{"gene":"TRIM27","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1992,"finding":"RFP (TRIM27) protein is strongly associated with the nuclear matrix and exhibits DNA-binding activity, preferentially binding double-stranded DNA over single-stranded DNA. Two forms were detected: a 58 kDa ubiquitous form and a 68 kDa testis-specific form.","method":"Western blot, nuclear matrix fractionation, DNA-binding assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear fractionation plus in vitro DNA-binding assay, single lab, two orthogonal methods","pmids":["1437549"],"is_preprint":false},{"year":1996,"finding":"TRIM27 (RFP) homomultimerization occurs through its coiled-coil domain; the B-box domain is not a direct interaction interface but its structural integrity is necessary for coiled-coil-mediated multimerization. Mutations in the RING finger and B-box alter subcellular compartmentalization of RFP in cell lines.","method":"Yeast two-hybrid, deletion/mutation analysis, subcellular localization by microscopy","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid with domain mutants plus localization, single lab, two orthogonal methods","pmids":["9247190"],"is_preprint":false},{"year":1996,"finding":"The RING finger motif of RFP (TRIM27) is critical for the transforming activity of the RFP/RET fusion oncogene; mutation of Cys-16, Cys-31, or His-33 in the RING finger markedly decreased transforming activity and tyrosine phosphorylation, while mutations in the B-box (Cys-118 or His-124) had no effect.","method":"Site-directed mutagenesis, NIH 3T3 transformation assay, phosphorylation analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis with functional readout, single lab","pmids":["8753810"],"is_preprint":false},{"year":1996,"finding":"Mouse rfp (TRIM27) protein is expressed as nuclear bodies resembling PML oncogenic domains (PODs) in cell nuclei, with highest expression in pachytene spermatocytes and round spermatids during spermatogenesis.","method":"Immunofluorescence, immunohistochemistry, subcellular localization in mouse tissues","journal":"Developmental genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization by immunofluorescence only, single lab, single method, no functional consequence directly established","pmids":["9023983"],"is_preprint":false},{"year":2002,"finding":"RFP (TRIM27) interacts with Enhancer of Polycomb 1 (EPC1) via the EPcA, EPcB, and CT regions of EPC1. O-glycosylation of the 68 kDa testis form of RFP enhances interaction with the EPC1 CT region; expression of EPcA region impairs transcriptional repressive activity of RFP.","method":"GST pull-down, co-immunoprecipitation from mouse testis, O-glycosidase treatment, luciferase reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP from native tissue plus glycosidase treatment plus reporter assay, single lab, multiple orthogonal methods","pmids":["11779184"],"is_preprint":false},{"year":2005,"finding":"RFP (TRIM27) interacts with bHLH transcription factors SCL, E47, MyoD, and mASH-1 (but not GATA-1 or PU.1) through its B-box and first coiled-coil region, and represses transcriptional activation by E47, MyoD, and mASH-1 in a trichostatin A-sensitive manner consistent with HDAC/Polycomb recruitment rather than ubiquitination-mediated degradation of the bHLH proteins.","method":"Co-immunoprecipitation, domain deletion mapping, luciferase reporter assay, trichostatin A treatment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping plus functional reporter assay, single lab, two orthogonal methods","pmids":["16007160"],"is_preprint":false},{"year":2012,"finding":"TRIM27 functions as an E3 ubiquitin ligase that physically interacts with NOD2 via the nucleotide-binding domain of NOD2; NOD2 activation enhances this interaction. TRIM27-dependent K48-linked ubiquitination of NOD2 leads to proteasomal degradation of NOD2, thereby negatively regulating NOD2-mediated pro-inflammatory signaling.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, siRNA knockdown with NF-κB reporter","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in-cell ubiquitination assay with proteasome inhibitor, functional signaling readout, single lab","pmids":["22829933"],"is_preprint":false},{"year":2012,"finding":"TRIM27 negatively regulates FcεRI (IgE receptor) signaling in mast cells by ubiquitinating and inhibiting PI3KC2β; TRIM27-knockout mice show increased susceptibility to anaphylaxis in vivo.","method":"Co-immunoprecipitation, ubiquitination assay, KCa3.1 channel activation assay, TRIM27-/- mouse model, in vivo anaphylaxis model","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ubiquitination assay, knockout mouse phenotype, in vivo model, multiple orthogonal methods in a single study","pmids":["22645315"],"is_preprint":false},{"year":2013,"finding":"TRIM27 forms a complex with USP7 (ubiquitin-specific protease), ubiquitinates USP7, and this complex controls TNF-α-induced apoptosis. USP7 in this complex deubiquitinates RIP1, which is required for TNF-α apoptotic signaling. Trim27-deficient MEFs and mice are resistant to TNF-α-induced apoptosis.","method":"Co-immunoprecipitation, ubiquitination assay, Trim27-/- mouse and MEF studies, TNF-α apoptosis assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in-cell ubiquitination assay, KO mouse plus MEF phenotype, multiple orthogonal methods","pmids":["24144979"],"is_preprint":false},{"year":2013,"finding":"RFP (TRIM27) acts as a novel E3 ubiquitin ligase for PTEN, promoting atypical (non-K48) polyubiquitination of PTEN that does not affect PTEN stability or localization but inhibits PTEN phosphatase activity, thereby relieving PTEN-mediated inhibition of AKT activation.","method":"Co-immunoprecipitation, in-cell ubiquitination assay, RNAi knockdown, PTEN phosphatase activity assay, AKT activation assay","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, phosphatase activity assay, RNAi rescue, single lab","pmids":["23419514"],"is_preprint":false},{"year":2014,"finding":"TRIM27 is a novel degradation target of the HSV-1 E3 ubiquitin ligase ICP0; TRIM27 protein is rapidly lost during HSV-1 infection in a manner dependent on ICP0's RING domain and the proteasome. A RING-mutant ICP0 co-immunoprecipitates endogenous TRIM27. Surprisingly, TRIM27 depletion decreases ICP0-null virus yields, suggesting TRIM27 can positively affect HSV-1 infection.","method":"Proteomic screen, co-immunoprecipitation, proteasome inhibitor treatment, RING-domain mutant ICP0, immunofluorescence, siRNA knockdown with viral yield assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, proteasome inhibitor, domain mutagenesis, functional viral yield, single lab","pmids":["25320289"],"is_preprint":false},{"year":2014,"finding":"TRIM27 forms a complex with MRTF-B (myocardin-related transcription factor B) in leading cancer cells and posttranscriptionally upregulates integrin β1 expression via suppression of microRNA-124, enabling integrin β1 mRNA stability and translation specifically in leading cells of collectively invading cancer groups. Depletion of TRIM27 or MRTF-B abrogates integrin β1 upregulation and blocks collective cancer invasion.","method":"Co-immunoprecipitation, RNAi knockdown, invasion assay in vitro and in vivo, miRNA reporter assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, RNAi with functional invasion readout, miRNA reporter, single lab","pmids":["24794433"],"is_preprint":false},{"year":2015,"finding":"TRIM27 is recruited by the Siglec1–DAP12–SHP2 signaling axis and induces K48-linked ubiquitination of TBK1 at Lys251 and Lys372, leading to TBK1 proteasomal degradation and suppression of type I IFN production during viral infection.","method":"Co-immunoprecipitation, ubiquitination assay with K48-linkage specific analysis, proteasome inhibitor, mutagenesis of TBK1 ubiquitination sites, RNAi knockdown","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, site-specific ubiquitination mutagenesis, proteasome inhibitor, multiple mechanistic layers in single study","pmids":["26358190"],"is_preprint":false},{"year":2016,"finding":"TRIM27 interacts with Slx2 and co-localizes with Slx2 in the XY body of spermatocytes during meiosis; Trim27 also co-localizes with γ-H2AX in the XY body, suggesting a role in XY body formation and meiotic regulation.","method":"Yeast two-hybrid, co-immunoprecipitation, mammalian two-hybrid, immunohistochemistry, immunocytochemistry","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, yeast/mammalian two-hybrid and localization, single lab, multiple methods","pmids":["27612028"],"is_preprint":false},{"year":2016,"finding":"TRIM27 functions as a host restriction factor against Mycobacterium tuberculosis by promoting innate immune responses and cell apoptosis via the JNK/p38 MAPK pathway. Mtb effector PtpA antagonizes this function by competitively binding to TRIM27's RING domain.","method":"Co-immunoprecipitation, RNAi knockdown, macrophage infection assay, MAPK pathway analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, RNAi with infection and signaling readout, competitive binding shown, single lab","pmids":["27698396"],"is_preprint":false},{"year":2018,"finding":"TRIM27 localizes to retromer-positive punctate structures and serves as a scaffold recruiting gp130, JAK1, and STAT3 to these structures, facilitating STAT3 phosphorylation downstream of IL-6. Knockdown of TRIM27 impairs IL-6-induced STAT3 activation, inflammatory cytokine expression, and colitis-associated carcinogenesis in mouse models.","method":"Co-immunoprecipitation, subcellular fractionation/immunofluorescence, TRIM27 knockdown with STAT3 phosphorylation readout, DSS/AOM mouse colitis model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, localization to retromer structures, in vivo KO mouse model, multiple orthogonal methods, in vitro and in vivo validation","pmids":["30143645"],"is_preprint":false},{"year":2018,"finding":"USP7 physically interacts with TRIM27, stabilizing it; USP7 overexpression promotes TRIM27-dependent K48-linked ubiquitination and degradation of TBK1, thereby suppressing type I IFN signaling. USP7 knockout leads to enhanced TRIM27 degradation, reduced TBK1 ubiquitination, and enhanced IFN signaling.","method":"Co-immunoprecipitation, ubiquitination assay, USP7 knockout, overexpression with IFN reporter, viral replication assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, USP7 KO, functional IFN readout, single lab","pmids":["29688809"],"is_preprint":false},{"year":2019,"finding":"TRIM27 interacts with and promotes ubiquitination of PIAS3 (a STAT3 inhibitor) in keratinocytes, leading to PIAS3 degradation and enhanced IL-6-induced STAT3 activation, cell proliferation, and inflammation factor production.","method":"Co-immunoprecipitation, ubiquitination assay, TRIM27 overexpression/silencing, PIAS3 silencing, STAT3 phosphorylation readout","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with ubiquitination assay plus functional signaling readout, single lab, multiple orthogonal methods","pmids":["31747314"],"is_preprint":false},{"year":2019,"finding":"TRIM27 directly interacts with PTEN and mediates its poly-ubiquitination in esophageal squamous cell carcinoma cells, activating AKT signaling; AKT inhibitor LY294002 blocks TRIM27's pro-proliferative effects.","method":"Co-immunoprecipitation, ubiquitination assay, AKT inhibitor treatment, overexpression/knockdown","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, pharmacological rescue, single lab","pmids":["31719796"],"is_preprint":false},{"year":2020,"finding":"TRIM27 mediates K48-linked ubiquitination and proteasomal degradation of SIX3 in non-small cell lung cancer cells, thereby activating β-catenin target gene expression (S100P, TGFB3, MMP-9); β-catenin inhibitor XAV939 blocks TRIM27-mediated cell proliferation and invasion.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, XAV939 inhibitor rescue, cell proliferation and invasion assay","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, pharmacological rescue, single lab","pmids":["33264103"],"is_preprint":false},{"year":2020,"finding":"TRIM27 mediates ubiquitination and degradation of p21, thereby suppressing cellular senescence in non-triple-negative breast cancer cells.","method":"Co-immunoprecipitation (coIP), ubiquitination assay, TRIM27 knockdown/overexpression, senescence assay","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP plus ubiquitination assay plus functional senescence readout, single lab","pmids":["33251042"],"is_preprint":false},{"year":2020,"finding":"TRIM27 ubiquitinates and degrades PPARγ in neuronal HT22 cells, promoting glutamate-induced apoptosis and IL-1β release; PPARγ agonist rosiglitazone reverses TRIM27 overexpression-induced apoptosis.","method":"Co-immunoprecipitation, ubiquitination assay, TRIM27 knockdown/overexpression, rosiglitazone rescue, apoptosis assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, pharmacological rescue, single lab","pmids":["33385414"],"is_preprint":false},{"year":2021,"finding":"TRIM27 and USP7 are integral components of the non-canonical PRC1.1 Polycomb complex. USP7 and TRIM27 are reciprocally required for incorporation into PRC1.1; USP7 counteracts TRIM27 E3 ligase activity to maintain PRC1.1 integrity. USP7 inhibition results in PRC1.1 disassembly, loss of chromatin binding, and reduced H2AK119ub and H3K27ac at PRC1.1 target loci.","method":"Co-immunoprecipitation/USP7 interactome analysis, ChIP, H2AK119ub and H3K27ac assays, USP7 inhibitor, TRIM27 knockdown, gene expression analysis","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interactome, ChIP, histone mark analysis, functional knockdown, single lab with multiple orthogonal methods","pmids":["34113809"],"is_preprint":false},{"year":2021,"finding":"TRIM27 directly interacts with IκBα (inhibitor of NF-κB) and promotes its K48-linked ubiquitination, leading to IκBα degradation and NF-κB activation in renal cell carcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, NF-κB reporter, TRIM27 overexpression/siRNA knockdown","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, NF-κB reporter, single lab","pmids":["34284744"],"is_preprint":false},{"year":2021,"finding":"TRIM27 interacts with p53 and promotes its ubiquitination in cardiomyocytes; heart-conditional TRIM27 knockout exacerbates MI/R injury via enhanced p53 expression, caspase-3 activation, and NF-κB-mediated inflammation.","method":"Co-immunoprecipitation, ubiquitination assay, heart-conditional KO mouse, MI/R model, p53 inhibition rescue","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, conditional KO mouse model, single lab","pmids":["33865220"],"is_preprint":false},{"year":2022,"finding":"TRIM27 directly polyubiquitinates ULK1 at K568 and K571 with K48-linked chains (for degradation) and ubiquitinates STK38L with non-degradative K6/K11 chains; STK38L ubiquitination activates it to phosphorylate ULK1 at Ser495, making ULK1 a better substrate for TRIM27-mediated hyper-ubiquitination, thus restraining autophagy amplitude. TRIM27 knockout mice show increased basal autophagy.","method":"In vitro ubiquitination assay, site-directed mutagenesis at ubiquitination sites, kinase phosphorylation assay, TRIM27 KO mouse model, autophagy flux assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitination reconstitution, mutagenesis of specific lysine sites, kinase assay, KO mouse with autophagy readout, multiple orthogonal methods in a single study","pmids":["35670107"],"is_preprint":false},{"year":2022,"finding":"TRIM27 is an autophagy substrate degraded via ATG7/ATG9-dependent autophagy and interacts with autophagy receptor SQSTM1/p62; induced TRIM27 expression causes mitochondrial clustering facilitated by SQSTM1/p62, and promotes mitophagy by stabilizing phosphorylated TBK1 on mitochondria. TRIM27 KO cells show reduced mitophagy, rescued by EGFP-TRIM27 re-introduction.","method":"Co-immunoprecipitation, TRIM27 KO cells, mitophagy assay, immunofluorescence, ATG7/ATG9 dependency experiments, TBK1 inhibitor, EGFP-TRIM27 reconstitution","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO rescue reconstitution, multiple Co-IPs, TBK1 inhibitor, ATG dependency, mitophagy assay, multiple orthogonal methods in single study","pmids":["36111389"],"is_preprint":false},{"year":2022,"finding":"CLEC16A localizes to early endosomes and interacts with endosomal retromer complex subunits and TRIM27; CLEC16A truncation abolishes both endosomal localization and interaction with TRIM27. CLEC16A knockdown increases TRIM27 adhesion to early endosomes and causes abnormal F-actin accumulation, indicating CLEC16A controls endosomal TRIM27 levels.","method":"Mass spectrometry interactome, co-immunoprecipitation, subcellular fractionation/imaging, domain truncation, CLEC16A knockdown with TRIM27 localization readout","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS interactome plus Co-IP plus functional localization readout, single lab, multiple methods","pmids":["36538041"],"is_preprint":false},{"year":2023,"finding":"WNK1 binds TRIM27 and is required for the TRIM27-USP7 complex formation; WNK1 knockdown reduces TRIM27 protein levels, disrupts WASH complex ubiquitination and endosomal actin polymerization, and increases EGFR degradation after ligand stimulation. TRIM27 depletion phenocopies WNK1 depletion on EGFR trafficking.","method":"Co-immunoprecipitation, WNK1/TRIM27 siRNA knockdown, EGFR degradation assay, endosomal actin polymerization assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, RNAi with functional trafficking readout, pharmacological/genetic parallel, single lab","pmids":["37307465"],"is_preprint":false},{"year":2023,"finding":"TRIM27 stabilizes β-catenin and activates Wnt/β-catenin signaling to promote intestinal stem cell (ISC) self-renewal; Trim27 KO mice display IBS-like symptoms, and organoid formation is disrupted in Trim27-deficient intestinal tissue but rescued by β-catenin reintroduction.","method":"Trim27 KO mouse model, organoid formation assay, β-catenin rescue, Wnt/β-catenin pathway analysis","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse plus organoid rescue, pathway analysis, single lab","pmids":["36596873"],"is_preprint":false},{"year":2024,"finding":"Nuclear-localized TRIM27 acts as a transcriptional activator of TFEB (an autophagy master regulator) by binding to the TFEB promoter and interacting with the transcription factor CREB1, enhancing CREB1 binding to the TFEB promoter to promote autophagy-related gene expression and autophagy flux against Mycobacterium tuberculosis. This activity is E3 ligase-independent.","method":"ChIP-seq, EMSA (electrophoretic mobility shift assay), co-immunoprecipitation, TRIM27 KO cell and mouse model, autophagy flux assay, TFEB activator rescue","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP-seq, EMSA with promoter binding, Co-IP, KO mouse model, pharmacological rescue, multiple orthogonal methods","pmids":["38390831"],"is_preprint":false},{"year":2024,"finding":"TRIM27 ubiquitinates KLF12 at K326 via K33-linked polyubiquitination through its E3 ligase activity, reducing KLF12 transcriptional repression of L1CAM and thereby promoting cisplatin resistance and metastasis in esophageal squamous cell carcinoma.","method":"Co-immunoprecipitation, ubiquitination assay with K33-linkage specificity, domain mapping of interaction, siRNA knockdown, cisplatin resistance assay","journal":"Drug resistance updates","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination, functional drug resistance readout, single lab","pmids":["38924996"],"is_preprint":false}],"current_model":"TRIM27 (RFP/RNF76) is a RING domain-containing E3 ubiquitin ligase that multimerizes via its coiled-coil domain, localizes to the nucleus and to retromer-positive/endosomal structures, and regulates diverse cellular processes by ubiquitinating—and typically degrading—key substrates including TBK1 (K48-linked, suppressing antiviral IFN responses), NOD2, PTEN, ULK1 (K48-linked, restraining autophagy), STK38L (K6/K11-linked, activating a phosphorylation relay to hyper-ubiquitinate ULK1), PI3KC2β (suppressing mast cell signaling), p21, p53, PPARγ, IκBα, PIAS3, SIX3, and KLF12, while also functioning as a non-catalytic transcriptional activator of TFEB to promote autophagy flux; it is stabilized by USP7 (which counteracts its auto-ubiquitination) and is an integral component of the non-canonical PRC1.1 Polycomb complex, facilitating STAT3 activation at retromer structures, and participating in endosomal actin dynamics via the WASH complex, mitophagy via phospho-TBK1, and ISC self-renewal via Wnt/β-catenin."},"narrative":{"mechanistic_narrative":"TRIM27 (RFP/RNF76) is a RING-domain E3 ubiquitin ligase that multimerizes through its coiled-coil domain and acts across nuclear chromatin and endosomal compartments to control immune signaling, autophagy, and cell-fate programs largely by ubiquitinating substrates for degradation or functional modulation [PMID:9247190, PMID:22829933]. Its RING finger is essential for catalytic and transforming activity, while the B-box is dispensable for catalysis but required for proper multimerization and subcellular compartmentalization [PMID:9247190, PMID:8753810]. As a negative regulator of innate and inflammatory signaling, TRIM27 drives K48-linked ubiquitination and proteasomal degradation of TBK1 and NOD2, suppressing type I IFN and pro-inflammatory output, and ubiquitinates PI3KC2β to restrain FcεRI signaling in mast cells [PMID:22829933, PMID:22645315, PMID:26358190]. It restrains autophagy amplitude by polyubiquitinating ULK1 (K48-linked, at K568/K571) and by attaching non-degradative K6/K11 chains to STK38L, which activates STK38L to phosphorylate ULK1 and amplify its TRIM27-dependent ubiquitination [PMID:35670107]. TRIM27 also targets PTEN through atypical polyubiquitination that inhibits phosphatase activity to relieve AKT, and degrades p21, p53, PPARγ, IκBα, PIAS3, SIX3, and KLF12 to promote proliferation, survival, NF-κB/STAT3/β-catenin signaling, and drug resistance in diverse cancers [PMID:23419514, PMID:33264103, PMID:34284744, PMID:38924996]. Independent of its ligase activity, nuclear TRIM27 is a transcriptional activator of the autophagy master regulator TFEB, binding the TFEB promoter together with CREB1 [PMID:38390831], and it associates with the non-canonical PRC1.1 Polycomb complex where its activity is counterbalanced by USP7 [PMID:34113809]. At retromer-positive endosomal structures, TRIM27 is stabilized by USP7 and scaffolds gp130/JAK1/STAT3 to promote STAT3 activation, while its endosomal levels and WASH-complex-dependent actin dynamics are controlled by CLEC16A and WNK1 [PMID:30143645, PMID:29688809, PMID:36538041, PMID:37307465]. TRIM27 additionally stabilizes phospho-TBK1 on mitochondria to promote mitophagy and is itself an autophagy substrate via SQSTM1/p62 [PMID:36111389].","teleology":[{"year":1992,"claim":"Established the earliest biochemical character of the protein—that it is a nuclear-matrix-associated, DNA-binding factor with a testis-specific isoform—framing it as a chromatin-linked regulator.","evidence":"Nuclear matrix fractionation, Western blot, and in vitro DNA-binding assay","pmids":["1437549"],"confidence":"Medium","gaps":["No sequence-specific DNA targets identified","Functional consequence of DNA binding unknown"]},{"year":1996,"claim":"Defined the domain architecture underlying activity: the coiled-coil drives homomultimerization, the B-box supports multimerization and localization, and the RING is required for transforming/catalytic activity.","evidence":"Yeast two-hybrid, deletion/site-directed mutagenesis, NIH 3T3 transformation and localization assays","pmids":["9247190","8753810"],"confidence":"Medium","gaps":["RING-dependent ubiquitin ligase activity not yet demonstrated directly","Transforming activity studied in the RFP/RET fusion context"]},{"year":2002,"claim":"Linked TRIM27 to transcriptional repression and Polycomb-type machinery through interaction with EPC1, with isoform glycosylation tuning the interaction.","evidence":"GST pull-down, Co-IP from mouse testis, O-glycosidase treatment, luciferase reporter","pmids":["11779184"],"confidence":"Medium","gaps":["Target genes of repression not mapped","Mechanism of repression not resolved"]},{"year":2005,"claim":"Showed TRIM27 represses bHLH transcription factors (SCL, E47, MyoD, mASH-1) via HDAC-sensitive, non-degradative means, distinguishing a transcriptional repressor function from its ligase activity.","evidence":"Co-IP, domain mapping, luciferase reporter, trichostatin A treatment","pmids":["16007160"],"confidence":"Medium","gaps":["Direct HDAC/Polycomb recruitment not biochemically defined","Physiological developmental role untested"]},{"year":2012,"claim":"Established TRIM27 as a bona fide E3 ligase that negatively regulates innate immune signaling by K48-ubiquitinating NOD2 for degradation and by inhibiting PI3KC2β in mast cells, with an in vivo anaphylaxis phenotype.","evidence":"Co-IP, in-cell ubiquitination assays, NF-κB reporter, TRIM27-/- mouse and in vivo anaphylaxis model","pmids":["22829933","22645315"],"confidence":"High","gaps":["Linkage chemistry on PI3KC2β not fully defined","Recruitment mechanism to substrates unresolved"]},{"year":2013,"claim":"Connected TRIM27 to apoptosis and PTEN/AKT regulation: it partners with USP7 to control TNF-α-induced apoptosis via RIP1, and atypically ubiquitinates PTEN to inhibit its phosphatase activity without degradation.","evidence":"Reciprocal Co-IP, ubiquitination and phosphatase assays, Trim27-/- MEFs and mice, TNF-α apoptosis assay","pmids":["24144979","23419514"],"confidence":"High","gaps":["Ubiquitin chain type on PTEN not fully characterized","Interplay of USP7 with TRIM27 catalysis incompletely defined at this stage"]},{"year":2014,"claim":"Revealed TRIM27 as both a viral target and a context-dependent host factor: HSV-1 ICP0 degrades TRIM27, yet TRIM27 can positively support infection; separately TRIM27/MRTF-B promote collective cancer invasion via integrin β1.","evidence":"Proteomic screen, Co-IP, proteasome inhibition, RING-mutant ICP0, invasion assays, miRNA reporter","pmids":["25320289","24794433"],"confidence":"Medium","gaps":["Pro- versus anti-viral balance mechanistically unresolved","How MRTF-B/TRIM27 suppress miR-124 not defined"]},{"year":2015,"claim":"Defined the mechanism by which TRIM27 suppresses antiviral IFN: recruited via Siglec1-DAP12-SHP2, it K48-ubiquitinates TBK1 at K251/K372 for degradation.","evidence":"Co-IP, linkage-specific ubiquitination, proteasome inhibitor, site-directed mutagenesis of TBK1, RNAi","pmids":["26358190"],"confidence":"High","gaps":["Spatial site of TBK1 ubiquitination not localized","Regulation of the recruitment axis incompletely defined"]},{"year":2016,"claim":"Extended TRIM27 functions to meiotic chromatin (XY body, with Slx2 and γ-H2AX) and to anti-mycobacterial immunity via JNK/p38 MAPK, with the Mtb effector PtpA antagonizing the RING domain.","evidence":"Yeast/mammalian two-hybrid, Co-IP, immunohistochemistry, macrophage infection and MAPK analysis","pmids":["27612028","27698396"],"confidence":"Medium","gaps":["Functional role in XY body formation not genetically tested","Substrates relevant to MAPK activation not identified"]},{"year":2018,"claim":"Identified the endosomal scaffolding function and a stability-control loop: at retromer puncta TRIM27 assembles gp130/JAK1/STAT3 to drive STAT3 activation, while USP7 stabilizes TRIM27 to sustain TBK1 degradation and IFN suppression.","evidence":"Co-IP, subcellular fractionation/IF, knockdown with STAT3 readout, DSS/AOM colitis model, USP7 KO with IFN reporter","pmids":["30143645","29688809"],"confidence":"High","gaps":["How scaffolding versus ligase functions are partitioned spatially unclear","Determinants of retromer recruitment undefined"]},{"year":2019,"claim":"Showed TRIM27 amplifies STAT3 signaling and AKT signaling in epithelial/cancer contexts by degrading the STAT3 inhibitor PIAS3 and ubiquitinating PTEN.","evidence":"Co-IP, ubiquitination assays, overexpression/silencing, AKT inhibitor rescue, STAT3 phosphorylation readouts","pmids":["31747314","31719796"],"confidence":"Medium","gaps":["Chain linkage on PIAS3 not defined","Tissue specificity of these effects not established"]},{"year":2020,"claim":"Broadened the degradative substrate repertoire driving proliferation/survival programs: TRIM27 degrades SIX3 (activating β-catenin targets), p21 (suppressing senescence), and PPARγ (promoting neuronal apoptosis).","evidence":"Co-IP, ubiquitination assays, knockdown/overexpression, pharmacological rescues (XAV939, rosiglitazone)","pmids":["33264103","33251042","33385414"],"confidence":"Medium","gaps":["Direct versus indirect ubiquitination not uniformly established","Substrate selection determinants unknown"]},{"year":2021,"claim":"Placed TRIM27 in the non-canonical PRC1.1 Polycomb complex (reciprocally with USP7) and connected it to NF-κB and p53 control in disease models, defining roles in chromatin regulation and tissue protection.","evidence":"Co-IP/interactome, ChIP and histone-mark analyses, USP7 inhibitor; ubiquitination assays with NF-κB reporter; heart-conditional KO MI/R model","pmids":["34113809","34284744","33865220"],"confidence":"Medium","gaps":["How PRC1.1 chromatin role relates to cytoplasmic ligase functions unclear","Direct catalytic role within PRC1.1 versus structural role unresolved"]},{"year":2022,"claim":"Resolved a multi-layered autophagy-restraint mechanism and a mitophagy role: TRIM27 K48-ubiquitinates ULK1 (K568/K571) and K6/K11-ubiquitinates STK38L to set up a phosphorylation relay, while stabilizing phospho-TBK1 on mitochondria; TRIM27 is itself degraded by autophagy via p62.","evidence":"In vitro ubiquitination reconstitution, site-directed mutagenesis, kinase assay, KO mice and KO-cell rescue, mitophagy/autophagy flux assays","pmids":["35670107","36111389"],"confidence":"High","gaps":["Signals switching TRIM27 between substrates not defined","Coordination of mitochondrial versus cytosolic pools unclear"]},{"year":2023,"claim":"Defined endosomal regulators and a tissue-homeostasis role: CLEC16A and WNK1 control endosomal TRIM27 levels, WASH-complex ubiquitination, and EGFR trafficking, while TRIM27 stabilizes β-catenin to support intestinal stem cell self-renewal.","evidence":"MS interactome, Co-IP, knockdowns with EGFR/actin readouts; Trim27 KO mice and organoid rescue with β-catenin","pmids":["36538041","37307465","36596873"],"confidence":"Medium","gaps":["Mechanism by which TRIM27 stabilizes β-catenin not defined","WASH substrate(s) of TRIM27 at endosomes not pinpointed"]},{"year":2024,"claim":"Established a ligase-independent transcriptional function—nuclear TRIM27 activates TFEB with CREB1 to promote autophagy against Mtb—and a K33-linked ubiquitination of KLF12 promoting drug resistance, distinguishing catalytic from non-catalytic outputs.","evidence":"ChIP-seq, EMSA, Co-IP, KO cell/mouse, autophagy flux; linkage-specific ubiquitination and cisplatin-resistance assays","pmids":["38390831","38924996"],"confidence":"High","gaps":["Switch between nuclear transcriptional and cytoplasmic ligase roles unresolved","Determinants of K33 versus K48 chain selection unknown"]},{"year":null,"claim":"How TRIM27 selects among its many substrates and chooses ubiquitin chain types (K48 versus atypical K6/K11/K33 versus non-catalytic outputs) across nuclear, endosomal, and mitochondrial pools remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate recognition","Signals partitioning catalytic versus scaffolding/transcriptional functions undefined","Spatial regulation across compartments not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[6,7,9,12,25,31]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,12,25]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[2,25,31]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,30]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,30]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[15,28]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,30]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[15,27,28]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[26]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,7,12,14]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[25,26,30]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,15,23,29]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,12,25,31]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[22]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[8,24]}],"complexes":["PRC1.1 (non-canonical Polycomb)","TRIM27-USP7 complex"],"partners":["USP7","TBK1","PTEN","NOD2","STK38L","ULK1","WNK1","CLEC16A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P14373","full_name":"Zinc finger protein RFP","aliases":["RING finger protein 76","Ret finger protein","Tripartite motif-containing protein 27"],"length_aa":513,"mass_kda":58.5,"function":"E3 ubiquitin-protein ligase that mediates ubiquitination of various substrates and thereby plays a role in diffent processes including proliferation, innate immunity, apoptosis, immune response or autophagy (PubMed:22829933, PubMed:24144979, PubMed:29688809, PubMed:36111389). Ubiquitinates PIK3C2B and inhibits its activity by mediating the formation of 'Lys-48'-linked polyubiquitin chains; the function inhibits CD4 T-cell activation. Acts as a regulator of retrograde transport: together with MAGEL2, mediates the formation of 'Lys-63'-linked polyubiquitin chains at 'Lys-220' of WASHC1, leading to promote endosomal F-actin assembly (PubMed:23452853). Has a transcriptional repressor activity by cooperating with EPC1. Induces apoptosis by activating Jun N-terminal kinase and p38 kinase and also increases caspase-3-like activity independently of mitochondrial events. May function in male germ cell development. Has DNA-binding activity and preferentially bound to double-stranded DNA. Forms a complex with and ubiquitinates the ubiquitin-specific protease USP7, which in turn deubiquitinates RIPK1 resulting in the positive regulation of TNF-induced apoptosis (PubMed:24144979). In addition, acts with USP7 or PTPN11 as an inhibitor of the antiviral signaling pathway by promoting kinase TBK1 ubiquitination and degradation (PubMed:26358190, PubMed:29688809). Acts as a negative regulator of NOD2 signaling by mediating ubiquitination of NOD2, promoting its degradation by the proteasome (PubMed:22829933). Alternatively, facilitates mitophagy via stabilization of active TBK1 (PubMed:36111389). Negatively regulates autophagy flux under basal conditions by directly polyubiquitinating ULK1 (PubMed:35670107). During starvation-induced autophagy, catalyzes non-degradative ubiquitination of the kinase STK38L promoting its activation and phosphorylation of ULK1 leading to its ubiquitination and degradation to restrain the amplitude and duration of autophagy (PubMed:35670107) (Microbial infection) Positively regulates hepatitis C virus replication by suppressing type I IFN response during infection","subcellular_location":"Nucleus; Cytoplasm; Nucleus, PML body; Early endosome; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/P14373/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM27","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HNRNPH1","stoichiometry":0.2},{"gene":"RBM14","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TRIM27","total_profiled":1310},"omim":[{"mim_id":"620334","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 42; TRIM42","url":"https://www.omim.org/entry/620334"},{"mim_id":"616863","title":"HAO-FOUNTAIN SYNDROME; HAFOUS","url":"https://www.omim.org/entry/616863"},{"mim_id":"614041","title":"RB TRANSCRIPTIONAL COREPRESSOR 1; RB1","url":"https://www.omim.org/entry/614041"},{"mim_id":"613184","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 68; TRIM68","url":"https://www.omim.org/entry/613184"},{"mim_id":"612548","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 50; TRIM50","url":"https://www.omim.org/entry/612548"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRIM27"},"hgnc":{"alias_symbol":["RNF76"],"prev_symbol":["RFP"]},"alphafold":{"accession":"P14373","domains":[{"cath_id":"3.30.40.10","chopping":"5-82","consensus_level":"high","plddt":88.9944,"start":5,"end":82},{"cath_id":"2.60.120.920","chopping":"321-488","consensus_level":"high","plddt":92.2012,"start":321,"end":488},{"cath_id":"1.20.5","chopping":"141-259","consensus_level":"medium","plddt":95.7543,"start":141,"end":259}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P14373","model_url":"https://alphafold.ebi.ac.uk/files/AF-P14373-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P14373-F1-predicted_aligned_error_v6.png","plddt_mean":88.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM27","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM27"},"sequence":{"accession":"P14373","fasta_url":"https://rest.uniprot.org/uniprotkb/P14373.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P14373/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P14373"}},"corpus_meta":[{"pmid":"16391121","id":"PMC_16391121","title":"New 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Two forms were detected: a 58 kDa ubiquitous form and a 68 kDa testis-specific form.\",\n      \"method\": \"Western blot, nuclear matrix fractionation, DNA-binding assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear fractionation plus in vitro DNA-binding assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"1437549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"TRIM27 (RFP) homomultimerization occurs through its coiled-coil domain; the B-box domain is not a direct interaction interface but its structural integrity is necessary for coiled-coil-mediated multimerization. Mutations in the RING finger and B-box alter subcellular compartmentalization of RFP in cell lines.\",\n      \"method\": \"Yeast two-hybrid, deletion/mutation analysis, subcellular localization by microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid with domain mutants plus localization, single lab, two orthogonal methods\",\n      \"pmids\": [\"9247190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The RING finger motif of RFP (TRIM27) is critical for the transforming activity of the RFP/RET fusion oncogene; mutation of Cys-16, Cys-31, or His-33 in the RING finger markedly decreased transforming activity and tyrosine phosphorylation, while mutations in the B-box (Cys-118 or His-124) had no effect.\",\n      \"method\": \"Site-directed mutagenesis, NIH 3T3 transformation assay, phosphorylation analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"8753810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Mouse rfp (TRIM27) protein is expressed as nuclear bodies resembling PML oncogenic domains (PODs) in cell nuclei, with highest expression in pachytene spermatocytes and round spermatids during spermatogenesis.\",\n      \"method\": \"Immunofluorescence, immunohistochemistry, subcellular localization in mouse tissues\",\n      \"journal\": \"Developmental genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization by immunofluorescence only, single lab, single method, no functional consequence directly established\",\n      \"pmids\": [\"9023983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"RFP (TRIM27) interacts with Enhancer of Polycomb 1 (EPC1) via the EPcA, EPcB, and CT regions of EPC1. O-glycosylation of the 68 kDa testis form of RFP enhances interaction with the EPC1 CT region; expression of EPcA region impairs transcriptional repressive activity of RFP.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation from mouse testis, O-glycosidase treatment, luciferase reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP from native tissue plus glycosidase treatment plus reporter assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"11779184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RFP (TRIM27) interacts with bHLH transcription factors SCL, E47, MyoD, and mASH-1 (but not GATA-1 or PU.1) through its B-box and first coiled-coil region, and represses transcriptional activation by E47, MyoD, and mASH-1 in a trichostatin A-sensitive manner consistent with HDAC/Polycomb recruitment rather than ubiquitination-mediated degradation of the bHLH proteins.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mapping, luciferase reporter assay, trichostatin A treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping plus functional reporter assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"16007160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM27 functions as an E3 ubiquitin ligase that physically interacts with NOD2 via the nucleotide-binding domain of NOD2; NOD2 activation enhances this interaction. TRIM27-dependent K48-linked ubiquitination of NOD2 leads to proteasomal degradation of NOD2, thereby negatively regulating NOD2-mediated pro-inflammatory signaling.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, siRNA knockdown with NF-κB reporter\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in-cell ubiquitination assay with proteasome inhibitor, functional signaling readout, single lab\",\n      \"pmids\": [\"22829933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM27 negatively regulates FcεRI (IgE receptor) signaling in mast cells by ubiquitinating and inhibiting PI3KC2β; TRIM27-knockout mice show increased susceptibility to anaphylaxis in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, KCa3.1 channel activation assay, TRIM27-/- mouse model, in vivo anaphylaxis model\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ubiquitination assay, knockout mouse phenotype, in vivo model, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"22645315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRIM27 forms a complex with USP7 (ubiquitin-specific protease), ubiquitinates USP7, and this complex controls TNF-α-induced apoptosis. USP7 in this complex deubiquitinates RIP1, which is required for TNF-α apoptotic signaling. Trim27-deficient MEFs and mice are resistant to TNF-α-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Trim27-/- mouse and MEF studies, TNF-α apoptosis assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in-cell ubiquitination assay, KO mouse plus MEF phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"24144979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RFP (TRIM27) acts as a novel E3 ubiquitin ligase for PTEN, promoting atypical (non-K48) polyubiquitination of PTEN that does not affect PTEN stability or localization but inhibits PTEN phosphatase activity, thereby relieving PTEN-mediated inhibition of AKT activation.\",\n      \"method\": \"Co-immunoprecipitation, in-cell ubiquitination assay, RNAi knockdown, PTEN phosphatase activity assay, AKT activation assay\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, phosphatase activity assay, RNAi rescue, single lab\",\n      \"pmids\": [\"23419514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIM27 is a novel degradation target of the HSV-1 E3 ubiquitin ligase ICP0; TRIM27 protein is rapidly lost during HSV-1 infection in a manner dependent on ICP0's RING domain and the proteasome. A RING-mutant ICP0 co-immunoprecipitates endogenous TRIM27. Surprisingly, TRIM27 depletion decreases ICP0-null virus yields, suggesting TRIM27 can positively affect HSV-1 infection.\",\n      \"method\": \"Proteomic screen, co-immunoprecipitation, proteasome inhibitor treatment, RING-domain mutant ICP0, immunofluorescence, siRNA knockdown with viral yield assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, proteasome inhibitor, domain mutagenesis, functional viral yield, single lab\",\n      \"pmids\": [\"25320289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIM27 forms a complex with MRTF-B (myocardin-related transcription factor B) in leading cancer cells and posttranscriptionally upregulates integrin β1 expression via suppression of microRNA-124, enabling integrin β1 mRNA stability and translation specifically in leading cells of collectively invading cancer groups. Depletion of TRIM27 or MRTF-B abrogates integrin β1 upregulation and blocks collective cancer invasion.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, invasion assay in vitro and in vivo, miRNA reporter assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, RNAi with functional invasion readout, miRNA reporter, single lab\",\n      \"pmids\": [\"24794433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM27 is recruited by the Siglec1–DAP12–SHP2 signaling axis and induces K48-linked ubiquitination of TBK1 at Lys251 and Lys372, leading to TBK1 proteasomal degradation and suppression of type I IFN production during viral infection.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with K48-linkage specific analysis, proteasome inhibitor, mutagenesis of TBK1 ubiquitination sites, RNAi knockdown\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, site-specific ubiquitination mutagenesis, proteasome inhibitor, multiple mechanistic layers in single study\",\n      \"pmids\": [\"26358190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIM27 interacts with Slx2 and co-localizes with Slx2 in the XY body of spermatocytes during meiosis; Trim27 also co-localizes with γ-H2AX in the XY body, suggesting a role in XY body formation and meiotic regulation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, mammalian two-hybrid, immunohistochemistry, immunocytochemistry\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, yeast/mammalian two-hybrid and localization, single lab, multiple methods\",\n      \"pmids\": [\"27612028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIM27 functions as a host restriction factor against Mycobacterium tuberculosis by promoting innate immune responses and cell apoptosis via the JNK/p38 MAPK pathway. Mtb effector PtpA antagonizes this function by competitively binding to TRIM27's RING domain.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, macrophage infection assay, MAPK pathway analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, RNAi with infection and signaling readout, competitive binding shown, single lab\",\n      \"pmids\": [\"27698396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM27 localizes to retromer-positive punctate structures and serves as a scaffold recruiting gp130, JAK1, and STAT3 to these structures, facilitating STAT3 phosphorylation downstream of IL-6. Knockdown of TRIM27 impairs IL-6-induced STAT3 activation, inflammatory cytokine expression, and colitis-associated carcinogenesis in mouse models.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation/immunofluorescence, TRIM27 knockdown with STAT3 phosphorylation readout, DSS/AOM mouse colitis model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, localization to retromer structures, in vivo KO mouse model, multiple orthogonal methods, in vitro and in vivo validation\",\n      \"pmids\": [\"30143645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP7 physically interacts with TRIM27, stabilizing it; USP7 overexpression promotes TRIM27-dependent K48-linked ubiquitination and degradation of TBK1, thereby suppressing type I IFN signaling. USP7 knockout leads to enhanced TRIM27 degradation, reduced TBK1 ubiquitination, and enhanced IFN signaling.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, USP7 knockout, overexpression with IFN reporter, viral replication assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, USP7 KO, functional IFN readout, single lab\",\n      \"pmids\": [\"29688809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM27 interacts with and promotes ubiquitination of PIAS3 (a STAT3 inhibitor) in keratinocytes, leading to PIAS3 degradation and enhanced IL-6-induced STAT3 activation, cell proliferation, and inflammation factor production.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, TRIM27 overexpression/silencing, PIAS3 silencing, STAT3 phosphorylation readout\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with ubiquitination assay plus functional signaling readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31747314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM27 directly interacts with PTEN and mediates its poly-ubiquitination in esophageal squamous cell carcinoma cells, activating AKT signaling; AKT inhibitor LY294002 blocks TRIM27's pro-proliferative effects.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, AKT inhibitor treatment, overexpression/knockdown\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, pharmacological rescue, single lab\",\n      \"pmids\": [\"31719796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM27 mediates K48-linked ubiquitination and proteasomal degradation of SIX3 in non-small cell lung cancer cells, thereby activating β-catenin target gene expression (S100P, TGFB3, MMP-9); β-catenin inhibitor XAV939 blocks TRIM27-mediated cell proliferation and invasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, XAV939 inhibitor rescue, cell proliferation and invasion assay\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, pharmacological rescue, single lab\",\n      \"pmids\": [\"33264103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM27 mediates ubiquitination and degradation of p21, thereby suppressing cellular senescence in non-triple-negative breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (coIP), ubiquitination assay, TRIM27 knockdown/overexpression, senescence assay\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP plus ubiquitination assay plus functional senescence readout, single lab\",\n      \"pmids\": [\"33251042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM27 ubiquitinates and degrades PPARγ in neuronal HT22 cells, promoting glutamate-induced apoptosis and IL-1β release; PPARγ agonist rosiglitazone reverses TRIM27 overexpression-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, TRIM27 knockdown/overexpression, rosiglitazone rescue, apoptosis assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, pharmacological rescue, single lab\",\n      \"pmids\": [\"33385414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM27 and USP7 are integral components of the non-canonical PRC1.1 Polycomb complex. USP7 and TRIM27 are reciprocally required for incorporation into PRC1.1; USP7 counteracts TRIM27 E3 ligase activity to maintain PRC1.1 integrity. USP7 inhibition results in PRC1.1 disassembly, loss of chromatin binding, and reduced H2AK119ub and H3K27ac at PRC1.1 target loci.\",\n      \"method\": \"Co-immunoprecipitation/USP7 interactome analysis, ChIP, H2AK119ub and H3K27ac assays, USP7 inhibitor, TRIM27 knockdown, gene expression analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interactome, ChIP, histone mark analysis, functional knockdown, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34113809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM27 directly interacts with IκBα (inhibitor of NF-κB) and promotes its K48-linked ubiquitination, leading to IκBα degradation and NF-κB activation in renal cell carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, NF-κB reporter, TRIM27 overexpression/siRNA knockdown\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, NF-κB reporter, single lab\",\n      \"pmids\": [\"34284744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM27 interacts with p53 and promotes its ubiquitination in cardiomyocytes; heart-conditional TRIM27 knockout exacerbates MI/R injury via enhanced p53 expression, caspase-3 activation, and NF-κB-mediated inflammation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, heart-conditional KO mouse, MI/R model, p53 inhibition rescue\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, conditional KO mouse model, single lab\",\n      \"pmids\": [\"33865220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM27 directly polyubiquitinates ULK1 at K568 and K571 with K48-linked chains (for degradation) and ubiquitinates STK38L with non-degradative K6/K11 chains; STK38L ubiquitination activates it to phosphorylate ULK1 at Ser495, making ULK1 a better substrate for TRIM27-mediated hyper-ubiquitination, thus restraining autophagy amplitude. TRIM27 knockout mice show increased basal autophagy.\",\n      \"method\": \"In vitro ubiquitination assay, site-directed mutagenesis at ubiquitination sites, kinase phosphorylation assay, TRIM27 KO mouse model, autophagy flux assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitination reconstitution, mutagenesis of specific lysine sites, kinase assay, KO mouse with autophagy readout, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"35670107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM27 is an autophagy substrate degraded via ATG7/ATG9-dependent autophagy and interacts with autophagy receptor SQSTM1/p62; induced TRIM27 expression causes mitochondrial clustering facilitated by SQSTM1/p62, and promotes mitophagy by stabilizing phosphorylated TBK1 on mitochondria. TRIM27 KO cells show reduced mitophagy, rescued by EGFP-TRIM27 re-introduction.\",\n      \"method\": \"Co-immunoprecipitation, TRIM27 KO cells, mitophagy assay, immunofluorescence, ATG7/ATG9 dependency experiments, TBK1 inhibitor, EGFP-TRIM27 reconstitution\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO rescue reconstitution, multiple Co-IPs, TBK1 inhibitor, ATG dependency, mitophagy assay, multiple orthogonal methods in single study\",\n      \"pmids\": [\"36111389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CLEC16A localizes to early endosomes and interacts with endosomal retromer complex subunits and TRIM27; CLEC16A truncation abolishes both endosomal localization and interaction with TRIM27. CLEC16A knockdown increases TRIM27 adhesion to early endosomes and causes abnormal F-actin accumulation, indicating CLEC16A controls endosomal TRIM27 levels.\",\n      \"method\": \"Mass spectrometry interactome, co-immunoprecipitation, subcellular fractionation/imaging, domain truncation, CLEC16A knockdown with TRIM27 localization readout\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS interactome plus Co-IP plus functional localization readout, single lab, multiple methods\",\n      \"pmids\": [\"36538041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WNK1 binds TRIM27 and is required for the TRIM27-USP7 complex formation; WNK1 knockdown reduces TRIM27 protein levels, disrupts WASH complex ubiquitination and endosomal actin polymerization, and increases EGFR degradation after ligand stimulation. TRIM27 depletion phenocopies WNK1 depletion on EGFR trafficking.\",\n      \"method\": \"Co-immunoprecipitation, WNK1/TRIM27 siRNA knockdown, EGFR degradation assay, endosomal actin polymerization assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, RNAi with functional trafficking readout, pharmacological/genetic parallel, single lab\",\n      \"pmids\": [\"37307465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM27 stabilizes β-catenin and activates Wnt/β-catenin signaling to promote intestinal stem cell (ISC) self-renewal; Trim27 KO mice display IBS-like symptoms, and organoid formation is disrupted in Trim27-deficient intestinal tissue but rescued by β-catenin reintroduction.\",\n      \"method\": \"Trim27 KO mouse model, organoid formation assay, β-catenin rescue, Wnt/β-catenin pathway analysis\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse plus organoid rescue, pathway analysis, single lab\",\n      \"pmids\": [\"36596873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nuclear-localized TRIM27 acts as a transcriptional activator of TFEB (an autophagy master regulator) by binding to the TFEB promoter and interacting with the transcription factor CREB1, enhancing CREB1 binding to the TFEB promoter to promote autophagy-related gene expression and autophagy flux against Mycobacterium tuberculosis. This activity is E3 ligase-independent.\",\n      \"method\": \"ChIP-seq, EMSA (electrophoretic mobility shift assay), co-immunoprecipitation, TRIM27 KO cell and mouse model, autophagy flux assay, TFEB activator rescue\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP-seq, EMSA with promoter binding, Co-IP, KO mouse model, pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"38390831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM27 ubiquitinates KLF12 at K326 via K33-linked polyubiquitination through its E3 ligase activity, reducing KLF12 transcriptional repression of L1CAM and thereby promoting cisplatin resistance and metastasis in esophageal squamous cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with K33-linkage specificity, domain mapping of interaction, siRNA knockdown, cisplatin resistance assay\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination, functional drug resistance readout, single lab\",\n      \"pmids\": [\"38924996\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM27 (RFP/RNF76) is a RING domain-containing E3 ubiquitin ligase that multimerizes via its coiled-coil domain, localizes to the nucleus and to retromer-positive/endosomal structures, and regulates diverse cellular processes by ubiquitinating—and typically degrading—key substrates including TBK1 (K48-linked, suppressing antiviral IFN responses), NOD2, PTEN, ULK1 (K48-linked, restraining autophagy), STK38L (K6/K11-linked, activating a phosphorylation relay to hyper-ubiquitinate ULK1), PI3KC2β (suppressing mast cell signaling), p21, p53, PPARγ, IκBα, PIAS3, SIX3, and KLF12, while also functioning as a non-catalytic transcriptional activator of TFEB to promote autophagy flux; it is stabilized by USP7 (which counteracts its auto-ubiquitination) and is an integral component of the non-canonical PRC1.1 Polycomb complex, facilitating STAT3 activation at retromer structures, and participating in endosomal actin dynamics via the WASH complex, mitophagy via phospho-TBK1, and ISC self-renewal via Wnt/β-catenin.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM27 (RFP/RNF76) is a RING-domain E3 ubiquitin ligase that multimerizes through its coiled-coil domain and acts across nuclear chromatin and endosomal compartments to control immune signaling, autophagy, and cell-fate programs largely by ubiquitinating substrates for degradation or functional modulation [#1, #6]. Its RING finger is essential for catalytic and transforming activity, while the B-box is dispensable for catalysis but required for proper multimerization and subcellular compartmentalization [#1, #2]. As a negative regulator of innate and inflammatory signaling, TRIM27 drives K48-linked ubiquitination and proteasomal degradation of TBK1 and NOD2, suppressing type I IFN and pro-inflammatory output, and ubiquitinates PI3KC2\\u03b2 to restrain Fc\\u03b5RI signaling in mast cells [#6, #7, #12]. It restrains autophagy amplitude by polyubiquitinating ULK1 (K48-linked, at K568/K571) and by attaching non-degradative K6/K11 chains to STK38L, which activates STK38L to phosphorylate ULK1 and amplify its TRIM27-dependent ubiquitination [#25]. TRIM27 also targets PTEN through atypical polyubiquitination that inhibits phosphatase activity to relieve AKT, and degrades p21, p53, PPAR\\u03b3, I\\u03baB\\u03b1, PIAS3, SIX3, and KLF12 to promote proliferation, survival, NF-\\u03baB/STAT3/\\u03b2-catenin signaling, and drug resistance in diverse cancers [#9, #19, #23, #31]. Independent of its ligase activity, nuclear TRIM27 is a transcriptional activator of the autophagy master regulator TFEB, binding the TFEB promoter together with CREB1 [#30], and it associates with the non-canonical PRC1.1 Polycomb complex where its activity is counterbalanced by USP7 [#22]. At retromer-positive endosomal structures, TRIM27 is stabilized by USP7 and scaffolds gp130/JAK1/STAT3 to promote STAT3 activation, while its endosomal levels and WASH-complex-dependent actin dynamics are controlled by CLEC16A and WNK1 [#15, #16, #27, #28]. TRIM27 additionally stabilizes phospho-TBK1 on mitochondria to promote mitophagy and is itself an autophagy substrate via SQSTM1/p62 [#26].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established the earliest biochemical character of the protein\\u2014that it is a nuclear-matrix-associated, DNA-binding factor with a testis-specific isoform\\u2014framing it as a chromatin-linked regulator.\",\n      \"evidence\": \"Nuclear matrix fractionation, Western blot, and in vitro DNA-binding assay\",\n      \"pmids\": [\"1437549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No sequence-specific DNA targets identified\", \"Functional consequence of DNA binding unknown\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined the domain architecture underlying activity: the coiled-coil drives homomultimerization, the B-box supports multimerization and localization, and the RING is required for transforming/catalytic activity.\",\n      \"evidence\": \"Yeast two-hybrid, deletion/site-directed mutagenesis, NIH 3T3 transformation and localization assays\",\n      \"pmids\": [\"9247190\", \"8753810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RING-dependent ubiquitin ligase activity not yet demonstrated directly\", \"Transforming activity studied in the RFP/RET fusion context\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linked TRIM27 to transcriptional repression and Polycomb-type machinery through interaction with EPC1, with isoform glycosylation tuning the interaction.\",\n      \"evidence\": \"GST pull-down, Co-IP from mouse testis, O-glycosidase treatment, luciferase reporter\",\n      \"pmids\": [\"11779184\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target genes of repression not mapped\", \"Mechanism of repression not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed TRIM27 represses bHLH transcription factors (SCL, E47, MyoD, mASH-1) via HDAC-sensitive, non-degradative means, distinguishing a transcriptional repressor function from its ligase activity.\",\n      \"evidence\": \"Co-IP, domain mapping, luciferase reporter, trichostatin A treatment\",\n      \"pmids\": [\"16007160\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HDAC/Polycomb recruitment not biochemically defined\", \"Physiological developmental role untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established TRIM27 as a bona fide E3 ligase that negatively regulates innate immune signaling by K48-ubiquitinating NOD2 for degradation and by inhibiting PI3KC2\\u03b2 in mast cells, with an in vivo anaphylaxis phenotype.\",\n      \"evidence\": \"Co-IP, in-cell ubiquitination assays, NF-\\u03baB reporter, TRIM27-/- mouse and in vivo anaphylaxis model\",\n      \"pmids\": [\"22829933\", \"22645315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Linkage chemistry on PI3KC2\\u03b2 not fully defined\", \"Recruitment mechanism to substrates unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected TRIM27 to apoptosis and PTEN/AKT regulation: it partners with USP7 to control TNF-\\u03b1-induced apoptosis via RIP1, and atypically ubiquitinates PTEN to inhibit its phosphatase activity without degradation.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination and phosphatase assays, Trim27-/- MEFs and mice, TNF-\\u03b1 apoptosis assay\",\n      \"pmids\": [\"24144979\", \"23419514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin chain type on PTEN not fully characterized\", \"Interplay of USP7 with TRIM27 catalysis incompletely defined at this stage\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed TRIM27 as both a viral target and a context-dependent host factor: HSV-1 ICP0 degrades TRIM27, yet TRIM27 can positively support infection; separately TRIM27/MRTF-B promote collective cancer invasion via integrin \\u03b21.\",\n      \"evidence\": \"Proteomic screen, Co-IP, proteasome inhibition, RING-mutant ICP0, invasion assays, miRNA reporter\",\n      \"pmids\": [\"25320289\", \"24794433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pro- versus anti-viral balance mechanistically unresolved\", \"How MRTF-B/TRIM27 suppress miR-124 not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the mechanism by which TRIM27 suppresses antiviral IFN: recruited via Siglec1-DAP12-SHP2, it K48-ubiquitinates TBK1 at K251/K372 for degradation.\",\n      \"evidence\": \"Co-IP, linkage-specific ubiquitination, proteasome inhibitor, site-directed mutagenesis of TBK1, RNAi\",\n      \"pmids\": [\"26358190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial site of TBK1 ubiquitination not localized\", \"Regulation of the recruitment axis incompletely defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended TRIM27 functions to meiotic chromatin (XY body, with Slx2 and \\u03b3-H2AX) and to anti-mycobacterial immunity via JNK/p38 MAPK, with the Mtb effector PtpA antagonizing the RING domain.\",\n      \"evidence\": \"Yeast/mammalian two-hybrid, Co-IP, immunohistochemistry, macrophage infection and MAPK analysis\",\n      \"pmids\": [\"27612028\", \"27698396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role in XY body formation not genetically tested\", \"Substrates relevant to MAPK activation not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified the endosomal scaffolding function and a stability-control loop: at retromer puncta TRIM27 assembles gp130/JAK1/STAT3 to drive STAT3 activation, while USP7 stabilizes TRIM27 to sustain TBK1 degradation and IFN suppression.\",\n      \"evidence\": \"Co-IP, subcellular fractionation/IF, knockdown with STAT3 readout, DSS/AOM colitis model, USP7 KO with IFN reporter\",\n      \"pmids\": [\"30143645\", \"29688809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How scaffolding versus ligase functions are partitioned spatially unclear\", \"Determinants of retromer recruitment undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed TRIM27 amplifies STAT3 signaling and AKT signaling in epithelial/cancer contexts by degrading the STAT3 inhibitor PIAS3 and ubiquitinating PTEN.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, overexpression/silencing, AKT inhibitor rescue, STAT3 phosphorylation readouts\",\n      \"pmids\": [\"31747314\", \"31719796\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chain linkage on PIAS3 not defined\", \"Tissue specificity of these effects not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Broadened the degradative substrate repertoire driving proliferation/survival programs: TRIM27 degrades SIX3 (activating \\u03b2-catenin targets), p21 (suppressing senescence), and PPAR\\u03b3 (promoting neuronal apoptosis).\",\n      \"evidence\": \"Co-IP, ubiquitination assays, knockdown/overexpression, pharmacological rescues (XAV939, rosiglitazone)\",\n      \"pmids\": [\"33264103\", \"33251042\", \"33385414\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect ubiquitination not uniformly established\", \"Substrate selection determinants unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed TRIM27 in the non-canonical PRC1.1 Polycomb complex (reciprocally with USP7) and connected it to NF-\\u03baB and p53 control in disease models, defining roles in chromatin regulation and tissue protection.\",\n      \"evidence\": \"Co-IP/interactome, ChIP and histone-mark analyses, USP7 inhibitor; ubiquitination assays with NF-\\u03baB reporter; heart-conditional KO MI/R model\",\n      \"pmids\": [\"34113809\", \"34284744\", \"33865220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PRC1.1 chromatin role relates to cytoplasmic ligase functions unclear\", \"Direct catalytic role within PRC1.1 versus structural role unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved a multi-layered autophagy-restraint mechanism and a mitophagy role: TRIM27 K48-ubiquitinates ULK1 (K568/K571) and K6/K11-ubiquitinates STK38L to set up a phosphorylation relay, while stabilizing phospho-TBK1 on mitochondria; TRIM27 is itself degraded by autophagy via p62.\",\n      \"evidence\": \"In vitro ubiquitination reconstitution, site-directed mutagenesis, kinase assay, KO mice and KO-cell rescue, mitophagy/autophagy flux assays\",\n      \"pmids\": [\"35670107\", \"36111389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals switching TRIM27 between substrates not defined\", \"Coordination of mitochondrial versus cytosolic pools unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined endosomal regulators and a tissue-homeostasis role: CLEC16A and WNK1 control endosomal TRIM27 levels, WASH-complex ubiquitination, and EGFR trafficking, while TRIM27 stabilizes \\u03b2-catenin to support intestinal stem cell self-renewal.\",\n      \"evidence\": \"MS interactome, Co-IP, knockdowns with EGFR/actin readouts; Trim27 KO mice and organoid rescue with \\u03b2-catenin\",\n      \"pmids\": [\"36538041\", \"37307465\", \"36596873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which TRIM27 stabilizes \\u03b2-catenin not defined\", \"WASH substrate(s) of TRIM27 at endosomes not pinpointed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a ligase-independent transcriptional function\\u2014nuclear TRIM27 activates TFEB with CREB1 to promote autophagy against Mtb\\u2014and a K33-linked ubiquitination of KLF12 promoting drug resistance, distinguishing catalytic from non-catalytic outputs.\",\n      \"evidence\": \"ChIP-seq, EMSA, Co-IP, KO cell/mouse, autophagy flux; linkage-specific ubiquitination and cisplatin-resistance assays\",\n      \"pmids\": [\"38390831\", \"38924996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Switch between nuclear transcriptional and cytoplasmic ligase roles unresolved\", \"Determinants of K33 versus K48 chain selection unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRIM27 selects among its many substrates and chooses ubiquitin chain types (K48 versus atypical K6/K11/K33 versus non-catalytic outputs) across nuclear, endosomal, and mitochondrial pools remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate recognition\", \"Signals partitioning catalytic versus scaffolding/transcriptional functions undefined\", \"Spatial regulation across compartments not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [6, 7, 9, 12, 25, 31]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 12, 25]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [2, 25, 31]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 30]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 30]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [15, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 30]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [15, 27, 28]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [26]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 7, 12, 14]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [25, 26, 30]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 15, 23, 29]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 12, 25, 31]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [8, 24]}\n    ],\n    \"complexes\": [\n      \"PRC1.1 (non-canonical Polycomb)\",\n      \"TRIM27-USP7 complex\"\n    ],\n    \"partners\": [\n      \"USP7\",\n      \"TBK1\",\n      \"PTEN\",\n      \"NOD2\",\n      \"STK38L\",\n      \"ULK1\",\n      \"WNK1\",\n      \"CLEC16A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}