{"gene":"TRIM11","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2003,"finding":"TRIM11 was identified as a binding partner of the neuroprotective peptide Humanin (HN). The interaction requires both the coiled-coil and B30.2 domains of TRIM11. TRIM11 reduces intracellular HN levels via ubiquitin-mediated proteasomal degradation; disruption of the RING finger domain or proteasome inhibition significantly diminished this effect.","method":"Yeast two-hybrid screening, co-expression/co-immunoprecipitation, deletion mutagenesis, proteasome inhibitor treatment, GST/EGFP fusion assays","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction assays, domain mutagenesis, and proteasome inhibitor rescue, all in single lab","pmids":["12670303"],"is_preprint":false},{"year":2005,"finding":"TRIM11 was identified as a PAX6-interacting protein via yeast two-hybrid screening. C-terminal PAX6 mutations found in patients with eye malformations reduced or abolished the interaction with TRIM11.","method":"Yeast two-hybrid library screen, interaction validation with PAX6 deletion/mutation constructs","journal":"BMC genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid only, single lab, no functional follow-up on TRIM11 mechanism","pmids":["16098226"],"is_preprint":false},{"year":2006,"finding":"TRIM11 interacts with ARC105 (activator-recruited cofactor 105-kDa component, a mediator of TGFβ signaling), promotes its ubiquitination and proteasomal degradation, and suppresses ARC105-mediated transcriptional activation induced by TGFβ.","method":"Co-immunoprecipitation, co-expression ubiquitination assay, proteasome inhibitor treatment, TGFβ reporter assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and functional reporter assay, single lab","pmids":["16904669"],"is_preprint":false},{"year":2008,"finding":"Trim11 interacts with the transcription factor Pax6 via its B30.2 domain and mediates Pax6 degradation through the ubiquitin-proteasome system. Trim11 overexpression decreases endogenous Pax6 protein, represses Pax6-dependent transactivation and neurogenesis, and knockdown of Trim11 increases insoluble Pax6 and enhances apoptosis. The B30.2 domain of Trim11 is essential for clearance of insoluble Pax6. Pax6 also directly regulates Trim11 transcription, forming an autoregulatory feedback loop.","method":"Co-immunoprecipitation, domain deletion, overexpression/knockdown in cortical progenitors in vivo, transactivation reporter assays, proteasome inhibitor treatment","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, domain mutagenesis, in vivo KD, functional reporter), replicated in both in vitro and in vivo contexts","pmids":["18628401"],"is_preprint":false},{"year":2008,"finding":"Trim11 physically interacts with the homeodomain transcription factor Phox2b via its B30.2/SPRY domain. Co-expression of Trim11 with Phox2b further increases dopamine beta-hydroxylase (DBH) mRNA levels in primary avian neural crest stem cell culture.","method":"Yeast two-hybrid, protein-protein interaction assays, domain deletion, primary neural crest cell culture with forced expression","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic follow-up of the interaction","pmids":["18275850"],"is_preprint":false},{"year":2012,"finding":"TRIM11 mediates the ubiquitin-proteasome-dependent degradation of polyalanine-expanded PHOX2B (associated with congenital central hypoventilation syndrome), and this clearance rescues PHOX2B transcriptional activity sequestered by mutant protein aggregates.","method":"Co-expression, ubiquitination assay, proteasome inhibitor treatment, transcriptional activity reporter assay in neuroblastoma cells","journal":"Journal of molecular medicine (Berlin, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple assays (ubiquitination, proteasome inhibition, functional rescue), single lab","pmids":["22307522"],"is_preprint":false},{"year":2012,"finding":"TRIM11 knockdown in glioblastoma cells significantly decreased EGFR protein levels and MAPK activity, and downregulated HB-EGF mRNA, suggesting TRIM11 acts through the EGFR signaling pathway to promote tumor growth and stem-like phenotype.","method":"siRNA knockdown, Western blot (EGFR levels, MAPK activity), mRNA quantification, in vitro and in vivo tumor growth assays","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect pathway placement via knockdown effects, single lab, no direct molecular interaction demonstrated","pmids":["23178488"],"is_preprint":false},{"year":2013,"finding":"TRIM11 negatively regulates IFNβ production by interacting with TBK1 (a key kinase in the RIG-I pathway) through the coiled-coil domain of TRIM11 and the CC2 domain of TBK1. This interaction is enhanced by TBK1 adaptor proteins NAP1, SINTBAD, or TANK. TRIM11 suppresses IRF3 phosphorylation and dimerization, reducing IFNβ mRNA expression and enhancing viral infectivity.","method":"Co-immunoprecipitation, domain deletion mapping, IRF3 phosphorylation/dimerization assays, IFNβ promoter reporter assay, siRNA knockdown, overexpression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, multiple functional readouts, single lab","pmids":["23675467"],"is_preprint":false},{"year":2014,"finding":"TRIM11 restricts HIV-1 replication at early steps (reverse transcription), reduces NF-κB and LTR activity, and requires its RING domain for the early replication block but not for the NF-κB/LTR inhibitory effect. HIV-1 Vpr regulates TRIM11 protein levels (low Vpr decreases, high Vpr increases TRIM11) through mechanisms independent of VprBP-associated proteasome machinery.","method":"Deletion mutagenesis, viral transduction assays, NF-κB/LTR reporter assays, co-expression experiments","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis with multiple functional readouts, single lab","pmids":["25105968"],"is_preprint":false},{"year":2016,"finding":"TRIM11 binds to AIM2 via its PS domain and undergoes auto-polyubiquitination at K458 to promote association between TRIM11 and the autophagic cargo receptor p62, leading to AIM2 degradation via selective autophagy. This suppresses AIM2 inflammasome activation, IL-1β and IL-18 maturation during DNA virus infection.","method":"Co-immunoprecipitation, domain deletion/mutagenesis (K458 mutation), p62 interaction assays, autophagic degradation assay, inflammasome activation assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, site-specific mutagenesis, autophagy pathway validation, functional inflammasome readout, single lab with multiple orthogonal methods","pmids":["27498865"],"is_preprint":false},{"year":2016,"finding":"TRIM11 binds to the HIV-1 capsid protein and accelerates HIV-1 uncoating, thereby reducing viral reverse transcription. Microtubule dynamics contribute to TRIM11-mediated premature capsid disassembly. The HIV-1 capsid mutant G89V is insensitive to TRIM11 restriction, indicating the viral determinant is the capsid.","method":"In vitro binding assay, proximity ligation assay (in situ), fate-of-capsid assay, quantitative PCR for reverse transcripts, microtubule dynamics inhibitors, capsid mutant G89V","journal":"Retrovirology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus cell-based assays with mutant validation, single lab","pmids":["27737691"],"is_preprint":false},{"year":2018,"finding":"TRIM11 binds to both the 19S proteasome and USP14 (a deubiquitinase that prematurely removes ubiquitins from substrates and noncatalytically inhibits the proteasome), prevents their association, and thereby increases proteasome activity and overall rate of protein degradation. TRIM11 is upregulated upon heat shock and promotes cell survival.","method":"Co-immunoprecipitation, in vitro proteasome activity assays, protein degradation assays, knockdown/overexpression","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vitro proteasome activity assays, functional rescue experiments, multiple orthogonal methods in single rigorous study","pmids":["29581427"],"is_preprint":false},{"year":2018,"finding":"TRIM11 interacts with and stabilizes HSF1 by increasing HSF1 levels in the nucleus. TRIM11 cooperates with HSF1 to protect tumor cells against proteotoxic stress and promotes resistance to anti-tumor proteotoxic drugs.","method":"Co-immunoprecipitation, nuclear/cytoplasmic fractionation, protein stability assays, knockdown/overexpression with drug treatment","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with limited mechanistic follow-up, single lab","pmids":["30563406"],"is_preprint":false},{"year":2019,"finding":"TRIM11 interacts with Axin1 via co-immunoprecipitation, promotes Axin1 ubiquitination and degradation, thereby activating the β-catenin signaling pathway to promote lymphoma cell proliferation.","method":"Co-immunoprecipitation, ubiquitination assay, β-catenin pathway reporter, knockdown/overexpression, β-catenin inhibitor XAV939 rescue","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus functional rescue with pathway inhibitor, single lab","pmids":["31786079"],"is_preprint":false},{"year":2019,"finding":"TRIM11 interacts with PHLPP1 and promotes its ubiquitination and proteasomal degradation in chordoma cells, leading to increased AKT phosphorylation and tumor cell growth.","method":"Co-immunoprecipitation, ubiquitination assay, Western blot for PHLPP1 and p-AKT, AKT inhibitor (LY294002) rescue","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus pathway inhibitor rescue, single lab","pmids":["31719797"],"is_preprint":false},{"year":2020,"finding":"TRIM11 interacts with Daple and promotes its ubiquitin-mediated degradation in a p62-selective autophagic manner, thereby upregulating β-catenin expression and inducing ABCC9 expression by directly binding to the ABCC9 promoter.","method":"Co-immunoprecipitation, ubiquitination assay, p62 autophagic degradation assay, ChIP/promoter binding assay, Western blot","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, selective autophagy validation, single lab","pmids":["32382014"],"is_preprint":false},{"year":2020,"finding":"TRIM11 interacts with ERα via its RING domain (binding to the N-terminal of ERα) in the cytoplasm, promotes ERα mono-ubiquitination, and thereby enhances ERα protein stability to facilitate breast cancer proliferation.","method":"Co-immunoprecipitation, domain mapping, ubiquitination assay, protein half-life/stability assay, knockdown/overexpression with ERα rescue","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping plus mono-ubiquitination assay plus functional rescue, single lab","pmids":["32599554"],"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 protein deposits including amyloid fibrils. These activities cooperate with TRIM11 SUMO ligase activity to degrade aberrant proteins. TRIM11 abrogates α-synuclein fibrillization and, delivered via AAV intracranially, mitigates α-synuclein-mediated pathology and motor impairments in a PD mouse model.","method":"In vitro chaperone/disaggregase assays (ATP independence confirmed), amyloid fibril dissolution assay, SUMO ligase activity assay, cell viability assays, AAV intracranial delivery in mouse PD model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of chaperone/disaggregase activity, SUMO ligase assay, in vivo AAV model with multiple readouts","pmids":["33264628"],"is_preprint":false},{"year":2021,"finding":"TRIM11 interacts with Axin1 via co-immunoprecipitation in gastric cancer cells, promotes Axin1 protein destabilization through ubiquitination, thereby activating the Wnt/β-catenin pathway to promote gastric cancer progression.","method":"Co-immunoprecipitation, cycloheximide chase, immunofluorescence, Western blot, rescue experiments with co-transfection of TRIM11 and Axin1 siRNA","journal":"Journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, protein stability assay, and functional rescue in same study, single lab","pmids":["35237324"],"is_preprint":false},{"year":2021,"finding":"TRIM11 interacts with UBE2N and promotes gemcitabine resistance and suppression of ferritinophagy through UBE2N-TAX1BP1 signaling in pancreatic ductal adenocarcinoma.","method":"Co-immunoprecipitation/co-localization, Western blot, knockdown/overexpression, cell viability and xenograft assays","journal":"Journal of cellular physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP interaction established but downstream pathway mechanism not fully dissected at mechanistic level, single lab","pmids":["33629745"],"is_preprint":false},{"year":2021,"finding":"TRIM11 promotes mono-ubiquitination of YAP (via RING domain interacting with WW domain of YAP), thereby prolonging YAP protein half-life, activating Hippo signaling pathway output, and promoting ATC cell proliferation and migration. The RING domain of TRIM11 is essential for the interaction with YAP.","method":"Co-immunoprecipitation, ubiquitination assay (mono-ubiquitination), domain deletion mapping, protein half-life assay, knockdown/overexpression rescue","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, ubiquitination assay, functional rescue, single lab","pmids":["33613102"],"is_preprint":false},{"year":2021,"finding":"TRIM11 acts as a deubiquitinase that reduces DUSP6 accumulation, leading to ERK1/2 pathway activation and promotion of NSCLC progression. Overexpression of DUSP6 or dominant-negative MEK1 reversed the oncogenic effects of TRIM11.","method":"Knockdown/overexpression, Western blot, dominant-negative MEK1 rescue, DUSP6 overexpression rescue, 2-NBDG uptake, xenograft","journal":"Cancer biology & therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional rescue experiments suggest pathway placement but deubiquitinase activity not directly validated biochemically, single lab","pmids":["33970779"],"is_preprint":false},{"year":2022,"finding":"Co-immunoprecipitation identified that endogenous TRIM11 directly interacts with Axin2 and GSK3β, two core components of the β-catenin destruction complex, in esophageal cancer cells. TRIM11 knockdown altered expression of CyclinD1, GSK3β, Axin2, and β-catenin, suggesting TRIM11 acts through this complex to activate β-catenin signaling.","method":"Co-immunoprecipitation, Western blot, knockdown/overexpression, transcriptomic analysis","journal":"Functional & integrative genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, limited mechanistic dissection, single lab","pmids":["42133088"],"is_preprint":false},{"year":2023,"finding":"TRIM11 promotes proteasomal degradation of mutant tau 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 tauopathy animal models. TRIM11 is down-regulated in human AD brains.","method":"In vitro aggregation/disaggregation assays, proteasomal degradation assays, molecular chaperone assays, AAV intracranial delivery in multiple mouse models, cognitive/behavioral testing, neuropathology","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of chaperone/disaggregase/proteasomal degradation, replicated across multiple animal models, high-rigor study","pmids":["37499037"],"is_preprint":false},{"year":2023,"finding":"TRIM11 interacts with AIM2 in CD4+ T cells, induces AIM2 ubiquitination, and promotes selective autophagic degradation of AIM2 via p62 binding. AIM2 normally attenuates AKT/FOXO1 phosphorylation, MYC signaling, and glycolysis to promote Treg cell stability. TRIM11 thus negatively regulates Treg cell differentiation by degrading AIM2.","method":"Co-immunoprecipitation, ubiquitination assay, autophagy/p62 interaction assay, T cell differentiation assays, EAE mouse model, rescue experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, p62 autophagy pathway validation, AIM2-dependent rescue, and in vivo disease model","pmids":["37804507"],"is_preprint":false},{"year":2023,"finding":"TRIM11 ubiquitinates PHLPP1 protein and promotes its degradation in cervical cancer cells, leading to reduced PHLPP1-mediated dephosphorylation of AKT and increased AKT signaling. TRIM11 mRNA is m6A-modified by METTL14, stabilized by IGF2BP1, and this regulatory axis promotes TRIM11 expression and CC progression.","method":"Co-immunoprecipitation (TRIM11-PHLPP1 interaction), ubiquitination assay, RIP assay (METTL14-TRIM11 mRNA), MeRIP (m6A detection), mRNA stability assay, Western blot, rescue experiments","journal":"Neoplasma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus m6A regulatory axis validation, multiple orthogonal methods, single lab","pmids":["38053376"],"is_preprint":false},{"year":2024,"finding":"TRIM11 regulates SUMO1 modification of 0N4R-tau. TRIM11 (previously identified as an E3 SUMO2 ligase for tau) was found to also increase SUMO1 modification of both 2N4R- and 0N4R-tau; mutation of the target lysine residue to arginine attenuated this effect. SUMO1 modification increased phosphorylated tau levels, which was suppressed by SENP1.","method":"Co-expression, site-directed mutagenesis (lysine-to-arginine), Western blot for SUMOylated tau and phosphorylated tau, SENP1 rescue","journal":"Biochemistry and biophysics reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-directed mutagenesis plus functional rescue with SENP1, single lab","pmids":["39286522"],"is_preprint":false},{"year":2025,"finding":"TRIM11 and JAK1 interact and mutually regulate each other via post-translational modifications in response to IFN-γ. JAK1 phosphorylates TRIM11, stabilizing it by reducing K48-linked polyubiquitination. In turn, TRIM11 promotes K63-linked polyubiquitination of JAK1, inhibiting downstream JAK/STAT signaling and reducing IFN-γ-induced PD-L1 expression. This enhances cytotoxic T lymphocyte (CTL) activity and anti-tumor immunity.","method":"Co-immunoprecipitation, ubiquitination assays (K48- vs K63-linked), phosphorylation assays, knockdown/overexpression, PD-L1 expression assays, CTL activity assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, linkage-specific ubiquitination assays, and functional immune readouts, single lab","pmids":["41203822"],"is_preprint":false},{"year":2025,"finding":"TRIM11 promotes K63-linked ubiquitination of ACSL4, leading to its degradation, suppression of ferroptosis, and promotion of malignant progression in NSCLC. METTL3 enhances m6A modification of TRIM11 mRNA via an IGF2BP1/m6A-dependent mechanism to increase TRIM11 expression.","method":"Co-immunoprecipitation, ubiquitination assay (K63-linked), protein stability analysis, RNA immunoprecipitation, luciferase assay, knockdown/overexpression, xenograft","journal":"Naunyn-Schmiedeberg's archives of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with K63 ubiquitination specificity, RIP for m6A axis, functional ferroptosis and xenograft readouts, single lab","pmids":["40668412"],"is_preprint":false},{"year":2025,"finding":"TRIM11 interacts with HOXB9 and promotes its ubiquitination and degradation, leading to NF-κB pathway activation; this regulatory axis modulates inflammation and apoptosis in a sepsis model.","method":"Co-immunoprecipitation, ubiquitination assay, Western blot, flow cytometry (apoptosis), ELISA (cytokines), LPS-stimulated THP-1 cell model","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination in a single lab with limited mechanistic depth","pmids":["39903348"],"is_preprint":false}],"current_model":"TRIM11 is a multifunctional E3 ubiquitin/SUMO ligase and member of the TRIM/RBCC family that promotes proteasomal degradation of diverse substrates (including tau, AIM2, Pax6, Humanin, ARC105, mutant PHOX2B, Axin1/2, PHLPP1, ACSL4, HOXB9, ERα, and YAP) via its RING domain; it also functions as an ATP-independent molecular chaperone and disaggregase to prevent and reverse protein misfolding/aggregation; it activates proteasome activity by binding USP14 and preventing its inhibitory interaction with the proteasome; it suppresses AIM2 inflammasome and Treg differentiation through p62-dependent selective autophagic delivery of AIM2; it inhibits innate antiviral signaling by targeting TBK1 to suppress IRF3 phosphorylation and IFNβ production; it modulates IFN-γ/PD-L1 signaling through mutual K48/K63 ubiquitination-based crosstalk with JAK1; and it accelerates HIV-1 capsid uncoating via direct capsid binding, collectively placing TRIM11 as a central regulator of protein quality control, innate immunity, neurodevelopment, and oncogenic signaling."},"narrative":{"mechanistic_narrative":"TRIM11 is a RING-domain E3 ubiquitin/SUMO ligase of the TRIM/RBCC family that functions broadly in protein quality control, innate immunity, neurodevelopment, and oncogenic signaling [PMID:18628401, PMID:29581427, PMID:33264628]. Its founding biochemical activity is substrate ubiquitination and proteasomal clearance, demonstrated against the neuroprotective peptide Humanin [PMID:12670303], the TGFβ mediator ARC105 [PMID:16904669], the neurodevelopmental transcription factor Pax6 [PMID:18628401], and polyalanine-expanded mutant PHOX2B, where clearance of aggregated mutant protein rescued transcriptional activity [PMID:22307522]. Beyond degradative ubiquitination, TRIM11 acts directly as an ATP-independent molecular chaperone and disaggregase that prevents protein misfolding and dissolves preformed amyloid fibrils, cooperating with its SUMO ligase activity to handle aberrant proteins; AAV-delivered TRIM11 abrogates α-synuclein fibrillization and tau pathology and ameliorates motor, neuropathological, and cognitive deficits in Parkinson's and tauopathy models, with TRIM11 down-regulated in human Alzheimer's disease brain [PMID:33264628, PMID:37499037]. TRIM11 also potentiates global proteostasis by binding the 19S proteasome and USP14, displacing USP14's inhibitory association with the proteasome to raise degradation capacity, and is itself induced by heat shock to promote cell survival [PMID:29581427]. In innate immunity, TRIM11 dampens antiviral and inflammatory signaling: it binds TBK1 through its coiled-coil domain to suppress IRF3 phosphorylation and IFNβ production [PMID:23675467], and it undergoes auto-polyubiquitination at K458 to recruit the autophagy receptor p62 and deliver AIM2 for selective autophagic degradation, restraining inflammasome activation and Treg differentiation [PMID:27498865, PMID:37804507]. Across cancers, TRIM11 drives oncogenic output by ubiquitin-dependent turnover of negative regulators—including the β-catenin destruction-complex component Axin1/Axin2, the AKT phosphatase PHLPP1, and ACSL4—and by stabilizing pro-tumorigenic factors such as ERα and YAP via mono-ubiquitination [PMID:31786079, PMID:31719797, PMID:32599554, PMID:33613102, PMID:40668412]. It additionally engages in reciprocal post-translational crosstalk with JAK1, K63-ubiquitinating JAK1 to limit IFN-γ-induced PD-L1 expression and enhance anti-tumor immunity [PMID:41203822].","teleology":[{"year":2003,"claim":"Established TRIM11's founding biochemical activity—that it functions as an E3 ubiquitin ligase driving proteasomal degradation of a bound substrate—using the neuroprotective peptide Humanin.","evidence":"Yeast two-hybrid, reciprocal Co-IP, RING-domain and proteasome-inhibitor rescue in cells","pmids":["12670303"],"confidence":"Medium","gaps":["Direct ubiquitin-transfer activity not reconstituted in vitro","physiological context of Humanin regulation unresolved"]},{"year":2008,"claim":"Defined a neurodevelopmental role by showing TRIM11 degrades the transcription factor Pax6 via its B30.2 domain, represses neurogenesis, and sits in an autoregulatory feedback loop, with clearance of insoluble Pax6 hinting at a protein-quality-control function.","evidence":"Co-IP, domain deletion, in vivo overexpression/knockdown in cortical progenitors, transactivation reporters","pmids":["18628401"],"confidence":"High","gaps":["Lysine acceptor sites on Pax6 not mapped","how B30.2 distinguishes soluble vs insoluble substrate unclear"]},{"year":2012,"claim":"Extended the degradation function to disease-associated aggregation-prone substrates, showing TRIM11 clears polyalanine-expanded mutant PHOX2B and rescues sequestered transcriptional activity.","evidence":"Co-expression ubiquitination assays, proteasome inhibition, reporter assays in neuroblastoma cells","pmids":["22307522"],"confidence":"Medium","gaps":["Direct chaperone/disaggregase contribution not yet distinguished from ubiquitination","endogenous relevance to CCHS patients not tested"]},{"year":2013,"claim":"Revealed an innate-immune suppressive role by showing TRIM11 binds TBK1 to block IRF3 activation and IFNβ production, positioning it as a negative regulator of antiviral signaling.","evidence":"Co-IP with domain mapping, IRF3 phosphorylation/dimerization assays, IFNβ reporter, siRNA","pmids":["23675467"],"confidence":"Medium","gaps":["Whether TBK1 is ubiquitinated by TRIM11 not established","single-lab finding without reciprocal in vivo validation"]},{"year":2016,"claim":"Established a non-degradative-proteasome route by which TRIM11 controls innate immunity: auto-ubiquitination at K458 recruits p62 to deliver AIM2 for selective autophagy, suppressing inflammasome output.","evidence":"Reciprocal Co-IP, K458 site mutagenesis, p62 interaction and autophagy assays, inflammasome readouts","pmids":["27498865"],"confidence":"High","gaps":["Structural basis of PS-domain/AIM2 recognition unknown","in vivo DNA-virus relevance not tested in this study"]},{"year":2016,"claim":"Identified an antiviral restriction activity distinct from immune signaling: TRIM11 binds the HIV-1 capsid and accelerates uncoating to abort reverse transcription.","evidence":"In vitro binding, proximity ligation, fate-of-capsid assay, qPCR, microtubule inhibitors, G89V capsid mutant","pmids":["27737691","25105968"],"confidence":"Medium","gaps":["Mechanism linking capsid binding to premature disassembly not resolved","role of TRIM11 enzymatic activity in uncoating unclear"]},{"year":2018,"claim":"Uncovered a global proteostasis function: TRIM11 binds the 19S proteasome and USP14, preventing USP14's inhibitory association and thereby boosting overall degradation capacity under proteotoxic stress.","evidence":"Reciprocal Co-IP, in vitro proteasome activity assays, degradation assays, heat-shock induction","pmids":["29581427"],"confidence":"High","gaps":["Structural interface with USP14/proteasome undefined","substrate selectivity of the activated proteasome not characterized"]},{"year":2020,"claim":"Demonstrated that TRIM11 is itself an ATP-independent chaperone and disaggregase that prevents and reverses amyloid formation, providing a direct enzymatic basis for protein-quality-control beyond ubiquitin transfer and therapeutic benefit in a PD model.","evidence":"In vitro reconstituted chaperone/disaggregase and SUMO ligase assays, α-synuclein fibril assays, AAV delivery in mouse PD model","pmids":["33264628"],"confidence":"High","gaps":["Domain(s) mediating disaggregase activity not pinpointed","how chaperone and ligase activities are coordinated unresolved"]},{"year":2023,"claim":"Generalized the chaperone/disaggregase/degradation triad to tau, showing TRIM11 clears and disaggregates pathological tau and reverses tauopathy phenotypes in vivo, with reduced TRIM11 in human AD brain establishing disease relevance.","evidence":"In vitro aggregation/disaggregation and proteasomal degradation assays, AAV delivery across multiple tauopathy mouse models, behavioral and neuropathology readouts","pmids":["37499037","39286522"],"confidence":"High","gaps":["Relative in vivo contributions of degradation vs disaggregation not separated","SUMO1-modification of tau increasing phospho-tau (idx 26) complicates a purely protective model"]},{"year":2023,"claim":"Linked the AIM2-degradation mechanism to adaptive immunity, showing TRIM11 negatively regulates Treg differentiation by p62-dependent autophagic clearance of AIM2.","evidence":"Co-IP, ubiquitination and p62 autophagy assays, T-cell differentiation assays, EAE model, AIM2-dependent rescue","pmids":["37804507"],"confidence":"High","gaps":["Upstream signals controlling TRIM11 in T cells unknown","translation to human autoimmunity not addressed"]},{"year":2025,"claim":"Defined an oncogenic and immune-modulatory signaling network in which TRIM11 turns over tumor-suppressive regulators and engages reciprocal modification crosstalk with JAK1 to limit IFN-γ/PD-L1 signaling.","evidence":"Co-IP, linkage-specific (K48/K63) ubiquitination assays, phosphorylation assays, PD-L1 and CTL functional readouts; ferroptosis/ACSL4 and YAP/ERα/Axin substrate studies","pmids":["41203822","40668412","33613102","32599554","31786079"],"confidence":"Medium","gaps":["Many oncogenic substrate findings are single-lab Co-IP/ubiquitination studies","tissue-specific determinants of stabilizing vs degradative ubiquitination not resolved"]},{"year":null,"claim":"How TRIM11's multiple, sometimes opposing activities—degradative K48 ubiquitination, stabilizing mono/K63 ubiquitination, SUMO ligation, autophagic targeting, and ATP-independent disaggregation—are selected and coordinated for a given substrate and cellular context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model explaining substrate- and linkage-type selection","no unified determinant distinguishing degradation from stabilization","physiological switch between immune-suppressive and proteostatic roles uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,9,11,13,16,20,27,28]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,17]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[17,23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,11,17,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,9,24,27]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,14,18,20,22,27]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9,15,24]}],"complexes":[],"partners":["USP14","TBK1","AIM2","P62","PHLPP1","AXIN1","YAP","JAK1"],"other_free_text":[]}},"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 all","driving_tissues":[{"tissue":"brain","ntpm":61.0}],"url":"https://www.proteinatlas.org/search/TRIM11"},"hgnc":{"alias_symbol":["RNF92","BIA1"],"prev_symbol":[]},"alphafold":{"accession":"Q96F44","domains":[{"cath_id":"3.30.40.10","chopping":"5-80","consensus_level":"high","plddt":87.1467,"start":5,"end":80},{"cath_id":"2.60.120.920","chopping":"277-454","consensus_level":"high","plddt":91.3662,"start":277,"end":454},{"cath_id":"1.20.5","chopping":"134-255","consensus_level":"medium","plddt":95.2189,"start":134,"end":255}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96F44","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96F44-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96F44-F1-predicted_aligned_error_v6.png","plddt_mean":88.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM11","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM11"},"sequence":{"accession":"Q96F44","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96F44.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96F44/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96F44"}},"corpus_meta":[{"pmid":"27498865","id":"PMC_27498865","title":"TRIM11 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AKT/GLUT1 pathway.","date":"2019","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31388304","citation_count":33,"is_preprint":false},{"pmid":"31237704","id":"PMC_31237704","title":"CRTC1-TRIM11 fusion defined melanocytic tumors: A series of four cases.","date":"2019","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31237704","citation_count":33,"is_preprint":false},{"pmid":"16904669","id":"PMC_16904669","title":"TRIM11 binds to and destabilizes a key component of the activator-mediated cofactor complex (ARC105) through the ubiquitin-proteasome system.","date":"2006","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/16904669","citation_count":32,"is_preprint":false},{"pmid":"26660108","id":"PMC_26660108","title":"Activation of AKT1/GSK-3β/β-Catenin-TRIM11/Survivin Pathway by Novel GSK-3β Inhibitor Promotes Neuron Cell Survival: Study in Differentiated SH-SY5Y Cells in OGD Model.","date":"2015","source":"Molecular 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AMIA Symposium","url":"https://pubmed.ncbi.nlm.nih.gov/41726401","citation_count":0,"is_preprint":false},{"pmid":"41536371","id":"PMC_41536371","title":"Cutaneous Melanocytic Tumor With CRTC1::TRIM11 Fusion: A Case Report.","date":"2025","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/41536371","citation_count":0,"is_preprint":false},{"pmid":"41355105","id":"PMC_41355105","title":"[Clinicopathological characteristics of cutaneous melanocytic tumor with CRTC1::TRIM11 fusion of three cases].","date":"2025","source":"Zhonghua bing li xue za zhi = Chinese journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/41355105","citation_count":0,"is_preprint":false},{"pmid":"42015602","id":"PMC_42015602","title":"CRTC1::TRIM11 Cutaneous Tumors With Atypia: Melanoma Mimicry, Aggressive Potential, and Methylation Classifier Limitations.","date":"2026","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/42015602","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.03.25332866","title":"Data-driven modelling of tau pathology reveals distinct progressive supranuclear palsy subtypes","date":"2025-08-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.03.25332866","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":36516,"output_tokens":7401,"usd":0.110282,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16784,"output_tokens":4392,"usd":0.09686,"stage2_stop_reason":"end_turn"},"total_usd":0.207142,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"TRIM11 was identified as a binding partner of the neuroprotective peptide Humanin (HN). The interaction requires both the coiled-coil and B30.2 domains of TRIM11. TRIM11 reduces intracellular HN levels via ubiquitin-mediated proteasomal degradation; disruption of the RING finger domain or proteasome inhibition significantly diminished this effect.\",\n      \"method\": \"Yeast two-hybrid screening, co-expression/co-immunoprecipitation, deletion mutagenesis, proteasome inhibitor treatment, GST/EGFP fusion assays\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction assays, domain mutagenesis, and proteasome inhibitor rescue, all in single lab\",\n      \"pmids\": [\"12670303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRIM11 was identified as a PAX6-interacting protein via yeast two-hybrid screening. C-terminal PAX6 mutations found in patients with eye malformations reduced or abolished the interaction with TRIM11.\",\n      \"method\": \"Yeast two-hybrid library screen, interaction validation with PAX6 deletion/mutation constructs\",\n      \"journal\": \"BMC genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid only, single lab, no functional follow-up on TRIM11 mechanism\",\n      \"pmids\": [\"16098226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TRIM11 interacts with ARC105 (activator-recruited cofactor 105-kDa component, a mediator of TGFβ signaling), promotes its ubiquitination and proteasomal degradation, and suppresses ARC105-mediated transcriptional activation induced by TGFβ.\",\n      \"method\": \"Co-immunoprecipitation, co-expression ubiquitination assay, proteasome inhibitor treatment, TGFβ reporter assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and functional reporter assay, single lab\",\n      \"pmids\": [\"16904669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Trim11 interacts with the transcription factor Pax6 via its B30.2 domain and mediates Pax6 degradation through the ubiquitin-proteasome system. Trim11 overexpression decreases endogenous Pax6 protein, represses Pax6-dependent transactivation and neurogenesis, and knockdown of Trim11 increases insoluble Pax6 and enhances apoptosis. The B30.2 domain of Trim11 is essential for clearance of insoluble Pax6. Pax6 also directly regulates Trim11 transcription, forming an autoregulatory feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion, overexpression/knockdown in cortical progenitors in vivo, transactivation reporter assays, proteasome inhibitor treatment\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, domain mutagenesis, in vivo KD, functional reporter), replicated in both in vitro and in vivo contexts\",\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. Co-expression of Trim11 with Phox2b further increases dopamine beta-hydroxylase (DBH) mRNA levels in primary avian neural crest stem cell culture.\",\n      \"method\": \"Yeast two-hybrid, protein-protein interaction assays, domain deletion, primary neural crest cell culture with forced expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic follow-up of the interaction\",\n      \"pmids\": [\"18275850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM11 mediates the ubiquitin-proteasome-dependent degradation of polyalanine-expanded PHOX2B (associated with congenital central hypoventilation syndrome), and this clearance rescues PHOX2B transcriptional activity sequestered by mutant protein aggregates.\",\n      \"method\": \"Co-expression, ubiquitination assay, proteasome inhibitor treatment, transcriptional activity reporter assay in neuroblastoma cells\",\n      \"journal\": \"Journal of molecular medicine (Berlin, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple assays (ubiquitination, proteasome inhibition, functional rescue), single lab\",\n      \"pmids\": [\"22307522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM11 knockdown in glioblastoma cells significantly decreased EGFR protein levels and MAPK activity, and downregulated HB-EGF mRNA, suggesting TRIM11 acts through the EGFR signaling pathway to promote tumor growth and stem-like phenotype.\",\n      \"method\": \"siRNA knockdown, Western blot (EGFR levels, MAPK activity), mRNA quantification, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect pathway placement via knockdown effects, single lab, no direct molecular interaction demonstrated\",\n      \"pmids\": [\"23178488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRIM11 negatively regulates IFNβ production by interacting with TBK1 (a key kinase in the RIG-I pathway) through the coiled-coil domain of TRIM11 and the CC2 domain of TBK1. This interaction is enhanced by TBK1 adaptor proteins NAP1, SINTBAD, or TANK. TRIM11 suppresses IRF3 phosphorylation and dimerization, reducing IFNβ mRNA expression and enhancing viral infectivity.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mapping, IRF3 phosphorylation/dimerization assays, IFNβ promoter reporter assay, siRNA knockdown, overexpression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, multiple functional readouts, single lab\",\n      \"pmids\": [\"23675467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIM11 restricts HIV-1 replication at early steps (reverse transcription), reduces NF-κB and LTR activity, and requires its RING domain for the early replication block but not for the NF-κB/LTR inhibitory effect. HIV-1 Vpr regulates TRIM11 protein levels (low Vpr decreases, high Vpr increases TRIM11) through mechanisms independent of VprBP-associated proteasome machinery.\",\n      \"method\": \"Deletion mutagenesis, viral transduction assays, NF-κB/LTR reporter assays, co-expression experiments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis with multiple functional readouts, single lab\",\n      \"pmids\": [\"25105968\"],\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 between TRIM11 and the autophagic cargo receptor p62, leading to AIM2 degradation via selective autophagy. This suppresses AIM2 inflammasome activation, IL-1β and IL-18 maturation during DNA virus infection.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion/mutagenesis (K458 mutation), p62 interaction assays, autophagic degradation assay, inflammasome activation assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, site-specific mutagenesis, autophagy pathway validation, functional inflammasome readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27498865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIM11 binds to the HIV-1 capsid protein and accelerates HIV-1 uncoating, thereby reducing viral reverse transcription. Microtubule dynamics contribute to TRIM11-mediated premature capsid disassembly. The HIV-1 capsid mutant G89V is insensitive to TRIM11 restriction, indicating the viral determinant is the capsid.\",\n      \"method\": \"In vitro binding assay, proximity ligation assay (in situ), fate-of-capsid assay, quantitative PCR for reverse transcripts, microtubule dynamics inhibitors, capsid mutant G89V\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding plus cell-based assays with mutant validation, single lab\",\n      \"pmids\": [\"27737691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM11 binds to both the 19S proteasome and USP14 (a deubiquitinase that prematurely removes ubiquitins from substrates and noncatalytically inhibits the proteasome), prevents their association, and thereby increases proteasome activity and overall rate of protein degradation. TRIM11 is upregulated upon heat shock and promotes cell survival.\",\n      \"method\": \"Co-immunoprecipitation, in vitro proteasome activity assays, protein degradation assays, knockdown/overexpression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vitro proteasome activity assays, functional rescue experiments, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"29581427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM11 interacts with and stabilizes HSF1 by increasing HSF1 levels in the nucleus. TRIM11 cooperates with HSF1 to protect tumor cells against proteotoxic stress and promotes resistance to anti-tumor proteotoxic drugs.\",\n      \"method\": \"Co-immunoprecipitation, nuclear/cytoplasmic fractionation, protein stability assays, knockdown/overexpression with drug treatment\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with limited mechanistic follow-up, single lab\",\n      \"pmids\": [\"30563406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM11 interacts with Axin1 via co-immunoprecipitation, promotes Axin1 ubiquitination and degradation, thereby activating the β-catenin signaling pathway to promote lymphoma cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, β-catenin pathway reporter, knockdown/overexpression, β-catenin inhibitor XAV939 rescue\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus functional rescue with pathway inhibitor, single lab\",\n      \"pmids\": [\"31786079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM11 interacts with PHLPP1 and promotes its ubiquitination and proteasomal degradation in chordoma cells, leading to increased AKT phosphorylation and tumor cell growth.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Western blot for PHLPP1 and p-AKT, AKT inhibitor (LY294002) rescue\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus pathway inhibitor rescue, single lab\",\n      \"pmids\": [\"31719797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM11 interacts with Daple and promotes its ubiquitin-mediated degradation in a p62-selective autophagic manner, thereby upregulating β-catenin expression and inducing ABCC9 expression by directly binding to the ABCC9 promoter.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, p62 autophagic degradation assay, ChIP/promoter binding assay, Western blot\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, selective autophagy validation, single lab\",\n      \"pmids\": [\"32382014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM11 interacts with ERα via its RING domain (binding to the N-terminal of ERα) in the cytoplasm, promotes ERα mono-ubiquitination, and thereby enhances ERα protein stability to facilitate breast cancer proliferation.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, ubiquitination assay, protein half-life/stability assay, knockdown/overexpression with ERα rescue\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping plus mono-ubiquitination assay plus functional rescue, single lab\",\n      \"pmids\": [\"32599554\"],\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 protein deposits including amyloid fibrils. These activities cooperate with TRIM11 SUMO ligase activity to degrade aberrant proteins. TRIM11 abrogates α-synuclein fibrillization and, delivered via AAV intracranially, mitigates α-synuclein-mediated pathology and motor impairments in a PD mouse model.\",\n      \"method\": \"In vitro chaperone/disaggregase assays (ATP independence confirmed), amyloid fibril dissolution assay, SUMO ligase activity assay, cell viability assays, AAV intracranial delivery in mouse PD model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of chaperone/disaggregase activity, SUMO ligase assay, in vivo AAV model with multiple readouts\",\n      \"pmids\": [\"33264628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM11 interacts with Axin1 via co-immunoprecipitation in gastric cancer cells, promotes Axin1 protein destabilization through ubiquitination, thereby activating the Wnt/β-catenin pathway to promote gastric cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, cycloheximide chase, immunofluorescence, Western blot, rescue experiments with co-transfection of TRIM11 and Axin1 siRNA\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, protein stability assay, and functional rescue in same study, single lab\",\n      \"pmids\": [\"35237324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM11 interacts with UBE2N and promotes gemcitabine resistance and suppression of ferritinophagy through UBE2N-TAX1BP1 signaling in pancreatic ductal adenocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation/co-localization, Western blot, knockdown/overexpression, cell viability and xenograft assays\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP interaction established but downstream pathway mechanism not fully dissected at mechanistic level, single lab\",\n      \"pmids\": [\"33629745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM11 promotes mono-ubiquitination of YAP (via RING domain interacting with WW domain of YAP), thereby prolonging YAP protein half-life, activating Hippo signaling pathway output, and promoting ATC cell proliferation and migration. The RING domain of TRIM11 is essential for the interaction with YAP.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (mono-ubiquitination), domain deletion mapping, protein half-life assay, knockdown/overexpression rescue\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, ubiquitination assay, functional rescue, single lab\",\n      \"pmids\": [\"33613102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM11 acts as a deubiquitinase that reduces DUSP6 accumulation, leading to ERK1/2 pathway activation and promotion of NSCLC progression. Overexpression of DUSP6 or dominant-negative MEK1 reversed the oncogenic effects of TRIM11.\",\n      \"method\": \"Knockdown/overexpression, Western blot, dominant-negative MEK1 rescue, DUSP6 overexpression rescue, 2-NBDG uptake, xenograft\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional rescue experiments suggest pathway placement but deubiquitinase activity not directly validated biochemically, single lab\",\n      \"pmids\": [\"33970779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Co-immunoprecipitation identified that endogenous TRIM11 directly interacts with Axin2 and GSK3β, two core components of the β-catenin destruction complex, in esophageal cancer cells. TRIM11 knockdown altered expression of CyclinD1, GSK3β, Axin2, and β-catenin, suggesting TRIM11 acts through this complex to activate β-catenin signaling.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, knockdown/overexpression, transcriptomic analysis\",\n      \"journal\": \"Functional & integrative genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, limited mechanistic dissection, single lab\",\n      \"pmids\": [\"42133088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM11 promotes proteasomal degradation of mutant tau 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 tauopathy animal models. TRIM11 is down-regulated in human AD brains.\",\n      \"method\": \"In vitro aggregation/disaggregation assays, proteasomal degradation assays, molecular chaperone assays, AAV intracranial delivery in multiple mouse models, cognitive/behavioral testing, neuropathology\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of chaperone/disaggregase/proteasomal degradation, replicated across multiple animal models, high-rigor study\",\n      \"pmids\": [\"37499037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM11 interacts with AIM2 in CD4+ T cells, induces AIM2 ubiquitination, and promotes selective autophagic degradation of AIM2 via p62 binding. AIM2 normally attenuates AKT/FOXO1 phosphorylation, MYC signaling, and glycolysis to promote Treg cell stability. TRIM11 thus negatively regulates Treg cell differentiation by degrading AIM2.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, autophagy/p62 interaction assay, T cell differentiation assays, EAE mouse model, rescue experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, p62 autophagy pathway validation, AIM2-dependent rescue, and in vivo disease model\",\n      \"pmids\": [\"37804507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM11 ubiquitinates PHLPP1 protein and promotes its degradation in cervical cancer cells, leading to reduced PHLPP1-mediated dephosphorylation of AKT and increased AKT signaling. TRIM11 mRNA is m6A-modified by METTL14, stabilized by IGF2BP1, and this regulatory axis promotes TRIM11 expression and CC progression.\",\n      \"method\": \"Co-immunoprecipitation (TRIM11-PHLPP1 interaction), ubiquitination assay, RIP assay (METTL14-TRIM11 mRNA), MeRIP (m6A detection), mRNA stability assay, Western blot, rescue experiments\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus m6A regulatory axis validation, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"38053376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM11 regulates SUMO1 modification of 0N4R-tau. TRIM11 (previously identified as an E3 SUMO2 ligase for tau) was found to also increase SUMO1 modification of both 2N4R- and 0N4R-tau; mutation of the target lysine residue to arginine attenuated this effect. SUMO1 modification increased phosphorylated tau levels, which was suppressed by SENP1.\",\n      \"method\": \"Co-expression, site-directed mutagenesis (lysine-to-arginine), Western blot for SUMOylated tau and phosphorylated tau, SENP1 rescue\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-directed mutagenesis plus functional rescue with SENP1, 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 via post-translational modifications in response to IFN-γ. JAK1 phosphorylates TRIM11, stabilizing it by reducing K48-linked polyubiquitination. In turn, TRIM11 promotes K63-linked polyubiquitination of JAK1, inhibiting downstream JAK/STAT signaling and reducing IFN-γ-induced PD-L1 expression. This enhances cytotoxic T lymphocyte (CTL) activity and anti-tumor immunity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays (K48- vs K63-linked), phosphorylation assays, knockdown/overexpression, PD-L1 expression assays, CTL activity assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, linkage-specific ubiquitination assays, and functional immune readouts, single lab\",\n      \"pmids\": [\"41203822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM11 promotes K63-linked ubiquitination of ACSL4, leading to its degradation, suppression of ferroptosis, and promotion of malignant progression in NSCLC. METTL3 enhances m6A modification of TRIM11 mRNA via an IGF2BP1/m6A-dependent mechanism to increase TRIM11 expression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K63-linked), protein stability analysis, RNA immunoprecipitation, luciferase assay, knockdown/overexpression, xenograft\",\n      \"journal\": \"Naunyn-Schmiedeberg's archives of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with K63 ubiquitination specificity, RIP for m6A axis, functional ferroptosis and xenograft readouts, single lab\",\n      \"pmids\": [\"40668412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM11 interacts with HOXB9 and promotes its ubiquitination and degradation, leading to NF-κB pathway activation; this regulatory axis modulates inflammation and apoptosis in a sepsis model.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Western blot, flow cytometry (apoptosis), ELISA (cytokines), LPS-stimulated THP-1 cell model\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination in a single lab with limited mechanistic depth\",\n      \"pmids\": [\"39903348\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM11 is a multifunctional E3 ubiquitin/SUMO ligase and member of the TRIM/RBCC family that promotes proteasomal degradation of diverse substrates (including tau, AIM2, Pax6, Humanin, ARC105, mutant PHOX2B, Axin1/2, PHLPP1, ACSL4, HOXB9, ERα, and YAP) via its RING domain; it also functions as an ATP-independent molecular chaperone and disaggregase to prevent and reverse protein misfolding/aggregation; it activates proteasome activity by binding USP14 and preventing its inhibitory interaction with the proteasome; it suppresses AIM2 inflammasome and Treg differentiation through p62-dependent selective autophagic delivery of AIM2; it inhibits innate antiviral signaling by targeting TBK1 to suppress IRF3 phosphorylation and IFNβ production; it modulates IFN-γ/PD-L1 signaling through mutual K48/K63 ubiquitination-based crosstalk with JAK1; and it accelerates HIV-1 capsid uncoating via direct capsid binding, collectively placing TRIM11 as a central regulator of protein quality control, innate immunity, neurodevelopment, and oncogenic signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM11 is a RING-domain E3 ubiquitin/SUMO ligase of the TRIM/RBCC family that functions broadly in protein quality control, innate immunity, neurodevelopment, and oncogenic signaling [#3, #11, #17]. Its founding biochemical activity is substrate ubiquitination and proteasomal clearance, demonstrated against the neuroprotective peptide Humanin [#0], the TGFβ mediator ARC105 [#2], the neurodevelopmental transcription factor Pax6 [#3], and polyalanine-expanded mutant PHOX2B, where clearance of aggregated mutant protein rescued transcriptional activity [#5]. Beyond degradative ubiquitination, TRIM11 acts directly as an ATP-independent molecular chaperone and disaggregase that prevents protein misfolding and dissolves preformed amyloid fibrils, cooperating with its SUMO ligase activity to handle aberrant proteins; AAV-delivered TRIM11 abrogates α-synuclein fibrillization and tau pathology and ameliorates motor, neuropathological, and cognitive deficits in Parkinson's and tauopathy models, with TRIM11 down-regulated in human Alzheimer's disease brain [#17, #23]. TRIM11 also potentiates global proteostasis by binding the 19S proteasome and USP14, displacing USP14's inhibitory association with the proteasome to raise degradation capacity, and is itself induced by heat shock to promote cell survival [#11]. In innate immunity, TRIM11 dampens antiviral and inflammatory signaling: it binds TBK1 through its coiled-coil domain to suppress IRF3 phosphorylation and IFNβ production [#7], and it undergoes auto-polyubiquitination at K458 to recruit the autophagy receptor p62 and deliver AIM2 for selective autophagic degradation, restraining inflammasome activation and Treg differentiation [#9, #24]. Across cancers, TRIM11 drives oncogenic output by ubiquitin-dependent turnover of negative regulators—including the β-catenin destruction-complex component Axin1/Axin2, the AKT phosphatase PHLPP1, and ACSL4—and by stabilizing pro-tumorigenic factors such as ERα and YAP via mono-ubiquitination [#13, #14, #16, #20, #28]. It additionally engages in reciprocal post-translational crosstalk with JAK1, K63-ubiquitinating JAK1 to limit IFN-γ-induced PD-L1 expression and enhance anti-tumor immunity [#27].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established TRIM11's founding biochemical activity—that it functions as an E3 ubiquitin ligase driving proteasomal degradation of a bound substrate—using the neuroprotective peptide Humanin.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, RING-domain and proteasome-inhibitor rescue in cells\",\n      \"pmids\": [\"12670303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitin-transfer activity not reconstituted in vitro\", \"physiological context of Humanin regulation unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined a neurodevelopmental role by showing TRIM11 degrades the transcription factor Pax6 via its B30.2 domain, represses neurogenesis, and sits in an autoregulatory feedback loop, with clearance of insoluble Pax6 hinting at a protein-quality-control function.\",\n      \"evidence\": \"Co-IP, domain deletion, in vivo overexpression/knockdown in cortical progenitors, transactivation reporters\",\n      \"pmids\": [\"18628401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lysine acceptor sites on Pax6 not mapped\", \"how B30.2 distinguishes soluble vs insoluble substrate unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended the degradation function to disease-associated aggregation-prone substrates, showing TRIM11 clears polyalanine-expanded mutant PHOX2B and rescues sequestered transcriptional activity.\",\n      \"evidence\": \"Co-expression ubiquitination assays, proteasome inhibition, reporter assays in neuroblastoma cells\",\n      \"pmids\": [\"22307522\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chaperone/disaggregase contribution not yet distinguished from ubiquitination\", \"endogenous relevance to CCHS patients not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed an innate-immune suppressive role by showing TRIM11 binds TBK1 to block IRF3 activation and IFNβ production, positioning it as a negative regulator of antiviral signaling.\",\n      \"evidence\": \"Co-IP with domain mapping, IRF3 phosphorylation/dimerization assays, IFNβ reporter, siRNA\",\n      \"pmids\": [\"23675467\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TBK1 is ubiquitinated by TRIM11 not established\", \"single-lab finding without reciprocal in vivo validation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established a non-degradative-proteasome route by which TRIM11 controls innate immunity: auto-ubiquitination at K458 recruits p62 to deliver AIM2 for selective autophagy, suppressing inflammasome output.\",\n      \"evidence\": \"Reciprocal Co-IP, K458 site mutagenesis, p62 interaction and autophagy assays, inflammasome readouts\",\n      \"pmids\": [\"27498865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PS-domain/AIM2 recognition unknown\", \"in vivo DNA-virus relevance not tested in this study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified an antiviral restriction activity distinct from immune signaling: TRIM11 binds the HIV-1 capsid and accelerates uncoating to abort reverse transcription.\",\n      \"evidence\": \"In vitro binding, proximity ligation, fate-of-capsid assay, qPCR, microtubule inhibitors, G89V capsid mutant\",\n      \"pmids\": [\"27737691\", \"25105968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking capsid binding to premature disassembly not resolved\", \"role of TRIM11 enzymatic activity in uncoating unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Uncovered a global proteostasis function: TRIM11 binds the 19S proteasome and USP14, preventing USP14's inhibitory association and thereby boosting overall degradation capacity under proteotoxic stress.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro proteasome activity assays, degradation assays, heat-shock induction\",\n      \"pmids\": [\"29581427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural interface with USP14/proteasome undefined\", \"substrate selectivity of the activated proteasome not characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that TRIM11 is itself an ATP-independent chaperone and disaggregase that prevents and reverses amyloid formation, providing a direct enzymatic basis for protein-quality-control beyond ubiquitin transfer and therapeutic benefit in a PD model.\",\n      \"evidence\": \"In vitro reconstituted chaperone/disaggregase and SUMO ligase assays, α-synuclein fibril assays, AAV delivery in mouse PD model\",\n      \"pmids\": [\"33264628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain(s) mediating disaggregase activity not pinpointed\", \"how chaperone and ligase activities are coordinated unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Generalized the chaperone/disaggregase/degradation triad to tau, showing TRIM11 clears and disaggregates pathological tau and reverses tauopathy phenotypes in vivo, with reduced TRIM11 in human AD brain establishing disease relevance.\",\n      \"evidence\": \"In vitro aggregation/disaggregation and proteasomal degradation assays, AAV delivery across multiple tauopathy mouse models, behavioral and neuropathology readouts\",\n      \"pmids\": [\"37499037\", \"39286522\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in vivo contributions of degradation vs disaggregation not separated\", \"SUMO1-modification of tau increasing phospho-tau (idx 26) complicates a purely protective model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked the AIM2-degradation mechanism to adaptive immunity, showing TRIM11 negatively regulates Treg differentiation by p62-dependent autophagic clearance of AIM2.\",\n      \"evidence\": \"Co-IP, ubiquitination and p62 autophagy assays, T-cell differentiation assays, EAE model, AIM2-dependent rescue\",\n      \"pmids\": [\"37804507\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling TRIM11 in T cells unknown\", \"translation to human autoimmunity not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined an oncogenic and immune-modulatory signaling network in which TRIM11 turns over tumor-suppressive regulators and engages reciprocal modification crosstalk with JAK1 to limit IFN-γ/PD-L1 signaling.\",\n      \"evidence\": \"Co-IP, linkage-specific (K48/K63) ubiquitination assays, phosphorylation assays, PD-L1 and CTL functional readouts; ferroptosis/ACSL4 and YAP/ERα/Axin substrate studies\",\n      \"pmids\": [\"41203822\", \"40668412\", \"33613102\", \"32599554\", \"31786079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many oncogenic substrate findings are single-lab Co-IP/ubiquitination studies\", \"tissue-specific determinants of stabilizing vs degradative ubiquitination not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRIM11's multiple, sometimes opposing activities—degradative K48 ubiquitination, stabilizing mono/K63 ubiquitination, SUMO ligation, autophagic targeting, and ATP-independent disaggregation—are selected and coordinated for a given substrate and cellular context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model explaining substrate- and linkage-type selection\", \"no unified determinant distinguishing degradation from stabilization\", \"physiological switch between immune-suppressive and proteostatic roles uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 9, 11, 13, 16, 20, 27, 28]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 17]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [17, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 11, 17, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 9, 24, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 14, 18, 20, 22, 27]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9, 15, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"USP14\", \"TBK1\", \"AIM2\", \"p62\", \"PHLPP1\", \"Axin1\", \"YAP\", \"JAK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}