR-TRIM56 complex), maintaining ATR stability and genomic integrity in nucleus pulposus cells; disassembly of the ATR-TRIM56 complex leads to USP5/TRIM25 liberation, shifting ATR ubiquitination from K63 to K48, causing proteasomal ATR degradation and promoting cGAS/STING-driven NP cell senescence.","method":"Co-immunoprecipitation, ubiquitination assay with linkage specificity, proteomic analysis, engineered extracellular vesicle delivery, IVDD mouse model","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ubiquitin linkage analysis, in vivo model; single lab, complex multi-component mechanism","pmids":["38488012"],"is_preprint":false},{"year":2024,"finding":"TRIM56 binds YBX1 and promotes its K48-linked ubiquitination and proteasomal degradation; this suppresses YBX1-mediated stabilization of ZBP1 mRNA, thereby reducing ZBP1-mediated PANoptosis in neurons after spinal cord injury.","method":"Molecular docking, immunoprecipitation/MS, RIP-seq, ubiquitination assay, knockdown/overexpression with PANoptosis readouts","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2/3 — IP/MS, ubiquitination assay, RIP-seq for mRNA stabilization; single lab","pmids":["39291396"],"is_preprint":false},{"year":2024,"finding":"TRIM56 restricts Coxsackievirus B3 (CVB3) by interacting with and mediating K48-linked polyubiquitination of the viral RNA-dependent RNA polymerase 3D at K220, promoting its proteasomal degradation; viral 3C protease cleaves TRIM56 as a countermeasure.","method":"Pull-down, co-immunoprecipitation, immunofluorescence colocalization, ubiquitination assay, overexpression with viral yield assay, site-directed mutagenesis (K220R)","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1/2 — direct pull-down, site-specific ubiquitination mutagenesis, viral yield readout, viral protease cleavage demonstrated","pmids":["39348396"],"is_preprint":false},{"year":2024,"finding":"HDAC6 deacetylates TRIM56 at K110, impairing TRIM56-mediated monoubiquitination of cGAS and its DNA-binding ability, thereby suppressing cGAS-STING-dependent IFN production; HSV-1 US3 protein phosphorylates HDAC6 to exploit this inhibitory axis.","method":"HDAC6 knockout cells and mice, deacetylation assay, cGAS ubiquitination assay, DNA-binding assay, IFN measurement, species-specific comparison (human vs. mouse K110)","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1/2 — biochemical deacetylation, ubiquitination and DNA binding assays, in vivo KO model, viral protein mechanism identified","pmids":["39747662"],"is_preprint":false},{"year":2024,"finding":"TRIM56 promotes K48-linked ubiquitination and proteasomal degradation of TLE3 in adipocytes in response to cold stimuli, activating thermogenic genes in subcutaneous white adipose tissue and promoting white adipose tissue browning.","method":"Co-immunoprecipitation, ubiquitination assay, adipocyte-specific TRIM56 overexpression mice, cold exposure and diet-induced obesity models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ubiquitination assay, in vivo mouse model; single lab","pmids":["39928840"],"is_preprint":false},{"year":2024,"finding":"PVT1 lncRNA interacts with TRIM56 post-transcriptionally and modulates TRIM56-mediated ubiquitination of AMPKα, leading to aberrant mitochondrial biogenesis and fission in diabetic podocytes; podocyte-specific TRIM56 KO mice phenocopy PVT1 KO.","method":"Co-immunoprecipitation, ubiquitination assay, podocyte-specific KO mice (Nphs2-Cre/Trim56flox/flox), mitochondrial morphology and function assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ubiquitination assay, conditional KO mice; mechanism of lncRNA-TRIM56 interaction is partially characterized","pmids":["39349450"],"is_preprint":false},{"year":2024,"finding":"TRIM56 promotes K63-linked polyubiquitination of ATR to stabilize it, whereas loss of the TRIM56-ATR complex releases USP5 and TRIM25, switching ATR to K48-linked ubiquitination and driving proteasomal degradation that exposes cytosolic DNA and activates the cGAS/STING inflammatory pathway in nucleus pulposus cells.","method":"Co-immunoprecipitation, ubiquitin linkage-specific assay, mass spectrometry proteomics, gene silencing","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP with proteomics and ubiquitin linkage assays; complex mechanism from single lab","pmids":["38488012"],"is_preprint":false},{"year":2024,"finding":"The TRIM56 coiled-coil domain and phosphorylation at Ser471, Ser475, and Ser710 are required for TRIM56 augmentation of TLR3-TRIF-dependent IFN-β and NF-κB signaling; Ser710 phosphorylation is specifically required for TRIM56-TRIF association, and TRIM56 phosphorylation at Ser471/Ser475 occurs in a biphasic manner following TLR3 stimulation.","method":"Transient transfection and Tet-regulated cell lines expressing alanine-substitution mutants, phospho-specific antibodies, IFN-β promoter reporter, NF-κB reporter, Co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple domain/phospho mutants, phospho-specific antibody detection of endogenous phosphorylation, multiple functional readouts; comprehensive mechanistic study","pmids":["38556084"],"is_preprint":false},{"year":2017,"finding":"TRIM56 ubiquitinates vimentin to promote its proteasomal degradation; loss of TRIM56 in normal ovarian cells stabilizes vimentin and increases migration/invasion, while TRIM56 overexpression in ovarian cancer cells reduces vimentin and suppresses invasiveness.","method":"Mass spectrometry of vimentin immunoprecipitate, RNAi knockdown and overexpression, proteasome inhibitor (MG-132) assay, migration/invasion assays","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2/3 — MS-identified interaction, KD/OE with functional readout; ubiquitination of vimentin by TRIM56 inferred but not directly demonstrated in vitro","pmids":["28771721"],"is_preprint":false},{"year":2022,"finding":"Exosomal circZNF451 enhances TRIM56-mediated ubiquitination and degradation of FXR1 in macrophages, activating the ELF4-IRF4 pathway to polarize macrophages toward an anti-inflammatory phenotype and exhaust CD8+ T cells, promoting anti-PD1 treatment resistance in lung adenocarcinoma.","method":"RNA pulldown, RNA immunoprecipitation, mass spectrometry, co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter, flow cytometry, transgenic ELF4-KO mice","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2/3 — multiple orthogonal methods (RIP, MS, Co-IP, luciferase, KO mice); single lab, TRIM56 role is one node in a larger mechanism","pmids":["36209117"],"is_preprint":false},{"year":2025,"finding":"TRIM56 interacts with Src via its B-box1 domain binding to the Src SH3 domain and catalyzes K63-linked polyubiquitination of Src at Lys184, promoting Src protein aggregation and intermolecular autophosphorylation-driven Src activation in hepatocellular carcinoma.","method":"Co-immunoprecipitation, domain mapping, ubiquitination assay with K63 linkage specificity, site-directed mutagenesis (K184R), Src activation assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP with domain mapping, site-specific ubiquitination mutagenesis, Src activation readout; single lab","pmids":["41102183"],"is_preprint":false},{"year":2025,"finding":"TRIM56 promotes K48-linked ubiquitination-dependent degradation of KLF4, reducing KLF4-activated ferroptosis-protective gene expression and thereby aggravating neuronal ferroptosis following cerebral ischemia-reperfusion injury.","method":"Co-immunoprecipitation, ubiquitination assay, TRIM56 KO mice, TRIM56 OE, neurological deficit assays, in vitro ferroptosis readouts","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ubiquitination assay, KO/OE mouse model; single lab, mechanistic link is direct but not reconstituted in vitro","pmids":["41214892"],"is_preprint":false},{"year":2024,"finding":"TRIM56 mediates K48-linked ubiquitination and proteasomal degradation of GCN2 at K619 in non-small cell lung cancer; CD147 suppresses TRIM56 expression to stabilize GCN2 and activate the GCN2/EIF2α/ATG12 axis for autophagy-mediated exosome secretion.","method":"Proteomics/mass spectrometry identifying TRIM56 as E3 ligase, Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K619), TRIM56 KD/OE","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2/3 — MS-based identification, site-specific ubiquitination, Co-IP; single lab","pmids":["41413248"],"is_preprint":false},{"year":2025,"finding":"TRIM56 mediates K48-linked ubiquitination of PTEN (recruited by ZC3H15 via its DFRP domain), promoting PTEN degradation and activating the AKT-mTOR signaling pathway in non-small cell lung cancer.","method":"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown studies with AKT-mTOR pathway readouts","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 — Co-IP with functional readout; TRIM56's direct ubiquitination of PTEN inferred from interaction with ZC3H15 scaffold; single lab, limited mechanistic validation","pmids":["41513632"],"is_preprint":false},{"year":2025,"finding":"TRIM56 stabilizes adenoviral E1A protein and assists E1A in antagonizing STING signaling, thereby enhancing adenoviral genome transcription and HAdV-C5 replication.","method":"Overexpression/knockdown studies, viral replication titer assays, E1A protein stability assay, STING antagonism assay","journal":"Journal of virology","confidence":"Low","confidence_rationale":"Tier 3 — functional OE/KD with viral replication readout; mechanism of E1A stabilization not biochemically reconstituted; single lab","pmids":["40459263"],"is_preprint":false},{"year":2025,"finding":"TRIM56 binds to ITGB4 (identified by Co-IP with mass spectrometry) and promotes its ubiquitination, which regulates MUC5AC expression in airway epithelial cells; inhibition of TRIM56 by BFF-4 reduces ITGB4 ubiquitination and mucus hypersecretion in COPD models.","method":"DARTS analysis (target identification), Co-IP/mass spectrometry, ubiquitination assay, TRIM56 overexpression, COPD mouse model","journal":"Journal of ethnopharmacology","confidence":"Low","confidence_rationale":"Tier 3 — Co-IP/MS with functional readout; single lab, ligand-target identification method (DARTS) has indirect readout","pmids":["41580166"],"is_preprint":false}],"current_model":"TRIM56 is a multifunctional RING-type E3 ubiquitin ligase (and RNA-binding protein) that regulates innate immunity and diverse cellular processes through context-dependent mechanisms: it catalyzes K63-linked ubiquitination of STING (promoting STING dimerization and TBK1 recruitment) and monoubiquitination of cGAS at K335 (enhancing cGAS dimerization, DNA binding, and cGAMP production) to amplify cytosolic DNA sensing; it positively regulates TLR3-TRIF signaling through a phosphorylation-dependent scaffolding interaction (requiring Ser471, Ser475, Ser710, and the coiled-coil domain) that is E3 ligase-independent; it directly restricts multiple RNA viruses by binding viral RNA or ubiquitinating viral polymerases for proteasomal degradation; and it targets diverse cellular substrates—including FASN, TLE3, vimentin, IQGAP1, TAK1, ERα, KLF4, and others—for K48- or K63-linked ubiquitination to control metabolism, migration, and cell survival, with its coiled-coil domain forming a tetramer scaffold that positions RING domains for ubiquitin transfer."},"narrative":{"teleology":[{"year":2010,"claim":"Establishing TRIM56 as an innate immune E3 ligase: it was unknown how STING dimerization was triggered; the demonstration that TRIM56 catalyzes K63-linked ubiquitination of STING to induce dimerization and TBK1 recruitment identified TRIM56 as a critical upstream activator of cytosolic DNA sensing.","evidence":"Co-immunoprecipitation, ubiquitination assay, and IFN-β reporter with overexpression/knockdown in human cells","pmids":["21074459"],"confidence":"High","gaps":["Ubiquitination site on STING not mapped","No in vivo validation in mouse models at this stage","Whether TRIM56 acts on other innate sensors was unknown"]},{"year":2011,"claim":"Defining TRIM56 as a direct-acting antiviral factor: it was unclear whether TRIM56 could restrict viruses beyond the STING pathway; showing E3 ligase-dependent restriction of BVDV but not VSV or HCV revealed virus-specific direct antiviral mechanisms.","evidence":"TRIM56 overexpression/knockdown with E3-dead and C-terminal deletion mutants, viral replication assays","pmids":["21289118"],"confidence":"High","gaps":["Viral substrate targeted by TRIM56 not identified","Mechanism of C-terminal requirement unclear"]},{"year":2012,"claim":"Separating TRIM56's scaffolding from ligase functions: the discovery that TRIM56 positively regulates TLR3-TRIF signaling independent of E3 ligase activity, via direct C-terminal binding to TRIF, revealed a second, non-catalytic mode of innate immune regulation.","evidence":"Reciprocal Co-IP, C-terminal domain mapping, IRF3 and IFN-β reporter assays","pmids":["22948160"],"confidence":"High","gaps":["Post-translational modifications governing TRIF binding not identified","In vivo relevance of TLR3 arm not tested"]},{"year":2014,"claim":"Broadening antiviral scope and dissecting domain requirements: TRIM56 restricted flaviviruses (YFV, DENV2) requiring both E3 and C-terminal domains but restricted HCoV-OC43 via E3 activity alone, indicating virus-specific mechanistic modules.","evidence":"Conditional cell lines with domain mutants, intracellular viral RNA quantification across multiple viruses","pmids":["25253338"],"confidence":"High","gaps":["Exact viral targets for ubiquitination not identified for flaviviruses","Host cofactors for C-terminal-mediated restriction unknown"]},{"year":2016,"claim":"Revealing an E3-independent RNA-binding antiviral mechanism: TRIM56 restriction of influenza A/B required only a 63-residue C-terminal tail and was independent of the RING, B-box, and coiled-coil domains, establishing a minimal antiviral module.","evidence":"Domain mutant expression with viral RNA synthesis assays; C-terminal segment sufficient for restriction","pmids":["26889027"],"confidence":"High","gaps":["Whether the C-terminal tail directly contacts viral RNA not shown","Structural basis of the 63-residue tail function unresolved"]},{"year":2018,"claim":"Identifying TRIM56 as the activating E3 ligase for cGAS: TRIM56-catalyzed monoubiquitination of cGAS at Lys335 enhanced cGAS dimerization and DNA binding, and TRIM56-knockout mice were highly susceptible to HSV-1, placing TRIM56 as an essential upstream regulator of cGAS-STING signaling in vivo.","evidence":"Site-directed mutagenesis (K335R), in vitro monoubiquitination assay, cGAS biochemical assays, TRIM56-KO mice with HSV-1 challenge","pmids":["29426904"],"confidence":"High","gaps":["Structural basis of TRIM56-cGAS recognition unknown","Whether additional E3 ligases redundantly activate cGAS not addressed"]},{"year":2019,"claim":"Demonstrating direct RNA-binding as the mechanism for Zika virus restriction: TRIM56's C-terminal 392 residues directly bound ZIKV RNA in a cell-free system, and a short C-terminal tail deletion abolished both RNA binding and antiviral activity, confirming RNA binding as the effector mechanism independent of Dicer.","evidence":"Recombinant protein–RNA binding assay, RNA immunoprecipitation, Dicer-KO epistasis","pmids":["31251739"],"confidence":"High","gaps":["RNA sequence/structure specificity not defined","No crystal structure of RNA-binding domain"]},{"year":2019,"claim":"Expanding TRIM56 substrates to non-immune targets: TRIM56 was shown to ubiquitinate ERα (K63-linked, stabilizing) and SAP18 (proteasomal degradation via KSHV vFLIP hijacking), linking TRIM56 to cancer cell proliferation and viral immune evasion beyond innate sensing.","evidence":"Co-IP with domain mapping, ubiquitination assays, xenograft and functional assays in breast cancer and KSHV-infected cells","pmids":["31000690","30670829"],"confidence":"Medium","gaps":["ERα ubiquitination site not mapped","vFLIP-TRIM56 interaction not reconstituted with purified components","Physiological relevance in non-cancer settings not established"]},{"year":2022,"claim":"Consolidating TRIM56 as a multi-substrate E3 ligase across signaling pathways: studies identified IQGAP1 (K48→K63 switch activating CDC42), TAK1 (M1-linked ubiquitination activating NF-κB), IκBα (ubiquitination promoting NF-κB against HBV), and vimentin (degradation controlling migration) as TRIM56 substrates, revealing its versatility in ubiquitin chain-type specification.","evidence":"Co-IP with linkage-specific ubiquitin analysis, domain mapping, knockdown/overexpression with functional readouts across glioma, HBV, and ovarian cancer models","pmids":["36870986","35952808","36084850","28771721"],"confidence":"Medium","gaps":["In vitro reconstitution of chain-type specificity switching not performed","Mechanism determining K48 vs K63 vs M1 chain selection by TRIM56 unknown","Most findings from single laboratories"]},{"year":2022,"claim":"Genetic confirmation that TRIM56 is required for both TLR3 and cGAS-STING pathways but dispensable for IFN-I downstream signaling: TRIM56-KO HeLa cells showed severely impaired ISG induction by extracellular dsRNA and cytosolic dsDNA but normal IFN-α response, clarifying TRIM56's position upstream of IFN production.","evidence":"CRISPR/Cas9 KO with dsRNA, dsDNA, and IFN-α stimulation and ISG/antiviral bioactivity readouts","pmids":["35062293"],"confidence":"High","gaps":["Single cell line (HeLa); generalizability across cell types not tested","Relative contributions of STING vs cGAS ubiquitination not separated"]},{"year":2023,"claim":"Structural basis for TRIM56 E3 activity: the crystal structure of the coiled-coil domain revealed an antiparallel dimer-of-dimers tetramer that positions two RING domains on each side for productive E2-ubiquitin transfer, explaining how quaternary organization supports catalysis.","evidence":"X-ray crystallography of the TRIM56 coiled-coil domain","pmids":["37168870"],"confidence":"High","gaps":["Full-length structure unavailable","How C-terminal substrate-recruiting domains are oriented relative to RING not resolved","No structure of RING-E2~Ub complex"]},{"year":2024,"claim":"Establishing TRIM56 as a metabolic regulator: TRIM56 directly ubiquitinates FASN (K48-linked) for proteasomal degradation to limit lipogenesis, and ubiquitinates TLE3 (K48-linked) to activate thermogenic gene programs in white adipose tissue, connecting TRIM56 to NAFLD protection and adaptive thermogenesis.","evidence":"Hepatocyte- and adipocyte-specific conditional KO/OE mice, NAFLD/obesity/cold models, ubiquitination assays","pmids":["38206764","39928840"],"confidence":"High","gaps":["Ubiquitination sites on FASN not mapped","Upstream signals regulating TRIM56 in metabolic tissues unknown","Whether metabolic and immune functions of TRIM56 are coordinately regulated is unexplored"]},{"year":2024,"claim":"Revealing regulation of TRIM56 itself: HDAC6 deacetylates TRIM56 at Lys110, impairing its ability to monoubiquitinate cGAS, and HSV-1 US3 protein exploits this axis by phosphorylating HDAC6, establishing TRIM56 acetylation as a regulatory switch for cGAS activation.","evidence":"HDAC6-KO cells and mice, deacetylation assay, cGAS ubiquitination and DNA-binding assays, HSV-1 US3 mechanism","pmids":["39747662"],"confidence":"High","gaps":["Acetyltransferase responsible for TRIM56 K110 acetylation not identified","Whether acetylation affects TRIM56 activity on substrates other than cGAS unknown"]},{"year":2024,"claim":"Defining phosphorylation codes for TLR3 signaling: Ser471, Ser475, and Ser710 phosphorylation of TRIM56 were shown to be required for TLR3-TRIF augmentation; Ser710 specifically governs TRIF association, and Ser471/Ser475 phosphorylation is biphasic after poly(I:C) stimulation, providing the first post-translational regulatory map for TRIM56's scaffolding function.","evidence":"Alanine-substitution mutants, phospho-specific antibodies, IFN-β and NF-κB reporters, Co-IP in Tet-regulated cell lines","pmids":["38556084"],"confidence":"High","gaps":["Kinase(s) responsible for Ser471/Ser475/Ser710 phosphorylation not identified","Whether phosphorylation regulates E3 ligase activity in other contexts not tested"]},{"year":2024,"claim":"Demonstrating TRIM56 as a direct antiviral E3 ligase targeting viral polymerases: TRIM56 ubiquitinates CVB3 RNA-dependent RNA polymerase 3D at Lys220 (K48-linked) for proteasomal degradation, and the virus counters by 3C protease-mediated cleavage of TRIM56, revealing an arms race dynamic.","evidence":"Pull-down, site-directed mutagenesis (K220R), ubiquitination assay, viral yield measurement, 3C cleavage assay","pmids":["39348396"],"confidence":"High","gaps":["Whether TRIM56 directly ubiquitinates polymerases of other viruses (flaviviruses, coronaviruses) remains untested","Cleavage site on TRIM56 not mapped"]},{"year":null,"claim":"Key unresolved questions include: the structural basis for TRIM56's dual RNA-binding and E3 ligase activities in a full-length context; the kinases and acetyltransferases that regulate TRIM56 post-translational modifications; how TRIM56 achieves ubiquitin chain-type specificity (K48, K63, M1, monoubiquitin) for different substrates; and the physiological integration of TRIM56's immune, metabolic, and cytoskeletal functions.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length TRIM56 structure","Chain-type specification mechanism unknown","Upstream kinases for Ser471/Ser475/Ser710 unidentified","Acetyltransferase for K110 unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5,6,8,11,13,16,19,21,27,28,29]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[7]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,5,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,24]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,6,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,5,14,20,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,12,13,27]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[16,21]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,5,15,16,19]}],"complexes":[],"partners":["STING","CGAS","TRIF","FASN","TAK1","IQGAP1","ATR","HDAC6"],"other_free_text":[]},"mechanistic_narrative":"TRIM56 is a RING-type E3 ubiquitin ligase that functions as a central amplifier of innate immune sensing and a versatile regulator of protein turnover across diverse cellular contexts. In the cytosolic DNA-sensing pathway, TRIM56 catalyzes K63-linked ubiquitination of STING to promote its dimerization and TBK1 recruitment, and monoubiquitinates cGAS at Lys335 to enhance cGAS dimerization, DNA binding, and cGAMP synthesis—activities regulated by HDAC6-mediated deacetylation of TRIM56 at Lys110 [PMID:21074459, PMID:29426904, PMID:39747662]. Independent of its E3 ligase activity, TRIM56 augments TLR3-TRIF signaling through a phosphorylation-dependent (Ser471/Ser475/Ser710) scaffolding interaction with TRIF, and restricts influenza and Zika viruses through direct C-terminal RNA binding, while it targets other viral polymerases (e.g., CVB3 3D) for K48-linked ubiquitination and proteasomal degradation [PMID:22948160, PMID:38556084, PMID:31251739, PMID:39348396]. Beyond innate immunity, TRIM56 ubiquitinates numerous cellular substrates—including FASN, TLE3, vimentin, IQGAP1, TAK1, Src, KLF4, and GCN2—using K48- or K63-linked chains to control lipid metabolism, adipose thermogenesis, cell migration, NF-κB signaling, and ferroptosis, with its coiled-coil domain forming a tetrameric scaffold that positions RING domains for ubiquitin transfer [PMID:38206764, PMID:39928840, PMID:36870986, PMID:35952808, PMID:37168870]."},"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 ubiquitin ligase TRIM56 regulates innate immune responses to intracellular double-stranded DNA.","date":"2010","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/21074459","citation_count":424,"is_preprint":false},{"pmid":"29426904","id":"PMC_29426904","title":"TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29426904","citation_count":190,"is_preprint":false},{"pmid":"21289118","id":"PMC_21289118","title":"TRIM56 is a virus- and interferon-inducible E3 ubiquitin ligase that restricts pestivirus infection.","date":"2011","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21289118","citation_count":99,"is_preprint":false},{"pmid":"22948160","id":"PMC_22948160","title":"TRIM56 is an essential component of the TLR3 antiviral signaling pathway.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22948160","citation_count":92,"is_preprint":false},{"pmid":"26889027","id":"PMC_26889027","title":"The C-Terminal Tail of TRIM56 Dictates Antiviral Restriction of Influenza A and B Viruses by Impeding Viral RNA Synthesis.","date":"2016","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/26889027","citation_count":92,"is_preprint":false},{"pmid":"25253338","id":"PMC_25253338","title":"Overlapping and distinct molecular determinants dictating the antiviral activities of TRIM56 against flaviviruses and coronavirus.","date":"2014","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/25253338","citation_count":90,"is_preprint":false},{"pmid":"36209117","id":"PMC_36209117","title":"Exosomal circZNF451 restrains anti-PD1 treatment in lung adenocarcinoma via polarizing macrophages by complexing with TRIM56 and FXR1.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/36209117","citation_count":68,"is_preprint":false},{"pmid":"31000690","id":"PMC_31000690","title":"Regulation of estrogen signaling and breast cancer proliferation by an ubiquitin ligase TRIM56.","date":"2019","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/31000690","citation_count":67,"is_preprint":false},{"pmid":"38206764","id":"PMC_38206764","title":"TRIM56 protects against nonalcoholic fatty liver disease by promoting the degradation of fatty acid synthase.","date":"2024","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/38206764","citation_count":56,"is_preprint":false},{"pmid":"28771721","id":"PMC_28771721","title":"The ubiquitin ligase TRIM56 inhibits ovarian cancer progression by targeting vimentin.","date":"2017","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28771721","citation_count":53,"is_preprint":false},{"pmid":"31251739","id":"PMC_31251739","title":"The E3 ligase TRIM56 is a host restriction factor of Zika virus and depends on its RNA-binding activity but not miRNA regulation, for antiviral function.","date":"2019","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/31251739","citation_count":46,"is_preprint":false},{"pmid":"38488012","id":"PMC_38488012","title":"Disassembly of the TRIM56-ATR complex promotes cytoDNA/cGAS/STING axis-dependent intervertebral disc inflammatory degeneration.","date":"2024","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/38488012","citation_count":40,"is_preprint":false},{"pmid":"30670829","id":"PMC_30670829","title":"Suppression of the SAP18/HDAC1 complex by targeting TRIM56 and Nanog is essential for oncogenic viral FLICE-inhibitory protein-induced acetylation of p65/RelA, NF-κB activation, and promotion of cell invasion and angiogenesis.","date":"2019","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/30670829","citation_count":39,"is_preprint":false},{"pmid":"38556084","id":"PMC_38556084","title":"Key roles for phosphorylation and the Coiled-coil domain in TRIM56-mediated positive regulation of TLR3-TRIF-dependent innate immunity.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38556084","citation_count":31,"is_preprint":false},{"pmid":"36471347","id":"PMC_36471347","title":"TRIM56 promotes malignant progression of glioblastoma by stabilizing cIAP1 protein.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/36471347","citation_count":28,"is_preprint":false},{"pmid":"39291396","id":"PMC_39291396","title":"TRIM56 Modulates YBX1 Degradation to Ameliorate ZBP1-Mediated Neuronal PANoptosis in Spinal Cord Injury.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39291396","citation_count":27,"is_preprint":false},{"pmid":"36902478","id":"PMC_36902478","title":"The Functions of TRIM56 in Antiviral Innate Immunity and Tumorigenesis.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36902478","citation_count":27,"is_preprint":false},{"pmid":"35952808","id":"PMC_35952808","title":"TRIM56 positively regulates TNFα-induced NF-κB signaling by enhancing the ubiquitination of TAK1.","date":"2022","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/35952808","citation_count":26,"is_preprint":false},{"pmid":"29214775","id":"PMC_29214775","title":"TRIM56 Suppresses Multiple Myeloma Progression by Activating TLR3/TRIF Signaling.","date":"2018","source":"Yonsei medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/29214775","citation_count":24,"is_preprint":false},{"pmid":"36084850","id":"PMC_36084850","title":"TRIM56 impairs HBV infection and replication by inhibiting HBV core promoter activity.","date":"2022","source":"Antiviral research","url":"https://pubmed.ncbi.nlm.nih.gov/36084850","citation_count":21,"is_preprint":false},{"pmid":"36870986","id":"PMC_36870986","title":"TRIM56 acts through the IQGAP1-CDC42 signaling axis to promote glioma cell migration and invasion.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36870986","citation_count":18,"is_preprint":false},{"pmid":"35696011","id":"PMC_35696011","title":"TRIM56 Reduces Radiosensitization of Human Glioblastoma by Regulating FOXM1-Mediated DNA Repair.","date":"2022","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/35696011","citation_count":17,"is_preprint":false},{"pmid":"30281912","id":"PMC_30281912","title":"Poly r(C) 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 Adenocarcinoma.","date":"2021","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33707970","citation_count":13,"is_preprint":false},{"pmid":"30637864","id":"PMC_30637864","title":"MiR-9 promotes multiple myeloma progression by regulating TRIM56/NF-κB pathway.","date":"2019","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/30637864","citation_count":13,"is_preprint":false},{"pmid":"35503719","id":"PMC_35503719","title":"TRIM56 overexpression restricts porcine epidemic diarrhoea virus replication in Marc-145 cells by enhancing TLR3-TRAF3-mediated IFN-β antiviral response.","date":"2022","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/35503719","citation_count":10,"is_preprint":false},{"pmid":"39348396","id":"PMC_39348396","title":"TRIM56 restricts Coxsackievirus B infection by mediating the ubiquitination of viral RNA-dependent RNA polymerase 3D.","date":"2024","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/39348396","citation_count":9,"is_preprint":false},{"pmid":"36450108","id":"PMC_36450108","title":"New Avenues to Explore in SARS-CoV-2 Infection: Both TRIM25 and TRIM56 Positively Correlate with VEGF, GAS6, and sAXL in COVID-19 Patients.","date":"2022","source":"Viral immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36450108","citation_count":8,"is_preprint":false},{"pmid":"32903131","id":"PMC_32903131","title":"Systematic review of the antiviral properties of TRIM56: a potential therapeutic intervention for COVID-19.","date":"2020","source":"Expert review of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32903131","citation_count":7,"is_preprint":false},{"pmid":"37168870","id":"PMC_37168870","title":"TRIM56 coiled-coil domain structure provides insights into its E3 ligase functions.","date":"2023","source":"Computational and structural biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/37168870","citation_count":7,"is_preprint":false},{"pmid":"39747662","id":"PMC_39747662","title":"HDAC6 deacetylates TRIM56 to negatively regulate cGAS-STING-mediated type I interferon responses.","date":"2025","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/39747662","citation_count":6,"is_preprint":false},{"pmid":"39928840","id":"PMC_39928840","title":"TRIM56 Promotes White Adipose Tissue Browning to Attenuate Obesity by Degrading TLE3.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39928840","citation_count":6,"is_preprint":false},{"pmid":"35062293","id":"PMC_35062293","title":"Impaired Antiviral Responses to Extracellular Double-Stranded RNA and Cytosolic DNA, but Not to Interferon-α Stimulation, in TRIM56-Deficient Cells.","date":"2022","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/35062293","citation_count":5,"is_preprint":false},{"pmid":"39059592","id":"PMC_39059592","title":"PGRMC1 promotes NSCLC stemness phenotypes by disrupting TRIM56-mediated ubiquitination of AHR.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/39059592","citation_count":3,"is_preprint":false},{"pmid":"38358243","id":"PMC_38358243","title":"TRIM56-mediated production of type I interferon inhibits intracellular replication of Rickettsia rickettsii.","date":"2024","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/38358243","citation_count":2,"is_preprint":false},{"pmid":"39861861","id":"PMC_39861861","title":"Emerging Roles of TRIM56 in Antiviral Innate Immunity.","date":"2025","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/39861861","citation_count":1,"is_preprint":false},{"pmid":"41214892","id":"PMC_41214892","title":"TRIM56 Aggravates Cerebral Ischemia-Reperfusion Injury via Inhibiting KLF4-Activated Ferroptosis Signaling.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41214892","citation_count":1,"is_preprint":false},{"pmid":"40459263","id":"PMC_40459263","title":"TRIM56 enhances adenoviral E1A steady state to improve oncolytic adenovirus therapy efficacy.","date":"2025","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/40459263","citation_count":1,"is_preprint":false},{"pmid":"40542888","id":"PMC_40542888","title":"The oncogenic role of TRIM56 in pancreatic cancer via the TRAF6/NF-kB axis.","date":"2025","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/40542888","citation_count":0,"is_preprint":false},{"pmid":"41413248","id":"PMC_41413248","title":"CD147 promotes NSCLC metastasis by inducing secretory autophagy-dependent exosome secretion via TRIM56-mediated ubiquitination and degradation of GCN2.","date":"2025","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/41413248","citation_count":0,"is_preprint":false},{"pmid":"41102183","id":"PMC_41102183","title":"The E3 ubiquitin ligase TRIM56 promotes aggregation and activation of Src protein through Lys63-linked polyubiquitination in hepatocellular carcinoma.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41102183","citation_count":0,"is_preprint":false},{"pmid":"41513632","id":"PMC_41513632","title":"ZC3H15 regulates the ubiquitination of PTEN via recruitment of TRIM56 and promotes malignant progression of non-small cell lung cancer.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41513632","citation_count":0,"is_preprint":false},{"pmid":"41580166","id":"PMC_41580166","title":"Bufei formula attenuates airway mucus hypersecretion in COPD through inhibition of TRIM56-mediated ITGB4 ubiquitination.","date":"2026","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41580166","citation_count":0,"is_preprint":false},{"pmid":"38051999","id":"PMC_38051999","title":"Expression of TRIM56 gene in SARS-CoV-2 variants and its relationship with progression of COVID-19.","date":"2023","source":"Future virology","url":"https://pubmed.ncbi.nlm.nih.gov/38051999","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.25.24317869","title":"Genomic predictors of response to antidepressants in Major depressive disorder (MDD): A GWAS-Based Study on Indian cohort","date":"2024-11-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.25.24317869","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25268,"output_tokens":7796,"usd":0.096372},"stage2":{"model":"claude-opus-4-6","input_tokens":11651,"output_tokens":4329,"usd":0.24972},"total_usd":0.346092,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"TRIM56 interacts with STING and catalyzes K63-linked ubiquitination of STING, 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.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown with IFN-β promoter reporter, ubiquitination assay\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ubiquitination assay, functional epistasis with KD/OE; foundational paper with 424 citations\",\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 does not affect VSV or HCV replication.\",\n      \"method\": \"TRIM56 overexpression/knockdown with viral replication assays; E3 ligase-dead mutant analysis; C-terminal deletion analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain/loss-of-function with domain mutants and direct viral replication readout; 99 citations\",\n      \"pmids\": [\"21289118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM56 physically interacts with the TLR3 adaptor TRIF via its C-terminal residues (621–750) and positively regulates TLR3 signaling to promote IRF3 activation and IFN-β induction; this function is independent of TRIM56's E3 ligase activity.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown with IRF3 activation and IFN-β reporter assays, C-terminal deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain mapping and functional epistasis; 92 citations\",\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 later step in the viral life cycle.\",\n      \"method\": \"Conditional cell lines expressing TRIM56 mutants; viral replication assays; intracellular viral RNA quantification\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — engineered cell lines with domain mutants, multiple viruses, orthogonal readouts; 90 citations\",\n      \"pmids\": [\"25253338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIM56 restricts influenza A and B virus replication by impairing intracellular viral RNA synthesis; this antiviral activity is independent of E3 ligase activity, B-box, or coiled-coil domain but requires a 63-residue C-terminal tail segment that is itself sufficient to inhibit influenza replication.\",\n      \"method\": \"Overexpression of TRIM56 domain mutants, viral RNA synthesis assays, C-terminal segment expression\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain dissection with multiple mutants, direct RNA synthesis readout; 92 citations\",\n      \"pmids\": [\"26889027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM56 induces monoubiquitination of cGAS at Lys335, which markedly increases cGAS dimerization, DNA-binding activity, and cGAMP production; TRIM56-deficient cells show impaired IFN-αβ production and mice show high susceptibility to HSV-1 infection.\",\n      \"method\": \"Monoubiquitination assay, site-directed mutagenesis (K335R), cGAS dimerization assay, DNA-binding assay, cGAMP quantification, TRIM56-knockout mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro ubiquitination assay with mutagenesis, biochemical activity assays, and in vivo mouse model; 190 citations\",\n      \"pmids\": [\"29426904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM56 associates 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 supporting ERα-positive breast cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping (WD40 deletion), ubiquitination assay, siRNA knockdown with proliferation assays in vitro and xenograft in vivo\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP with domain mapping, ubiquitination assay; single lab, moderate mechanistic follow-up\",\n      \"pmids\": [\"31000690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM56 restricts Zika virus (ZIKV) by directly binding ZIKV RNA via its C-terminal 392 residues; deletion of a short C-terminal tail abrogates both RNA binding and antiviral activity; this restriction is independent of Dicer/miRNA activity.\",\n      \"method\": \"TRIM56 overexpression/knockout, E3-dead mutant analysis, RNA immunoprecipitation in infected cells, cell-free RNA binding assay with recombinant C-terminal TRIM56 fragment, Dicer-knockout cells\",\n      \"journal\": \"PLoS neglected tropical diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro direct RNA binding with recombinant protein, cell-based RIP, domain mutagenesis, and Dicer-KO epistasis\",\n      \"pmids\": [\"31251739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM56 is recruited by KSHV vFLIP to ubiquitinate and degrade SAP18 via the proteasome pathway, dismantling the SAP18-HDAC1 complex, enhancing p65 acetylation, and activating NF-κB to promote cell invasion and angiogenesis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination/degradation assay, siRNA knockdown, NF-κB reporter assay, migration/invasion assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP, proteasomal degradation assay, functional downstream readout; single lab\",\n      \"pmids\": [\"30670829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM56 deubiquitinates cIAP1 primarily through its zinc finger domain (amino acids 21–205), reducing cIAP1 degradation and stabilizing it to promote glioblastoma progression.\",\n      \"method\": \"Ubiquitin array, co-immunoprecipitation, domain deletion analysis, xenograft model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP with domain mapping and in vivo xenograft; deubiquitinase activity inferred but not directly reconstituted\",\n      \"pmids\": [\"36471347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM56 stabilizes FOXM1 by deubiquitination, enhancing FOXM1-mediated DNA damage repair and thereby reducing radiosensitivity of glioblastoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, knockdown with clonogenic/DNA repair assays, xenograft model\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP, ubiquitination assay, functional phenotype; single lab, deubiquitinase mechanism not reconstituted in vitro\",\n      \"pmids\": [\"35696011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM56 promotes K48-to-K63-linked polyubiquitination transition of IQGAP1 at Lys-1230 by physically interacting with IQGAP1, which activates CDC42 and drives glioma cell migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with linkage-specific analysis, CDC42 activation assay, knockdown/overexpression with invasion/migration assays, in vivo glioma model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, site-specific ubiquitination analysis, downstream signaling validated, in vivo model; single lab\",\n      \"pmids\": [\"36870986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM56 Ring domain-mediated ubiquitination of IκBα promotes NF-κB p65 phosphorylation, which subsequently inhibits HBV core promoter activity; the C-terminal domain is required for TRIM56 nuclear translocation during HBV infection.\",\n      \"method\": \"TRIM56 overexpression/knockdown, domain deletion/mutation analysis, ubiquitination assay, NF-κB reporter, HBV replication assays in HepG2-NTCP and primary hepatocytes\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — domain dissection with functional viral replication readout, ubiquitination assay; single lab\",\n      \"pmids\": [\"36084850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM56 positively regulates TNFα-induced NF-κB signaling by interacting with TAK1 via its C-terminal domain and promoting M1-linked polyubiquitination of TAK1 through its RING domain, strengthening TAK1-IKKα complex interactions.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with linkage-specific analysis, domain deletion constructs, knockdown/overexpression with NF-κB reporter\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP, ubiquitin linkage analysis, domain mapping; single lab, not reconstituted in vitro\",\n      \"pmids\": [\"35952808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM56 knockout in HeLa cells severely impairs ISG upregulation by extracellular dsRNA (TLR3 pathway) and weakens the response to cytosolic dsDNA (cGAS-STING pathway), but does not compromise ISG induction or antiviral state established by IFN-α treatment.\",\n      \"method\": \"CRISPR/Cas9 TRIM56 knockout HeLa cells, ISG qRT-PCR, IFN-α stimulation, VSV-based antiviral bioactivity assay\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with multiple orthogonal assays distinguishing TLR3, cGAS-STING, and IFN-I downstream pathways\",\n      \"pmids\": [\"35062293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The crystal structure of the TRIM56 coiled-coil domain reveals that two anti-parallel dimers form a tetramer, positioning two RING domains on each side to support active homodimerization for ubiquitin transfer from E2 to nearby substrates recruited by C-terminal domains.\",\n      \"method\": \"X-ray crystallography of coiled-coil domain, structural analysis\",\n      \"journal\": \"Computational and structural biotechnology journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mechanistic interpretation of E3 ligase quaternary architecture\",\n      \"pmids\": [\"37168870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM56 directly binds to and promotes K48-linked ubiquitination-dependent proteasomal degradation of fatty acid synthase (FASN), limiting lipogenesis; TRIM56 loss exacerbates NAFLD and TRIM56 overexpression suppresses it.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, hepatocyte-specific TRIM56 KO and overexpression mice, NAFLD/NASH models, AI-based small-molecule screening\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — direct binding Co-IP, K48 ubiquitination assay, conditional KO and OE mouse models, replicated in disease context\",\n      \"pmids\": [\"38206764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM56 mediates K63-linked ubiquitination of ATR (via an ATR-TRIM56 complex), maintaining ATR stability and genomic integrity in nucleus pulposus cells; disassembly of the ATR-TRIM56 complex leads to USP5/TRIM25 liberation, shifting ATR ubiquitination from K63 to K48, causing proteasomal ATR degradation and promoting cGAS/STING-driven NP cell senescence.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with linkage specificity, proteomic analysis, engineered extracellular vesicle delivery, IVDD mouse model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitin linkage analysis, in vivo model; single lab, complex multi-component mechanism\",\n      \"pmids\": [\"38488012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM56 binds YBX1 and promotes its K48-linked ubiquitination and proteasomal degradation; this suppresses YBX1-mediated stabilization of ZBP1 mRNA, thereby reducing ZBP1-mediated PANoptosis in neurons after spinal cord injury.\",\n      \"method\": \"Molecular docking, immunoprecipitation/MS, RIP-seq, ubiquitination assay, knockdown/overexpression with PANoptosis readouts\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — IP/MS, ubiquitination assay, RIP-seq for mRNA stabilization; single lab\",\n      \"pmids\": [\"39291396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM56 restricts Coxsackievirus B3 (CVB3) by interacting with and mediating K48-linked polyubiquitination of the viral RNA-dependent RNA polymerase 3D at K220, promoting its proteasomal degradation; viral 3C protease cleaves TRIM56 as a countermeasure.\",\n      \"method\": \"Pull-down, co-immunoprecipitation, immunofluorescence colocalization, ubiquitination assay, overexpression with viral yield assay, site-directed mutagenesis (K220R)\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — direct pull-down, site-specific ubiquitination mutagenesis, viral yield readout, viral protease cleavage demonstrated\",\n      \"pmids\": [\"39348396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HDAC6 deacetylates TRIM56 at K110, impairing TRIM56-mediated monoubiquitination of cGAS and its DNA-binding ability, thereby suppressing cGAS-STING-dependent IFN production; HSV-1 US3 protein phosphorylates HDAC6 to exploit this inhibitory axis.\",\n      \"method\": \"HDAC6 knockout cells and mice, deacetylation assay, cGAS ubiquitination assay, DNA-binding assay, IFN measurement, species-specific comparison (human vs. mouse K110)\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — biochemical deacetylation, ubiquitination and DNA binding assays, in vivo KO model, viral protein mechanism identified\",\n      \"pmids\": [\"39747662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM56 promotes K48-linked ubiquitination and proteasomal degradation of TLE3 in adipocytes in response to cold stimuli, activating thermogenic genes in subcutaneous white adipose tissue and promoting white adipose tissue browning.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, adipocyte-specific TRIM56 overexpression mice, cold exposure and diet-induced obesity models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination assay, in vivo mouse model; single lab\",\n      \"pmids\": [\"39928840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PVT1 lncRNA interacts with TRIM56 post-transcriptionally and modulates TRIM56-mediated ubiquitination of AMPKα, leading to aberrant mitochondrial biogenesis and fission in diabetic podocytes; podocyte-specific TRIM56 KO mice phenocopy PVT1 KO.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, podocyte-specific KO mice (Nphs2-Cre/Trim56flox/flox), mitochondrial morphology and function assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination assay, conditional KO mice; mechanism of lncRNA-TRIM56 interaction is partially characterized\",\n      \"pmids\": [\"39349450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM56 promotes K63-linked polyubiquitination of ATR to stabilize it, whereas loss of the TRIM56-ATR complex releases USP5 and TRIM25, switching ATR to K48-linked ubiquitination and driving proteasomal degradation that exposes cytosolic DNA and activates the cGAS/STING inflammatory pathway in nucleus pulposus cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin linkage-specific assay, mass spectrometry proteomics, gene silencing\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP with proteomics and ubiquitin linkage assays; complex mechanism from single lab\",\n      \"pmids\": [\"38488012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The TRIM56 coiled-coil domain and phosphorylation at Ser471, Ser475, and Ser710 are required for TRIM56 augmentation of TLR3-TRIF-dependent IFN-β and NF-κB signaling; Ser710 phosphorylation is specifically required for TRIM56-TRIF association, and TRIM56 phosphorylation at Ser471/Ser475 occurs in a biphasic manner following TLR3 stimulation.\",\n      \"method\": \"Transient transfection and Tet-regulated cell lines expressing alanine-substitution mutants, phospho-specific antibodies, IFN-β promoter reporter, NF-κB reporter, Co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple domain/phospho mutants, phospho-specific antibody detection of endogenous phosphorylation, multiple functional readouts; comprehensive mechanistic study\",\n      \"pmids\": [\"38556084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIM56 ubiquitinates vimentin to promote its proteasomal degradation; loss of TRIM56 in normal ovarian cells stabilizes vimentin and increases migration/invasion, while TRIM56 overexpression in ovarian cancer cells reduces vimentin and suppresses invasiveness.\",\n      \"method\": \"Mass spectrometry of vimentin immunoprecipitate, RNAi knockdown and overexpression, proteasome inhibitor (MG-132) assay, migration/invasion assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — MS-identified interaction, KD/OE with functional readout; ubiquitination of vimentin by TRIM56 inferred but not directly demonstrated in vitro\",\n      \"pmids\": [\"28771721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Exosomal circZNF451 enhances TRIM56-mediated ubiquitination and degradation of FXR1 in macrophages, activating the ELF4-IRF4 pathway to polarize macrophages toward an anti-inflammatory phenotype and exhaust CD8+ T cells, promoting anti-PD1 treatment resistance in lung adenocarcinoma.\",\n      \"method\": \"RNA pulldown, RNA immunoprecipitation, mass spectrometry, co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter, flow cytometry, transgenic ELF4-KO mice\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — multiple orthogonal methods (RIP, MS, Co-IP, luciferase, KO mice); single lab, TRIM56 role is one node in a larger mechanism\",\n      \"pmids\": [\"36209117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM56 interacts with Src via its B-box1 domain binding to the Src SH3 domain and catalyzes K63-linked polyubiquitination of Src at Lys184, promoting Src protein aggregation and intermolecular autophosphorylation-driven Src activation in hepatocellular carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, ubiquitination assay with K63 linkage specificity, site-directed mutagenesis (K184R), Src activation assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP with domain mapping, site-specific ubiquitination mutagenesis, Src activation readout; single lab\",\n      \"pmids\": [\"41102183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM56 promotes K48-linked ubiquitination-dependent degradation of KLF4, reducing KLF4-activated ferroptosis-protective gene expression and thereby aggravating neuronal ferroptosis following cerebral ischemia-reperfusion injury.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, TRIM56 KO mice, TRIM56 OE, neurological deficit assays, in vitro ferroptosis readouts\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination assay, KO/OE mouse model; single lab, mechanistic link is direct but not reconstituted in vitro\",\n      \"pmids\": [\"41214892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM56 mediates K48-linked ubiquitination and proteasomal degradation of GCN2 at K619 in non-small cell lung cancer; CD147 suppresses TRIM56 expression to stabilize GCN2 and activate the GCN2/EIF2α/ATG12 axis for autophagy-mediated exosome secretion.\",\n      \"method\": \"Proteomics/mass spectrometry identifying TRIM56 as E3 ligase, Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K619), TRIM56 KD/OE\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — MS-based identification, site-specific ubiquitination, Co-IP; single lab\",\n      \"pmids\": [\"41413248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM56 mediates K48-linked ubiquitination of PTEN (recruited by ZC3H15 via its DFRP domain), promoting PTEN degradation and activating the AKT-mTOR signaling pathway in non-small cell lung cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown studies with AKT-mTOR pathway readouts\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with functional readout; TRIM56's direct ubiquitination of PTEN inferred from interaction with ZC3H15 scaffold; single lab, limited mechanistic validation\",\n      \"pmids\": [\"41513632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM56 stabilizes adenoviral E1A protein and assists E1A in antagonizing STING signaling, thereby enhancing adenoviral genome transcription and HAdV-C5 replication.\",\n      \"method\": \"Overexpression/knockdown studies, viral replication titer assays, E1A protein stability assay, STING antagonism assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — functional OE/KD with viral replication readout; mechanism of E1A stabilization not biochemically reconstituted; single lab\",\n      \"pmids\": [\"40459263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM56 binds to ITGB4 (identified by Co-IP with mass spectrometry) and promotes its ubiquitination, which regulates MUC5AC expression in airway epithelial cells; inhibition of TRIM56 by BFF-4 reduces ITGB4 ubiquitination and mucus hypersecretion in COPD models.\",\n      \"method\": \"DARTS analysis (target identification), Co-IP/mass spectrometry, ubiquitination assay, TRIM56 overexpression, COPD mouse model\",\n      \"journal\": \"Journal of ethnopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP/MS with functional readout; single lab, ligand-target identification method (DARTS) has indirect readout\",\n      \"pmids\": [\"41580166\"],\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 immunity and diverse cellular processes through context-dependent mechanisms: it catalyzes K63-linked ubiquitination of STING (promoting STING dimerization and TBK1 recruitment) and monoubiquitination of cGAS at K335 (enhancing cGAS dimerization, DNA binding, and cGAMP production) to amplify cytosolic DNA sensing; it positively regulates TLR3-TRIF signaling through a phosphorylation-dependent scaffolding interaction (requiring Ser471, Ser475, Ser710, and the coiled-coil domain) that is E3 ligase-independent; it directly restricts multiple RNA viruses by binding viral RNA or ubiquitinating viral polymerases for proteasomal degradation; and it targets diverse cellular substrates—including FASN, TLE3, vimentin, IQGAP1, TAK1, ERα, KLF4, and others—for K48- or K63-linked ubiquitination to control metabolism, migration, and cell survival, with its coiled-coil domain forming a tetramer scaffold that positions RING domains for ubiquitin transfer.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TRIM56 is a RING-type E3 ubiquitin ligase that functions as a central amplifier of innate immune sensing and a versatile regulator of protein turnover across diverse cellular contexts. In the cytosolic DNA-sensing pathway, TRIM56 catalyzes K63-linked ubiquitination of STING to promote its dimerization and TBK1 recruitment, and monoubiquitinates cGAS at Lys335 to enhance cGAS dimerization, DNA binding, and cGAMP synthesis—activities regulated by HDAC6-mediated deacetylation of TRIM56 at Lys110 [PMID:21074459, PMID:29426904, PMID:39747662]. Independent of its E3 ligase activity, TRIM56 augments TLR3-TRIF signaling through a phosphorylation-dependent (Ser471/Ser475/Ser710) scaffolding interaction with TRIF, and restricts influenza and Zika viruses through direct C-terminal RNA binding, while it targets other viral polymerases (e.g., CVB3 3D) for K48-linked ubiquitination and proteasomal degradation [PMID:22948160, PMID:38556084, PMID:31251739, PMID:39348396]. Beyond innate immunity, TRIM56 ubiquitinates numerous cellular substrates—including FASN, TLE3, vimentin, IQGAP1, TAK1, Src, KLF4, and GCN2—using K48- or K63-linked chains to control lipid metabolism, adipose thermogenesis, cell migration, NF-κB signaling, and ferroptosis, with its coiled-coil domain forming a tetrameric scaffold that positions RING domains for ubiquitin transfer [PMID:38206764, PMID:39928840, PMID:36870986, PMID:35952808, PMID:37168870].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing TRIM56 as an innate immune E3 ligase: it was unknown how STING dimerization was triggered; the demonstration that TRIM56 catalyzes K63-linked ubiquitination of STING to induce dimerization and TBK1 recruitment identified TRIM56 as a critical upstream activator of cytosolic DNA sensing.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assay, and IFN-β reporter with overexpression/knockdown in human cells\",\n      \"pmids\": [\"21074459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitination site on STING not mapped\", \"No in vivo validation in mouse models at this stage\", \"Whether TRIM56 acts on other innate sensors was unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defining TRIM56 as a direct-acting antiviral factor: it was unclear whether TRIM56 could restrict viruses beyond the STING pathway; showing E3 ligase-dependent restriction of BVDV but not VSV or HCV revealed virus-specific direct antiviral mechanisms.\",\n      \"evidence\": \"TRIM56 overexpression/knockdown with E3-dead and C-terminal deletion mutants, viral replication assays\",\n      \"pmids\": [\"21289118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Viral substrate targeted by TRIM56 not identified\", \"Mechanism of C-terminal requirement unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Separating TRIM56's scaffolding from ligase functions: the discovery that TRIM56 positively regulates TLR3-TRIF signaling independent of E3 ligase activity, via direct C-terminal binding to TRIF, revealed a second, non-catalytic mode of innate immune regulation.\",\n      \"evidence\": \"Reciprocal Co-IP, C-terminal domain mapping, IRF3 and IFN-β reporter assays\",\n      \"pmids\": [\"22948160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Post-translational modifications governing TRIF binding not identified\", \"In vivo relevance of TLR3 arm not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Broadening antiviral scope and dissecting domain requirements: TRIM56 restricted flaviviruses (YFV, DENV2) requiring both E3 and C-terminal domains but restricted HCoV-OC43 via E3 activity alone, indicating virus-specific mechanistic modules.\",\n      \"evidence\": \"Conditional cell lines with domain mutants, intracellular viral RNA quantification across multiple viruses\",\n      \"pmids\": [\"25253338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact viral targets for ubiquitination not identified for flaviviruses\", \"Host cofactors for C-terminal-mediated restriction unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealing an E3-independent RNA-binding antiviral mechanism: TRIM56 restriction of influenza A/B required only a 63-residue C-terminal tail and was independent of the RING, B-box, and coiled-coil domains, establishing a minimal antiviral module.\",\n      \"evidence\": \"Domain mutant expression with viral RNA synthesis assays; C-terminal segment sufficient for restriction\",\n      \"pmids\": [\"26889027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the C-terminal tail directly contacts viral RNA not shown\", \"Structural basis of the 63-residue tail function unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying TRIM56 as the activating E3 ligase for cGAS: TRIM56-catalyzed monoubiquitination of cGAS at Lys335 enhanced cGAS dimerization and DNA binding, and TRIM56-knockout mice were highly susceptible to HSV-1, placing TRIM56 as an essential upstream regulator of cGAS-STING signaling in vivo.\",\n      \"evidence\": \"Site-directed mutagenesis (K335R), in vitro monoubiquitination assay, cGAS biochemical assays, TRIM56-KO mice with HSV-1 challenge\",\n      \"pmids\": [\"29426904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TRIM56-cGAS recognition unknown\", \"Whether additional E3 ligases redundantly activate cGAS not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating direct RNA-binding as the mechanism for Zika virus restriction: TRIM56's C-terminal 392 residues directly bound ZIKV RNA in a cell-free system, and a short C-terminal tail deletion abolished both RNA binding and antiviral activity, confirming RNA binding as the effector mechanism independent of Dicer.\",\n      \"evidence\": \"Recombinant protein–RNA binding assay, RNA immunoprecipitation, Dicer-KO epistasis\",\n      \"pmids\": [\"31251739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA sequence/structure specificity not defined\", \"No crystal structure of RNA-binding domain\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanding TRIM56 substrates to non-immune targets: TRIM56 was shown to ubiquitinate ERα (K63-linked, stabilizing) and SAP18 (proteasomal degradation via KSHV vFLIP hijacking), linking TRIM56 to cancer cell proliferation and viral immune evasion beyond innate sensing.\",\n      \"evidence\": \"Co-IP with domain mapping, ubiquitination assays, xenograft and functional assays in breast cancer and KSHV-infected cells\",\n      \"pmids\": [\"31000690\", \"30670829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ERα ubiquitination site not mapped\", \"vFLIP-TRIM56 interaction not reconstituted with purified components\", \"Physiological relevance in non-cancer settings not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Consolidating TRIM56 as a multi-substrate E3 ligase across signaling pathways: studies identified IQGAP1 (K48→K63 switch activating CDC42), TAK1 (M1-linked ubiquitination activating NF-κB), IκBα (ubiquitination promoting NF-κB against HBV), and vimentin (degradation controlling migration) as TRIM56 substrates, revealing its versatility in ubiquitin chain-type specification.\",\n      \"evidence\": \"Co-IP with linkage-specific ubiquitin analysis, domain mapping, knockdown/overexpression with functional readouts across glioma, HBV, and ovarian cancer models\",\n      \"pmids\": [\"36870986\", \"35952808\", \"36084850\", \"28771721\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro reconstitution of chain-type specificity switching not performed\", \"Mechanism determining K48 vs K63 vs M1 chain selection by TRIM56 unknown\", \"Most findings from single laboratories\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Genetic confirmation that TRIM56 is required for both TLR3 and cGAS-STING pathways but dispensable for IFN-I downstream signaling: TRIM56-KO HeLa cells showed severely impaired ISG induction by extracellular dsRNA and cytosolic dsDNA but normal IFN-α response, clarifying TRIM56's position upstream of IFN production.\",\n      \"evidence\": \"CRISPR/Cas9 KO with dsRNA, dsDNA, and IFN-α stimulation and ISG/antiviral bioactivity readouts\",\n      \"pmids\": [\"35062293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single cell line (HeLa); generalizability across cell types not tested\", \"Relative contributions of STING vs cGAS ubiquitination not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Structural basis for TRIM56 E3 activity: the crystal structure of the coiled-coil domain revealed an antiparallel dimer-of-dimers tetramer that positions two RING domains on each side for productive E2-ubiquitin transfer, explaining how quaternary organization supports catalysis.\",\n      \"evidence\": \"X-ray crystallography of the TRIM56 coiled-coil domain\",\n      \"pmids\": [\"37168870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length structure unavailable\", \"How C-terminal substrate-recruiting domains are oriented relative to RING not resolved\", \"No structure of RING-E2~Ub complex\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Establishing TRIM56 as a metabolic regulator: TRIM56 directly ubiquitinates FASN (K48-linked) for proteasomal degradation to limit lipogenesis, and ubiquitinates TLE3 (K48-linked) to activate thermogenic gene programs in white adipose tissue, connecting TRIM56 to NAFLD protection and adaptive thermogenesis.\",\n      \"evidence\": \"Hepatocyte- and adipocyte-specific conditional KO/OE mice, NAFLD/obesity/cold models, ubiquitination assays\",\n      \"pmids\": [\"38206764\", \"39928840\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitination sites on FASN not mapped\", \"Upstream signals regulating TRIM56 in metabolic tissues unknown\", \"Whether metabolic and immune functions of TRIM56 are coordinately regulated is unexplored\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealing regulation of TRIM56 itself: HDAC6 deacetylates TRIM56 at Lys110, impairing its ability to monoubiquitinate cGAS, and HSV-1 US3 protein exploits this axis by phosphorylating HDAC6, establishing TRIM56 acetylation as a regulatory switch for cGAS activation.\",\n      \"evidence\": \"HDAC6-KO cells and mice, deacetylation assay, cGAS ubiquitination and DNA-binding assays, HSV-1 US3 mechanism\",\n      \"pmids\": [\"39747662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetyltransferase responsible for TRIM56 K110 acetylation not identified\", \"Whether acetylation affects TRIM56 activity on substrates other than cGAS unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining phosphorylation codes for TLR3 signaling: Ser471, Ser475, and Ser710 phosphorylation of TRIM56 were shown to be required for TLR3-TRIF augmentation; Ser710 specifically governs TRIF association, and Ser471/Ser475 phosphorylation is biphasic after poly(I:C) stimulation, providing the first post-translational regulatory map for TRIM56's scaffolding function.\",\n      \"evidence\": \"Alanine-substitution mutants, phospho-specific antibodies, IFN-β and NF-κB reporters, Co-IP in Tet-regulated cell lines\",\n      \"pmids\": [\"38556084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase(s) responsible for Ser471/Ser475/Ser710 phosphorylation not identified\", \"Whether phosphorylation regulates E3 ligase activity in other contexts not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating TRIM56 as a direct antiviral E3 ligase targeting viral polymerases: TRIM56 ubiquitinates CVB3 RNA-dependent RNA polymerase 3D at Lys220 (K48-linked) for proteasomal degradation, and the virus counters by 3C protease-mediated cleavage of TRIM56, revealing an arms race dynamic.\",\n      \"evidence\": \"Pull-down, site-directed mutagenesis (K220R), ubiquitination assay, viral yield measurement, 3C cleavage assay\",\n      \"pmids\": [\"39348396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRIM56 directly ubiquitinates polymerases of other viruses (flaviviruses, coronaviruses) remains untested\", \"Cleavage site on TRIM56 not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for TRIM56's dual RNA-binding and E3 ligase activities in a full-length context; the kinases and acetyltransferases that regulate TRIM56 post-translational modifications; how TRIM56 achieves ubiquitin chain-type specificity (K48, K63, M1, monoubiquitin) for different substrates; and the physiological integration of TRIM56's immune, metabolic, and cytoskeletal functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length TRIM56 structure\", \"Chain-type specification mechanism unknown\", \"Upstream kinases for Ser471/Ser475/Ser710 unidentified\", \"Acetyltransferase for K110 unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5, 6, 8, 11, 13, 16, 19, 21, 27, 28, 29]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 5, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 6, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 5, 14, 20, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 12, 13, 27]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [16, 21]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 5, 15, 16, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"STING\",\n      \"CGAS\",\n      \"TRIF\",\n      \"FASN\",\n      \"TAK1\",\n      \"IQGAP1\",\n      \"ATR\",\n      \"HDAC6\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}