{"gene":"TRIM11","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2003,"finding":"TRIM11 binds to Humanin (HN) neuroprotective peptide via its coiled-coil and B30.2 domains, and promotes ubiquitin-mediated proteasomal degradation of intracellular HN; deletion of the RING domain or proteasome inhibition abolished this effect.","method":"Yeast two-hybrid screening, co-expression assays, deletion mutagenesis, proteasome inhibitor treatment","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in single lab, domain mapping with mutagenesis","pmids":["12670303"],"is_preprint":false},{"year":2006,"finding":"TRIM11 binds to ARC105 (activator-recruited cofactor 105-kDa component) and promotes its ubiquitin-proteasome-dependent degradation, thereby suppressing ARC105-mediated transcriptional activation of TGFβ signaling.","method":"Co-immunoprecipitation, co-expression ubiquitination assay, proteasome inhibitor treatment, transcriptional reporter assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP, ubiquitination assay, and functional reporter assay in single lab","pmids":["16904669"],"is_preprint":false},{"year":2005,"finding":"TRIM11 physically interacts with the C-terminal domain of PAX6; C-terminal PAX6 mutations found in patients with eye malformations reduced or abolished this interaction.","method":"Yeast two-hybrid library screen","journal":"BMC genetics","confidence":"Low","confidence_rationale":"Tier 3 — single yeast two-hybrid method, no functional follow-up in mammalian cells","pmids":["16098226"],"is_preprint":false},{"year":2008,"finding":"TRIM11 interacts with PAX6 via its B30.2 domain and promotes PAX6 degradation via the ubiquitin-proteasome system; TRIM11 overexpression decreases endogenous PAX6 protein levels and represses Pax6-dependent transactivation and neurogenesis, while abrogation of TRIM11 increases insoluble Pax6 and enhances apoptosis; the B30.2 domain is essential for clearance of insoluble proteins; Pax6 directly regulates Trim11 expression forming an autoregulatory feedback loop.","method":"Co-immunoprecipitation, overexpression/knockdown in cortical progenitors, in vivo cortex electroporation, transcriptional reporter assays, ChIP","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including in vitro assays, in vivo loss-of-function, and domain mutagenesis in a high-impact journal","pmids":["18628401"],"is_preprint":false},{"year":2008,"finding":"TRIM11 physically interacts with the homeodomain transcription factor Phox2b via its B30.2/SPRY domain, and co-expression of Trim11 with Phox2b further increases dopamine beta-hydroxylase (DBH) gene mRNA levels in primary avian neural crest stem cells.","method":"Yeast two-hybrid, protein-protein interaction assays, co-expression in primary NCSC culture, RT-PCR","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping and functional mRNA readout, single lab","pmids":["18275850"],"is_preprint":false},{"year":2012,"finding":"TRIM11 mediates proteasomal degradation of polyalanine-expanded PHOX2B (mutant causing congenital central hypoventilation syndrome), rescuing PHOX2B transcriptional activity; clearance of mutant PHOX2B by TRIM11 correlates with rescue of wild-type PHOX2B function.","method":"Co-expression assays, ubiquitination assays, proteasome inhibitor treatment, transcriptional reporter assay, neuroblastoma cell experiments","journal":"Journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitination assay plus functional transcriptional rescue, single lab","pmids":["22307522"],"is_preprint":false},{"year":2012,"finding":"TRIM11 knockdown in glioblastoma cells inhibits proliferation, migration, and invasion, significantly decreases EGFR levels and MAPK activity, and downregulates HB-EGF mRNA; TRIM11 overexpression promotes tumorsphere formation and glial tumor growth in vivo, suggesting TRIM11 acts through the EGFR signaling pathway.","method":"siRNA knockdown, overexpression, in vitro proliferation/migration/invasion assays, in vivo xenograft, western blot","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO/OE with defined cellular and in vivo phenotypes, pathway marker analysis","pmids":["23178488"],"is_preprint":false},{"year":2013,"finding":"TRIM11 negatively regulates IFNβ production by interacting with TBK1 (via CC domain of TRIM11 and CC2 domain of TBK1), inhibiting IRF3 phosphorylation and dimerization; this interaction was enhanced by TBK1 adaptor proteins NAP1, SINTBAD, and TANK. TRIM11 overexpression enhanced viral infectivity while knockdown had the opposite effect.","method":"Co-immunoprecipitation, deletion mutagenesis, IFNβ promoter reporter assays, IRF3 phosphorylation assay, viral infectivity assay, siRNA knockdown","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with domain mapping, multiple orthogonal functional assays, single lab","pmids":["23675467"],"is_preprint":false},{"year":2016,"finding":"TRIM11 binds to AIM2 via its PS domain and undergoes auto-polyubiquitination at K458 to promote association with the autophagic cargo receptor p62, mediating selective autophagic degradation of AIM2 and suppression of AIM2 inflammasome activation.","method":"Co-immunoprecipitation, site-directed mutagenesis (K458), ubiquitination assay, autophagy inhibitor experiments, siRNA knockdown, IL-1β/IL-18 maturation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods with mutagenesis identifying specific ubiquitination site, functional inflammasome readout","pmids":["27498865"],"is_preprint":false},{"year":2016,"finding":"TRIM11 interacts with HIV-1 capsid and accelerates viral uncoating, reducing reverse transcription; microtubule dynamics contribute to TRIM11-mediated premature capsid disassembly; the capsid G89V mutation confers insensitivity to TRIM11 restriction.","method":"In vitro binding assay, in situ proximity ligation assay, fate-of-capsid assay, quantitative PCR, microtubule dynamics inhibitors, capsid mutant analysis","journal":"Retrovirology","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro binding plus multiple orthogonal functional assays and genetic mutant validation","pmids":["27737691"],"is_preprint":false},{"year":2014,"finding":"TRIM11 suppresses early steps of HIV-1 transduction (reducing reverse transcripts) and inhibits HIV-1 LTR activity via inhibition of NF-κB; the RING domain is required for the former but dispensable for the latter; HIV-1 Vpr regulates TRIM11 protein levels independently of VprBP-associated proteasome machinery.","method":"Deletion mutant experiments, luciferase reporter assay (LTR/NF-κB), quantitative PCR of reverse transcripts, overexpression/knockdown","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — domain mutagenesis with multiple functional readouts, single lab","pmids":["25105968"],"is_preprint":false},{"year":2018,"finding":"TRIM11 binds to USP14 (a deubiquitinase and noncatalytic proteasome inhibitor) and precludes USP14-proteasome association, thereby activating the proteasome and enhancing overall proteolytic rate; TRIM11 also binds directly to the proteasome. TRIM11 is upregulated upon heat shock and is required for tumor growth.","method":"Co-immunoprecipitation, in vitro proteasome activity assays, proteasome binding assays, USP14 competition assays, cell-based degradation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro proteasome activity assays plus reciprocal Co-IP and multiple orthogonal functional assays in a high-impact journal","pmids":["29581427"],"is_preprint":false},{"year":2018,"finding":"TRIM11 interacts with and stabilizes HSF1, increasing HSF1 nuclear levels, and cooperates with HSF1 to suppress the anti-tumor effect of proteotoxic stress drugs; TRIM11 promotes removal of protein aggregates in an HSF1-dependent manner.","method":"Co-immunoprecipitation, nuclear fractionation, protein aggregate clearance assays, drug sensitivity assays","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with functional nuclear localization and aggregate clearance data, single lab","pmids":["30563406"],"is_preprint":false},{"year":2019,"finding":"TRIM11 interacts with Axin1 and promotes its ubiquitination and degradation, thereby activating β-catenin signaling in lymphoma cells.","method":"Co-immunoprecipitation, ubiquitination detection, western blot, β-catenin inhibitor rescue experiments","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ubiquitination assay with pathway rescue, single lab","pmids":["31786079"],"is_preprint":false},{"year":2019,"finding":"TRIM11 promotes mono-ubiquitination of YAP (via interaction between TRIM11 RING domain and YAP WW domain), prolonging YAP protein half-life and activating Hippo-YAP/TEAD target genes in anaplastic thyroid cancer; SOX13 activates TRIM11 transcription by binding to the TRIM11 promoter.","method":"Co-immunoprecipitation, ubiquitin-based immunoprecipitation, protein half-life assay, reporter assays, promoter analysis","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping with ubiquitination assay and functional pathway readout, single lab","pmids":["33613102"],"is_preprint":false},{"year":2020,"finding":"TRIM11 promotes mono-ubiquitination of ERα (via interaction between TRIM11 RING domain and ERα N-terminus in the cytoplasm), enhancing ERα protein stability and ERα-dependent transcriptional activity and cell proliferation in breast cancer.","method":"Co-immunoprecipitation, domain deletion mutagenesis, ubiquitination assay, protein stability assay, RNA-seq, ERE reporter assay","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping, ubiquitination assay, and functional transcriptional readout, single lab","pmids":["32599554"],"is_preprint":false},{"year":2020,"finding":"TRIM11 promotes p62-selective autophagic degradation of Daple (a Gα-interacting protein), upregulating β-catenin expression to induce ABCC9 transcription and thereby enhancing multidrug resistance in nasopharyngeal carcinoma.","method":"Co-immunoprecipitation, ubiquitination assay, autophagy inhibition experiments, western blot, in vivo xenograft","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with ubiquitination and functional pathway rescue, single lab","pmids":["32382014"],"is_preprint":false},{"year":2020,"finding":"TRIM11 functions as an ATP-independent molecular chaperone and disaggregase, preventing formation of protein aggregates and dissolving pre-existing aggregates including amyloid fibrils; these activities cooperate with TRIM11 SUMO ligase activity to degrade aberrant proteins. TRIM11 abrogates α-synuclein fibrillization and, when delivered via AAV intracranially, mitigates α-synuclein pathology, neurodegeneration, and motor impairments in a PD mouse model.","method":"In vitro aggregation assays, amyloid fibril dissolution assays, SUMO ligase assays, cell viability assays, AAV delivery in PD mouse model, motor behavior testing","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of chaperone/disaggregase activity plus in vivo AAV rescue with multiple phenotypic readouts","pmids":["33264628"],"is_preprint":false},{"year":2021,"finding":"TRIM11 interacts with and colocalizes with UBE2N, and promotes gemcitabine resistance and suppresses ferritinophagy through UBE2N-TAX1BP1 signaling in pancreatic ductal adenocarcinoma.","method":"Co-immunoprecipitation, western blot, cell viability assay, xenograft model","journal":"Journal of cellular physiology","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP with limited mechanistic follow-up","pmids":["33629745"],"is_preprint":false},{"year":2019,"finding":"TRIM11 interacts with PHLPP1 (a protein phosphatase that dephosphorylates AKT) and promotes PHLPP1 ubiquitination, reducing PHLPP1 protein levels and sustaining AKT phosphorylation in chordoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, AKT inhibitor rescue, western blot","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ubiquitination assay with AKT pathway functional validation, single lab","pmids":["31719797"],"is_preprint":false},{"year":2022,"finding":"TRIM11 interacts with Axin1 via Co-IP and destabilizes Axin1 protein, activating the Wnt/β-catenin pathway in gastric cancer; TRIM11 and Axin1 expression are negatively correlated in GC tissues.","method":"Co-immunoprecipitation, cycloheximide chase assay, immunofluorescence, western blot, rescue experiments with Axin1 siRNA","journal":"Journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP, protein stability assay, and functional rescue, single lab","pmids":["35237324"],"is_preprint":false},{"year":2023,"finding":"TRIM11 promotes proteasomal degradation of mutant and superfluous normal tau, acts as a molecular chaperone to prevent tau misfolding, and functions as a disaggregase to dissolve preformed tau fibrils; intracranial AAV delivery of TRIM11 ameliorated pathology, neuroinflammation, and cognitive impairments in multiple animal models of tauopathies. TRIM11 is markedly downregulated in AD brains.","method":"In vitro aggregation/disaggregation assays, proteasome degradation assays, chaperone assays, AAV delivery in tauopathy mouse models, behavioral testing, neuropathology","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — reconstitution of chaperone and disaggregase activities in vitro, replicated across multiple animal models in a high-impact journal","pmids":["37499037"],"is_preprint":false},{"year":2023,"finding":"TRIM11 interacts with AIM2 and promotes selective autophagic degradation of AIM2 (via AIM2 ubiquitination and p62 binding) in CD4+ T cells, specifically negatively regulating Treg cell differentiation and attenuating AKT/FOXO1 phosphorylation, MYC signaling, and glycolysis downstream of AIM2.","method":"Co-immunoprecipitation, ubiquitination assay, T cell differentiation assays, AKT/FOXO1 phosphorylation assay, EAE mouse model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods with in vivo validation, builds on earlier AIM2-TRIM11 work","pmids":["37804507"],"is_preprint":false},{"year":2024,"finding":"TRIM11 increases SUMO1 modification of tau (both 2N4R- and 0N4R-tau), acting as a SUMO E3 ligase; mutation of the target lysine residue to arginine abolished SUMO1 modification by TRIM11.","method":"Co-expression SUMOylation assays, lysine-to-arginine mutagenesis, western blot","journal":"Biochemistry and biophysics reports","confidence":"Medium","confidence_rationale":"Tier 1–2 — enzymatic activity assay with mutagenesis, single lab","pmids":["39286522"],"is_preprint":false},{"year":2025,"finding":"TRIM11 and JAK1 interact and mutually regulate each other: JAK1 phosphorylates TRIM11, reducing its K48-linked polyubiquitination and stabilizing it; TRIM11 in turn promotes K63-linked polyubiquitination of JAK1, inhibiting downstream JAK/STAT signaling and reducing IFN-γ-induced PD-L1 expression, thereby enhancing cytotoxic T lymphocyte activity.","method":"Co-immunoprecipitation, ubiquitination assays (K48/K63-linkage specific), phosphorylation assays, STAT signaling assays, CTL killing assays, mouse tumor models","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal regulatory mechanism established with linkage-specific ubiquitination assays, phosphorylation mapping, and in vivo functional validation","pmids":["41203822"],"is_preprint":false},{"year":2021,"finding":"TRIM11 promotes K63-linked ubiquitination of ACSL4, leading to its degradation and suppression of ferroptosis in NSCLC; METTL3 enhances m6A modification of TRIM11 mRNA via an IGF2BP1-dependent mechanism, stabilizing TRIM11 mRNA and increasing TRIM11 expression.","method":"IP/ubiquitination assay, RNA immunoprecipitation, luciferase reporter, MeRIP assay, protein stability analysis, xenograft","journal":"Naunyn-Schmiedeberg's archives of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitination assay with linkage specificity and multiple RNA regulatory assays, single lab","pmids":["40668412"],"is_preprint":false},{"year":2025,"finding":"TRIM11 promotes ubiquitination of HOXB9 and regulates the NF-κB signaling pathway in sepsis-associated inflammation, reversing HOXB9-induced NF-κB activation.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, western blot, flow cytometry","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP/ubiquitination with limited mechanistic follow-up, single lab","pmids":["39903348"],"is_preprint":false},{"year":2023,"finding":"TRIM11 ubiquitinates PHLPP1, reducing PHLPP1 protein levels and activating AKT signaling in cervical cancer; TRIM11 mRNA is stabilized by m6A modification mediated by METTL14 and read by IGF2BP1.","method":"Co-immunoprecipitation, ubiquitination assay, MeRIP assay, RNA stability assay, actinomycin D treatment","journal":"Neoplasma","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitination assay with m6A RNA regulatory mechanism, single lab","pmids":["38053376"],"is_preprint":false}],"current_model":"TRIM11 is a multifunctional RING-domain E3 ubiquitin ligase (and SUMO ligase) that regulates protein quality control by: (1) promoting proteasomal degradation of diverse substrates (tau, Humanin, PAX6, AIM2, PHOX2B, ARC105, Axin1, PHLPP1, ERα, YAP) via K48-linked ubiquitination; (2) activating the proteasome by displacing the inhibitory deubiquitinase USP14; (3) acting as an ATP-independent molecular chaperone and disaggregase that prevents and reverses protein aggregation including amyloid fibrils; (4) mediating selective autophagic degradation of AIM2 via auto-polyubiquitination and p62 recruitment; (5) inhibiting innate immune signaling by interacting with TBK1 and reducing IRF3 phosphorylation; and (6) engaging in a mutual regulatory axis with JAK1 where JAK1 phosphorylates and stabilizes TRIM11 while TRIM11 promotes K63-linked ubiquitination of JAK1 to suppress PD-L1 induction."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing that TRIM11 is an E3 ligase directing substrates to the proteasome: the first demonstration that TRIM11 promotes ubiquitin-dependent proteasomal degradation of a binding partner (Humanin), requiring its RING domain.","evidence":"Yeast two-hybrid, co-expression assays, deletion mutagenesis, and proteasome inhibitor treatment in mammalian cells","pmids":["12670303"],"confidence":"Medium","gaps":["No in vitro ubiquitination reconstitution","Physiological relevance of Humanin regulation unclear","E2 enzyme identity unknown"]},{"year":2006,"claim":"Extending TRIM11 substrate scope to a transcriptional cofactor: TRIM11 was shown to degrade ARC105 and thereby suppress TGF-β-dependent transcription, establishing TRIM11 as a regulator of signaling-pathway output.","evidence":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, and TGF-β transcriptional reporter in mammalian cells","pmids":["16904669"],"confidence":"Medium","gaps":["Single lab finding","Endogenous confirmation lacking","No in vivo validation"]},{"year":2008,"claim":"Linking TRIM11 to protein quality control and neurodevelopment: TRIM11 degrades PAX6 via its B30.2 domain and clears insoluble PAX6 aggregates in cortical progenitors; Pax6 itself transcriptionally activates Trim11, forming a feedback loop controlling neurogenesis.","evidence":"Co-IP, overexpression/knockdown in cortical progenitors, in vivo cortical electroporation, ChIP, and domain mutagenesis","pmids":["18628401"],"confidence":"High","gaps":["Mechanism of insoluble protein clearance not biochemically dissected","Whether TRIM11 chaperone function versus ubiquitin ligase function drives aggregate clearance was unresolved"]},{"year":2012,"claim":"Demonstrating TRIM11 can rescue pathogenic protein aggregates: TRIM11 degrades polyalanine-expanded PHOX2B (causative for congenital central hypoventilation syndrome), restoring wild-type PHOX2B transcriptional function.","evidence":"Ubiquitination assays, proteasome inhibitor treatment, and transcriptional reporter assays in neuroblastoma cells","pmids":["22307522"],"confidence":"Medium","gaps":["No in vivo disease model tested","Single lab","Whether TRIM11 distinguishes mutant from wild-type PHOX2B unclear"]},{"year":2013,"claim":"Revealing TRIM11 as a negative regulator of innate antiviral signaling: TRIM11 interacts with TBK1 via their respective coiled-coil domains, blocking IRF3 phosphorylation and dimerization and thereby suppressing IFN-β production.","evidence":"Reciprocal Co-IP with domain mapping, IFN-β promoter reporter, IRF3 phosphorylation assays, and viral infectivity assays","pmids":["23675467"],"confidence":"High","gaps":["Whether TRIM11 ubiquitinates TBK1 or acts non-catalytically was not determined","In vivo immune phenotype not examined"]},{"year":2014,"claim":"Identifying a dual mechanism of HIV-1 restriction: TRIM11 suppresses reverse transcription (RING-dependent) and inhibits NF-κB-driven LTR activity (RING-independent), while HIV-1 Vpr counteracts TRIM11 by regulating its protein levels.","evidence":"Deletion mutants, quantitative PCR of reverse transcripts, LTR/NF-κB luciferase reporters, overexpression/knockdown","pmids":["25105968"],"confidence":"Medium","gaps":["Mechanism of Vpr-mediated TRIM11 regulation not resolved","No identification of the ubiquitinated viral target"]},{"year":2016,"claim":"Uncovering a non-degradative autophagy arm: TRIM11 auto-polyubiquitinates at K458 to recruit the cargo receptor p62 and direct AIM2 for selective autophagic degradation, thereby suppressing inflammasome activation — establishing TRIM11 as an autophagy adapter.","evidence":"Co-IP, K458 site-directed mutagenesis, autophagy inhibitor experiments, and IL-1β/IL-18 maturation assays","pmids":["27498865"],"confidence":"High","gaps":["Whether other TRIM11 substrates are also degraded by autophagy was unknown","Structural basis of p62 recognition of TRIM11 ubiquitin chains not determined"]},{"year":2016,"claim":"Demonstrating direct antiviral capsid targeting: TRIM11 binds HIV-1 capsid and accelerates uncoating via microtubule-dependent mechanisms, reducing reverse transcription; the capsid G89V mutation escapes this restriction.","evidence":"In vitro capsid binding, proximity ligation, fate-of-capsid assay, microtubule inhibitors, capsid mutant analysis","pmids":["27737691"],"confidence":"High","gaps":["Whether TRIM11 ubiquitinates capsid directly was not shown","Relevance in primary immune cells not assessed"]},{"year":2018,"claim":"Establishing TRIM11 as a proteasome activator: TRIM11 binds the 26S proteasome and competitively displaces the inhibitory deubiquitinase USP14, enhancing global proteolytic capacity — a mechanism distinct from its E3 ligase function.","evidence":"In vitro proteasome activity assays, USP14 competition binding assays, reciprocal Co-IP, cell-based degradation assays","pmids":["29581427"],"confidence":"High","gaps":["Structural basis of proteasome/USP14 competition not resolved","Relative contribution of proteasome activation versus direct substrate ubiquitination to aggregate clearance unclear"]},{"year":2019,"claim":"Broadening TRIM11 signal transduction roles: TRIM11 ubiquitinates and degrades Axin1 to activate Wnt/β-catenin signaling, and separately ubiquitinates PHLPP1 to sustain AKT phosphorylation, revealing TRIM11 as a positive regulator of multiple pro-survival/pro-proliferative pathways.","evidence":"Co-IP, ubiquitination assays, AKT/β-catenin inhibitor rescue experiments in lymphoma and chordoma cells","pmids":["31786079","31719797"],"confidence":"Medium","gaps":["In vivo confirmation limited to xenografts","Substrate selectivity mechanism unknown","Whether these pathways are relevant in non-cancer contexts not addressed"]},{"year":2020,"claim":"Defining TRIM11 as a bona fide ATP-independent chaperone and disaggregase: purified TRIM11 prevents α-synuclein fibrillization and dissolves preformed amyloid fibrils in vitro, and AAV-delivered TRIM11 rescues Parkinson's disease pathology in mice, establishing a direct proteostasis function beyond ubiquitin ligation.","evidence":"In vitro aggregation/dissolution assays with purified protein, SUMO ligase reconstitution, AAV intracranial delivery in PD mouse model with motor behavior testing","pmids":["33264628"],"confidence":"High","gaps":["Structural basis of chaperone/disaggregase activity undetermined","Whether chaperone and SUMO ligase activities are mechanistically coupled or independent unclear","Efficacy in human neurons not tested"]},{"year":2023,"claim":"Extending the chaperone/disaggregase paradigm to tauopathy: TRIM11 prevents tau misfolding, dissolves preformed tau fibrils, promotes tau proteasomal degradation, and ameliorates pathology and cognitive deficits across multiple tauopathy mouse models; TRIM11 is downregulated in Alzheimer's disease brains.","evidence":"In vitro chaperone/disaggregation/degradation assays, AAV delivery in multiple tauopathy mouse models, behavioral testing, neuropathology","pmids":["37499037"],"confidence":"High","gaps":["Human genetic evidence linking TRIM11 to AD risk absent","Whether TRIM11 downregulation is cause or consequence of disease not established"]},{"year":2023,"claim":"Establishing an immune-regulatory circuit: TRIM11-mediated autophagic degradation of AIM2 in CD4+ T cells negatively regulates Treg differentiation by suppressing AKT/FOXO1 signaling, MYC activity, and glycolysis, linking TRIM11 to adaptive immune homeostasis.","evidence":"Co-IP, ubiquitination assay, T cell differentiation assays, AKT/FOXO1 phosphorylation, EAE mouse model","pmids":["37804507"],"confidence":"High","gaps":["Whether TRIM11 affects other T cell subsets not addressed","Human T cell validation lacking"]},{"year":2024,"claim":"Confirming TRIM11 SUMO E3 ligase activity on a disease-relevant substrate: TRIM11 catalyzes SUMO1 modification of tau at specific lysine residues, as demonstrated by lysine-to-arginine mutagenesis.","evidence":"Co-expression SUMOylation assays with site-directed mutagenesis","pmids":["39286522"],"confidence":"Medium","gaps":["Downstream consequences of tau SUMOylation for degradation versus aggregation not fully resolved","In vivo relevance of tau SUMOylation not tested"]},{"year":2025,"claim":"Revealing a mutual regulatory axis with JAK1: JAK1 phosphorylates TRIM11, reducing its K48-linked ubiquitination and stabilizing it, while TRIM11 reciprocally promotes K63-linked ubiquitination of JAK1 to suppress JAK/STAT signaling and IFN-γ-induced PD-L1 expression, enhancing anti-tumor immunity.","evidence":"Reciprocal Co-IP, linkage-specific ubiquitination assays, phosphorylation mapping, STAT signaling and CTL killing assays, mouse tumor models","pmids":["41203822"],"confidence":"High","gaps":["Phosphorylation sites on TRIM11 not fully mapped","Whether other JAK family members similarly regulate TRIM11 unknown","Clinical relevance to immunotherapy response not established"]},{"year":null,"claim":"Key unresolved questions include the structural basis for TRIM11's ATP-independent disaggregase activity, how substrate selectivity is determined across its diverse degradation targets, whether the chaperone and E3 ligase/SUMO ligase functions are mechanistically separable in vivo, and the physiological relevance of TRIM11 downregulation in Alzheimer's disease.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of TRIM11 or TRIM11-substrate complexes","No systematic identification of the E2 enzymes partnering with TRIM11 for different ubiquitin chain types","In vivo genetic loss-of-function (knockout mouse) phenotype not reported in the primary mechanistic literature"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,5,8,13,14,15,19,24,25]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[17,21]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,8,17,23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[11,24]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11,15,17]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,12]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,8,22,24]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8,16,22]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,13,14,19,24]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[25]}],"complexes":[],"partners":["PAX6","TBK1","AIM2","USP14","AXIN1","PHLPP1","JAK1","MAPT"],"other_free_text":[]},"mechanistic_narrative":"TRIM11 is a RING-domain E3 ubiquitin ligase that functions as a central regulator of protein quality control and signal transduction through ubiquitin-dependent degradation, molecular chaperoning, and disaggregase activity. TRIM11 promotes K48-linked ubiquitination and proteasomal degradation of diverse substrates including Humanin, PAX6, ARC105, Axin1, PHLPP1, and PHOX2B, and additionally activates the proteasome by binding USP14 and displacing it from the 26S complex [PMID:12670303, PMID:18628401, PMID:29581427, PMID:31786079, PMID:31719797]. Independent of ATP, TRIM11 acts as a molecular chaperone and disaggregase that prevents protein aggregation and dissolves preformed amyloid fibrils of α-synuclein and tau, coupling these activities with SUMO E3 ligase function to target aberrant proteins for degradation; AAV-mediated TRIM11 delivery ameliorates pathology in mouse models of Parkinson's disease and tauopathy [PMID:33264628, PMID:37499037, PMID:39286522]. TRIM11 also restrains innate immune signaling by interacting with TBK1 to suppress IRF3 phosphorylation, directing AIM2 for p62-dependent selective autophagy to limit inflammasome activation, and engaging in a mutual regulatory axis with JAK1 in which JAK1-mediated phosphorylation stabilizes TRIM11 while TRIM11 promotes K63-linked ubiquitination of JAK1 to suppress JAK/STAT-driven PD-L1 expression [PMID:23675467, PMID:27498865, PMID:37804507, PMID:41203822]."},"prefetch_data":{"uniprot":{"accession":"Q96F44","full_name":"E3 ubiquitin-protein ligase TRIM11","aliases":["Protein BIA1","RING finger protein 92","Tripartite motif-containing protein 11"],"length_aa":468,"mass_kda":52.8,"function":"E3 ubiquitin-protein ligase that promotes the degradation of insoluble ubiquitinated proteins, including insoluble PAX6, poly-Gln repeat expanded HTT and poly-Ala repeat expanded ARX (By similarity). Mediates PAX6 ubiquitination leading to proteasomal degradation, thereby modulating cortical neurogenesis (By similarity). May also inhibit PAX6 transcriptional activity, possibly in part by preventing the binding of PAX6 to its consensus sequences (By similarity). May contribute to the regulation of the intracellular level of HN (humanin) or HN-containing proteins through the proteasomal degradation pathway (By similarity). Mediates MED15 ubiquitination leading to proteasomal degradation (PubMed:16904669). May contribute to the innate restriction of retroviruses (PubMed:18248090). Upon overexpression, reduces HIV-1 and murine leukemia virus infectivity, by suppressing viral gene expression (PubMed:18248090). Antiviral activity depends on a functional E3 ubiquitin-protein ligase domain (PubMed:18248090). May regulate TRIM5 turnover via the proteasome pathway, thus counteracting the TRIM5-mediated cross-species restriction of retroviral infection at early stages of the retroviral life cycle (PubMed:18248090). Acts as an inhibitor of the AIM2 inflammasome by promoting autophagy-dependent degradation of AIM2 (PubMed:27498865). Mechanistically, undergoes autoubiquitination upon DNA stimulation, promoting interaction with AIM2 and SQSTM1/p62, leading to AIM2 recruitment to autophagosomes (PubMed:27498865)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96F44/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM11","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRIM11","total_profiled":1310},"omim":[{"mim_id":"607868","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 11; TRIM11","url":"https://www.omim.org/entry/607868"},{"mim_id":"561010","title":"RIBOSOMAL RNA, MITOCHONDRIAL, 16S; MTRNR2","url":"https://www.omim.org/entry/561010"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in 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deletion of the RING domain or proteasome inhibition abolished this effect.\",\n      \"method\": \"Yeast two-hybrid screening, co-expression assays, deletion mutagenesis, proteasome inhibitor treatment\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in single lab, domain mapping with mutagenesis\",\n      \"pmids\": [\"12670303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TRIM11 binds to ARC105 (activator-recruited cofactor 105-kDa component) and promotes its ubiquitin-proteasome-dependent degradation, thereby suppressing ARC105-mediated transcriptional activation of TGFβ signaling.\",\n      \"method\": \"Co-immunoprecipitation, co-expression ubiquitination assay, proteasome inhibitor treatment, transcriptional reporter assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ubiquitination assay, and functional reporter assay in single lab\",\n      \"pmids\": [\"16904669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRIM11 physically interacts with the C-terminal domain of PAX6; C-terminal PAX6 mutations found in patients with eye malformations reduced or abolished this interaction.\",\n      \"method\": \"Yeast two-hybrid library screen\",\n      \"journal\": \"BMC genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single yeast two-hybrid method, no functional follow-up in mammalian cells\",\n      \"pmids\": [\"16098226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRIM11 interacts with PAX6 via its B30.2 domain and promotes PAX6 degradation via the ubiquitin-proteasome system; TRIM11 overexpression decreases endogenous PAX6 protein levels and represses Pax6-dependent transactivation and neurogenesis, while abrogation of TRIM11 increases insoluble Pax6 and enhances apoptosis; the B30.2 domain is essential for clearance of insoluble proteins; Pax6 directly regulates Trim11 expression forming an autoregulatory feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown in cortical progenitors, in vivo cortex electroporation, transcriptional reporter assays, ChIP\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including in vitro assays, in vivo loss-of-function, and domain mutagenesis in a high-impact journal\",\n      \"pmids\": [\"18628401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRIM11 physically interacts with the homeodomain transcription factor Phox2b via its B30.2/SPRY domain, and co-expression of Trim11 with Phox2b further increases dopamine beta-hydroxylase (DBH) gene mRNA levels in primary avian neural crest stem cells.\",\n      \"method\": \"Yeast two-hybrid, protein-protein interaction assays, co-expression in primary NCSC culture, RT-PCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping and functional mRNA readout, single lab\",\n      \"pmids\": [\"18275850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM11 mediates proteasomal degradation of polyalanine-expanded PHOX2B (mutant causing congenital central hypoventilation syndrome), rescuing PHOX2B transcriptional activity; clearance of mutant PHOX2B by TRIM11 correlates with rescue of wild-type PHOX2B function.\",\n      \"method\": \"Co-expression assays, ubiquitination assays, proteasome inhibitor treatment, transcriptional reporter assay, neuroblastoma cell experiments\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination assay plus functional transcriptional rescue, single lab\",\n      \"pmids\": [\"22307522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM11 knockdown in glioblastoma cells inhibits proliferation, migration, and invasion, significantly decreases EGFR levels and MAPK activity, and downregulates HB-EGF mRNA; TRIM11 overexpression promotes tumorsphere formation and glial tumor growth in vivo, suggesting TRIM11 acts through the EGFR signaling pathway.\",\n      \"method\": \"siRNA knockdown, overexpression, in vitro proliferation/migration/invasion assays, in vivo xenograft, western blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/OE with defined cellular and in vivo phenotypes, pathway marker analysis\",\n      \"pmids\": [\"23178488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRIM11 negatively regulates IFNβ production by interacting with TBK1 (via CC domain of TRIM11 and CC2 domain of TBK1), inhibiting IRF3 phosphorylation and dimerization; this interaction was enhanced by TBK1 adaptor proteins NAP1, SINTBAD, and TANK. TRIM11 overexpression enhanced viral infectivity while knockdown had the opposite effect.\",\n      \"method\": \"Co-immunoprecipitation, deletion mutagenesis, IFNβ promoter reporter assays, IRF3 phosphorylation assay, viral infectivity assay, siRNA knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain mapping, multiple orthogonal functional assays, single lab\",\n      \"pmids\": [\"23675467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIM11 binds to AIM2 via its PS domain and undergoes auto-polyubiquitination at K458 to promote association with the autophagic cargo receptor p62, mediating selective autophagic degradation of AIM2 and suppression of AIM2 inflammasome activation.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (K458), ubiquitination assay, autophagy inhibitor experiments, siRNA knockdown, IL-1β/IL-18 maturation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods with mutagenesis identifying specific ubiquitination site, functional inflammasome readout\",\n      \"pmids\": [\"27498865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIM11 interacts with HIV-1 capsid and accelerates viral uncoating, reducing reverse transcription; microtubule dynamics contribute to TRIM11-mediated premature capsid disassembly; the capsid G89V mutation confers insensitivity to TRIM11 restriction.\",\n      \"method\": \"In vitro binding assay, in situ proximity ligation assay, fate-of-capsid assay, quantitative PCR, microtubule dynamics inhibitors, capsid mutant analysis\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro binding plus multiple orthogonal functional assays and genetic mutant validation\",\n      \"pmids\": [\"27737691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIM11 suppresses early steps of HIV-1 transduction (reducing reverse transcripts) and inhibits HIV-1 LTR activity via inhibition of NF-κB; the RING domain is required for the former but dispensable for the latter; HIV-1 Vpr regulates TRIM11 protein levels independently of VprBP-associated proteasome machinery.\",\n      \"method\": \"Deletion mutant experiments, luciferase reporter assay (LTR/NF-κB), quantitative PCR of reverse transcripts, overexpression/knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis with multiple functional readouts, single lab\",\n      \"pmids\": [\"25105968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM11 binds to USP14 (a deubiquitinase and noncatalytic proteasome inhibitor) and precludes USP14-proteasome association, thereby activating the proteasome and enhancing overall proteolytic rate; TRIM11 also binds directly to the proteasome. TRIM11 is upregulated upon heat shock and is required for tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, in vitro proteasome activity assays, proteasome binding assays, USP14 competition assays, cell-based degradation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro proteasome activity assays plus reciprocal Co-IP and multiple orthogonal functional assays in a high-impact journal\",\n      \"pmids\": [\"29581427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM11 interacts with and stabilizes HSF1, increasing HSF1 nuclear levels, and cooperates with HSF1 to suppress the anti-tumor effect of proteotoxic stress drugs; TRIM11 promotes removal of protein aggregates in an HSF1-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, protein aggregate clearance assays, drug sensitivity assays\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with functional nuclear localization and aggregate clearance data, single lab\",\n      \"pmids\": [\"30563406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM11 interacts with Axin1 and promotes its ubiquitination and degradation, thereby activating β-catenin signaling in lymphoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination detection, western blot, β-catenin inhibitor rescue experiments\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination assay with pathway rescue, single lab\",\n      \"pmids\": [\"31786079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM11 promotes mono-ubiquitination of YAP (via interaction between TRIM11 RING domain and YAP WW domain), prolonging YAP protein half-life and activating Hippo-YAP/TEAD target genes in anaplastic thyroid cancer; SOX13 activates TRIM11 transcription by binding to the TRIM11 promoter.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin-based immunoprecipitation, protein half-life assay, reporter assays, promoter analysis\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping with ubiquitination assay and functional pathway readout, single lab\",\n      \"pmids\": [\"33613102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM11 promotes mono-ubiquitination of ERα (via interaction between TRIM11 RING domain and ERα N-terminus in the cytoplasm), enhancing ERα protein stability and ERα-dependent transcriptional activity and cell proliferation in breast cancer.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutagenesis, ubiquitination assay, protein stability assay, RNA-seq, ERE reporter assay\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping, ubiquitination assay, and functional transcriptional readout, single lab\",\n      \"pmids\": [\"32599554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM11 promotes p62-selective autophagic degradation of Daple (a Gα-interacting protein), upregulating β-catenin expression to induce ABCC9 transcription and thereby enhancing multidrug resistance in nasopharyngeal carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, autophagy inhibition experiments, western blot, in vivo xenograft\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with ubiquitination and functional pathway rescue, single lab\",\n      \"pmids\": [\"32382014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM11 functions as an ATP-independent molecular chaperone and disaggregase, preventing formation of protein aggregates and dissolving pre-existing aggregates including amyloid fibrils; these activities cooperate with TRIM11 SUMO ligase activity to degrade aberrant proteins. TRIM11 abrogates α-synuclein fibrillization and, when delivered via AAV intracranially, mitigates α-synuclein pathology, neurodegeneration, and motor impairments in a PD mouse model.\",\n      \"method\": \"In vitro aggregation assays, amyloid fibril dissolution assays, SUMO ligase assays, cell viability assays, AAV delivery in PD mouse model, motor behavior testing\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of chaperone/disaggregase activity plus in vivo AAV rescue with multiple phenotypic readouts\",\n      \"pmids\": [\"33264628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM11 interacts with and colocalizes with UBE2N, and promotes gemcitabine resistance and suppresses ferritinophagy through UBE2N-TAX1BP1 signaling in pancreatic ductal adenocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation, western blot, cell viability assay, xenograft model\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with limited mechanistic follow-up\",\n      \"pmids\": [\"33629745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM11 interacts with PHLPP1 (a protein phosphatase that dephosphorylates AKT) and promotes PHLPP1 ubiquitination, reducing PHLPP1 protein levels and sustaining AKT phosphorylation in chordoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, AKT inhibitor rescue, western blot\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination assay with AKT pathway functional validation, single lab\",\n      \"pmids\": [\"31719797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM11 interacts with Axin1 via Co-IP and destabilizes Axin1 protein, activating the Wnt/β-catenin pathway in gastric cancer; TRIM11 and Axin1 expression are negatively correlated in GC tissues.\",\n      \"method\": \"Co-immunoprecipitation, cycloheximide chase assay, immunofluorescence, western blot, rescue experiments with Axin1 siRNA\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, protein stability assay, and functional rescue, single lab\",\n      \"pmids\": [\"35237324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM11 promotes proteasomal degradation of mutant and superfluous normal tau, acts as a molecular chaperone to prevent tau misfolding, and functions as a disaggregase to dissolve preformed tau fibrils; intracranial AAV delivery of TRIM11 ameliorated pathology, neuroinflammation, and cognitive impairments in multiple animal models of tauopathies. TRIM11 is markedly downregulated in AD brains.\",\n      \"method\": \"In vitro aggregation/disaggregation assays, proteasome degradation assays, chaperone assays, AAV delivery in tauopathy mouse models, behavioral testing, neuropathology\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution of chaperone and disaggregase activities in vitro, replicated across multiple animal models in a high-impact journal\",\n      \"pmids\": [\"37499037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM11 interacts with AIM2 and promotes selective autophagic degradation of AIM2 (via AIM2 ubiquitination and p62 binding) in CD4+ T cells, specifically negatively regulating Treg cell differentiation and attenuating AKT/FOXO1 phosphorylation, MYC signaling, and glycolysis downstream of AIM2.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, T cell differentiation assays, AKT/FOXO1 phosphorylation assay, EAE mouse model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods with in vivo validation, builds on earlier AIM2-TRIM11 work\",\n      \"pmids\": [\"37804507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM11 increases SUMO1 modification of tau (both 2N4R- and 0N4R-tau), acting as a SUMO E3 ligase; mutation of the target lysine residue to arginine abolished SUMO1 modification by TRIM11.\",\n      \"method\": \"Co-expression SUMOylation assays, lysine-to-arginine mutagenesis, western blot\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — enzymatic activity assay with mutagenesis, single lab\",\n      \"pmids\": [\"39286522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM11 and JAK1 interact and mutually regulate each other: JAK1 phosphorylates TRIM11, reducing its K48-linked polyubiquitination and stabilizing it; TRIM11 in turn promotes K63-linked polyubiquitination of JAK1, inhibiting downstream JAK/STAT signaling and reducing IFN-γ-induced PD-L1 expression, thereby enhancing cytotoxic T lymphocyte activity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays (K48/K63-linkage specific), phosphorylation assays, STAT signaling assays, CTL killing assays, mouse tumor models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal regulatory mechanism established with linkage-specific ubiquitination assays, phosphorylation mapping, and in vivo functional validation\",\n      \"pmids\": [\"41203822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM11 promotes K63-linked ubiquitination of ACSL4, leading to its degradation and suppression of ferroptosis in NSCLC; METTL3 enhances m6A modification of TRIM11 mRNA via an IGF2BP1-dependent mechanism, stabilizing TRIM11 mRNA and increasing TRIM11 expression.\",\n      \"method\": \"IP/ubiquitination assay, RNA immunoprecipitation, luciferase reporter, MeRIP assay, protein stability analysis, xenograft\",\n      \"journal\": \"Naunyn-Schmiedeberg's archives of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination assay with linkage specificity and multiple RNA regulatory assays, single lab\",\n      \"pmids\": [\"40668412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM11 promotes ubiquitination of HOXB9 and regulates the NF-κB signaling pathway in sepsis-associated inflammation, reversing HOXB9-induced NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, western blot, flow cytometry\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/ubiquitination with limited mechanistic follow-up, single lab\",\n      \"pmids\": [\"39903348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM11 ubiquitinates PHLPP1, reducing PHLPP1 protein levels and activating AKT signaling in cervical cancer; TRIM11 mRNA is stabilized by m6A modification mediated by METTL14 and read by IGF2BP1.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, MeRIP assay, RNA stability assay, actinomycin D treatment\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination assay with m6A RNA regulatory mechanism, single lab\",\n      \"pmids\": [\"38053376\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM11 is a multifunctional RING-domain E3 ubiquitin ligase (and SUMO ligase) that regulates protein quality control by: (1) promoting proteasomal degradation of diverse substrates (tau, Humanin, PAX6, AIM2, PHOX2B, ARC105, Axin1, PHLPP1, ERα, YAP) via K48-linked ubiquitination; (2) activating the proteasome by displacing the inhibitory deubiquitinase USP14; (3) acting as an ATP-independent molecular chaperone and disaggregase that prevents and reverses protein aggregation including amyloid fibrils; (4) mediating selective autophagic degradation of AIM2 via auto-polyubiquitination and p62 recruitment; (5) inhibiting innate immune signaling by interacting with TBK1 and reducing IRF3 phosphorylation; and (6) engaging in a mutual regulatory axis with JAK1 where JAK1 phosphorylates and stabilizes TRIM11 while TRIM11 promotes K63-linked ubiquitination of JAK1 to suppress PD-L1 induction.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TRIM11 is a RING-domain E3 ubiquitin ligase that functions as a central regulator of protein quality control and signal transduction through ubiquitin-dependent degradation, molecular chaperoning, and disaggregase activity. TRIM11 promotes K48-linked ubiquitination and proteasomal degradation of diverse substrates including Humanin, PAX6, ARC105, Axin1, PHLPP1, and PHOX2B, and additionally activates the proteasome by binding USP14 and displacing it from the 26S complex [PMID:12670303, PMID:18628401, PMID:29581427, PMID:31786079, PMID:31719797]. Independent of ATP, TRIM11 acts as a molecular chaperone and disaggregase that prevents protein aggregation and dissolves preformed amyloid fibrils of α-synuclein and tau, coupling these activities with SUMO E3 ligase function to target aberrant proteins for degradation; AAV-mediated TRIM11 delivery ameliorates pathology in mouse models of Parkinson's disease and tauopathy [PMID:33264628, PMID:37499037, PMID:39286522]. TRIM11 also restrains innate immune signaling by interacting with TBK1 to suppress IRF3 phosphorylation, directing AIM2 for p62-dependent selective autophagy to limit inflammasome activation, and engaging in a mutual regulatory axis with JAK1 in which JAK1-mediated phosphorylation stabilizes TRIM11 while TRIM11 promotes K63-linked ubiquitination of JAK1 to suppress JAK/STAT-driven PD-L1 expression [PMID:23675467, PMID:27498865, PMID:37804507, PMID:41203822].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that TRIM11 is an E3 ligase directing substrates to the proteasome: the first demonstration that TRIM11 promotes ubiquitin-dependent proteasomal degradation of a binding partner (Humanin), requiring its RING domain.\",\n      \"evidence\": \"Yeast two-hybrid, co-expression assays, deletion mutagenesis, and proteasome inhibitor treatment in mammalian cells\",\n      \"pmids\": [\"12670303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro ubiquitination reconstitution\", \"Physiological relevance of Humanin regulation unclear\", \"E2 enzyme identity unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extending TRIM11 substrate scope to a transcriptional cofactor: TRIM11 was shown to degrade ARC105 and thereby suppress TGF-β-dependent transcription, establishing TRIM11 as a regulator of signaling-pathway output.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, and TGF-β transcriptional reporter in mammalian cells\",\n      \"pmids\": [\"16904669\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab finding\", \"Endogenous confirmation lacking\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linking TRIM11 to protein quality control and neurodevelopment: TRIM11 degrades PAX6 via its B30.2 domain and clears insoluble PAX6 aggregates in cortical progenitors; Pax6 itself transcriptionally activates Trim11, forming a feedback loop controlling neurogenesis.\",\n      \"evidence\": \"Co-IP, overexpression/knockdown in cortical progenitors, in vivo cortical electroporation, ChIP, and domain mutagenesis\",\n      \"pmids\": [\"18628401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of insoluble protein clearance not biochemically dissected\", \"Whether TRIM11 chaperone function versus ubiquitin ligase function drives aggregate clearance was unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating TRIM11 can rescue pathogenic protein aggregates: TRIM11 degrades polyalanine-expanded PHOX2B (causative for congenital central hypoventilation syndrome), restoring wild-type PHOX2B transcriptional function.\",\n      \"evidence\": \"Ubiquitination assays, proteasome inhibitor treatment, and transcriptional reporter assays in neuroblastoma cells\",\n      \"pmids\": [\"22307522\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo disease model tested\", \"Single lab\", \"Whether TRIM11 distinguishes mutant from wild-type PHOX2B unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealing TRIM11 as a negative regulator of innate antiviral signaling: TRIM11 interacts with TBK1 via their respective coiled-coil domains, blocking IRF3 phosphorylation and dimerization and thereby suppressing IFN-β production.\",\n      \"evidence\": \"Reciprocal Co-IP with domain mapping, IFN-β promoter reporter, IRF3 phosphorylation assays, and viral infectivity assays\",\n      \"pmids\": [\"23675467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRIM11 ubiquitinates TBK1 or acts non-catalytically was not determined\", \"In vivo immune phenotype not examined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying a dual mechanism of HIV-1 restriction: TRIM11 suppresses reverse transcription (RING-dependent) and inhibits NF-κB-driven LTR activity (RING-independent), while HIV-1 Vpr counteracts TRIM11 by regulating its protein levels.\",\n      \"evidence\": \"Deletion mutants, quantitative PCR of reverse transcripts, LTR/NF-κB luciferase reporters, overexpression/knockdown\",\n      \"pmids\": [\"25105968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Vpr-mediated TRIM11 regulation not resolved\", \"No identification of the ubiquitinated viral target\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovering a non-degradative autophagy arm: TRIM11 auto-polyubiquitinates at K458 to recruit the cargo receptor p62 and direct AIM2 for selective autophagic degradation, thereby suppressing inflammasome activation — establishing TRIM11 as an autophagy adapter.\",\n      \"evidence\": \"Co-IP, K458 site-directed mutagenesis, autophagy inhibitor experiments, and IL-1β/IL-18 maturation assays\",\n      \"pmids\": [\"27498865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other TRIM11 substrates are also degraded by autophagy was unknown\", \"Structural basis of p62 recognition of TRIM11 ubiquitin chains not determined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating direct antiviral capsid targeting: TRIM11 binds HIV-1 capsid and accelerates uncoating via microtubule-dependent mechanisms, reducing reverse transcription; the capsid G89V mutation escapes this restriction.\",\n      \"evidence\": \"In vitro capsid binding, proximity ligation, fate-of-capsid assay, microtubule inhibitors, capsid mutant analysis\",\n      \"pmids\": [\"27737691\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRIM11 ubiquitinates capsid directly was not shown\", \"Relevance in primary immune cells not assessed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing TRIM11 as a proteasome activator: TRIM11 binds the 26S proteasome and competitively displaces the inhibitory deubiquitinase USP14, enhancing global proteolytic capacity — a mechanism distinct from its E3 ligase function.\",\n      \"evidence\": \"In vitro proteasome activity assays, USP14 competition binding assays, reciprocal Co-IP, cell-based degradation assays\",\n      \"pmids\": [\"29581427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of proteasome/USP14 competition not resolved\", \"Relative contribution of proteasome activation versus direct substrate ubiquitination to aggregate clearance unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Broadening TRIM11 signal transduction roles: TRIM11 ubiquitinates and degrades Axin1 to activate Wnt/β-catenin signaling, and separately ubiquitinates PHLPP1 to sustain AKT phosphorylation, revealing TRIM11 as a positive regulator of multiple pro-survival/pro-proliferative pathways.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, AKT/β-catenin inhibitor rescue experiments in lymphoma and chordoma cells\",\n      \"pmids\": [\"31786079\", \"31719797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo confirmation limited to xenografts\", \"Substrate selectivity mechanism unknown\", \"Whether these pathways are relevant in non-cancer contexts not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defining TRIM11 as a bona fide ATP-independent chaperone and disaggregase: purified TRIM11 prevents α-synuclein fibrillization and dissolves preformed amyloid fibrils in vitro, and AAV-delivered TRIM11 rescues Parkinson's disease pathology in mice, establishing a direct proteostasis function beyond ubiquitin ligation.\",\n      \"evidence\": \"In vitro aggregation/dissolution assays with purified protein, SUMO ligase reconstitution, AAV intracranial delivery in PD mouse model with motor behavior testing\",\n      \"pmids\": [\"33264628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of chaperone/disaggregase activity undetermined\", \"Whether chaperone and SUMO ligase activities are mechanistically coupled or independent unclear\", \"Efficacy in human neurons not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extending the chaperone/disaggregase paradigm to tauopathy: TRIM11 prevents tau misfolding, dissolves preformed tau fibrils, promotes tau proteasomal degradation, and ameliorates pathology and cognitive deficits across multiple tauopathy mouse models; TRIM11 is downregulated in Alzheimer's disease brains.\",\n      \"evidence\": \"In vitro chaperone/disaggregation/degradation assays, AAV delivery in multiple tauopathy mouse models, behavioral testing, neuropathology\",\n      \"pmids\": [\"37499037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human genetic evidence linking TRIM11 to AD risk absent\", \"Whether TRIM11 downregulation is cause or consequence of disease not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing an immune-regulatory circuit: TRIM11-mediated autophagic degradation of AIM2 in CD4+ T cells negatively regulates Treg differentiation by suppressing AKT/FOXO1 signaling, MYC activity, and glycolysis, linking TRIM11 to adaptive immune homeostasis.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, T cell differentiation assays, AKT/FOXO1 phosphorylation, EAE mouse model\",\n      \"pmids\": [\"37804507\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRIM11 affects other T cell subsets not addressed\", \"Human T cell validation lacking\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirming TRIM11 SUMO E3 ligase activity on a disease-relevant substrate: TRIM11 catalyzes SUMO1 modification of tau at specific lysine residues, as demonstrated by lysine-to-arginine mutagenesis.\",\n      \"evidence\": \"Co-expression SUMOylation assays with site-directed mutagenesis\",\n      \"pmids\": [\"39286522\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream consequences of tau SUMOylation for degradation versus aggregation not fully resolved\", \"In vivo relevance of tau SUMOylation not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealing a mutual regulatory axis with JAK1: JAK1 phosphorylates TRIM11, reducing its K48-linked ubiquitination and stabilizing it, while TRIM11 reciprocally promotes K63-linked ubiquitination of JAK1 to suppress JAK/STAT signaling and IFN-γ-induced PD-L1 expression, enhancing anti-tumor immunity.\",\n      \"evidence\": \"Reciprocal Co-IP, linkage-specific ubiquitination assays, phosphorylation mapping, STAT signaling and CTL killing assays, mouse tumor models\",\n      \"pmids\": [\"41203822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation sites on TRIM11 not fully mapped\", \"Whether other JAK family members similarly regulate TRIM11 unknown\", \"Clinical relevance to immunotherapy response not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for TRIM11's ATP-independent disaggregase activity, how substrate selectivity is determined across its diverse degradation targets, whether the chaperone and E3 ligase/SUMO ligase functions are mechanistically separable in vivo, and the physiological relevance of TRIM11 downregulation in Alzheimer's disease.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of TRIM11 or TRIM11-substrate complexes\", \"No systematic identification of the E2 enzymes partnering with TRIM11 for different ubiquitin chain types\", \"In vivo genetic loss-of-function (knockout mouse) phenotype not reported in the primary mechanistic literature\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 5, 8, 13, 14, 15, 19, 24, 25]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [17, 21]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 8, 17, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11, 15, 17]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0392499\", \"supporting_discovery_ids\": [0, 1, 3, 5, 11, 13, 17, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 8, 22, 24]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8, 16, 22]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 13, 14, 19, 24]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PAX6\",\n      \"TBK1\",\n      \"AIM2\",\n      \"USP14\",\n      \"AXIN1\",\n      \"PHLPP1\",\n      \"JAK1\",\n      \"MAPT\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}