{"gene":"TRIM33","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2006,"finding":"TIF1γ selectively binds receptor-phosphorylated Smad2/3 in competition with Smad4, forming a distinct branch of the TGFβ pathway. In hematopoietic cells, Smad2/3-TIF1γ mediates erythroid differentiation while Smad2/3-Smad4 mediates the antiproliferative response.","method":"Co-immunoprecipitation, cell-based TGFβ signaling assays, loss-of-function in human hematopoietic stem/progenitor cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP across multiple cell types, genetic loss-of-function with defined phenotypic readouts, replicated in multiple cell lineages","pmids":["16751102"],"is_preprint":false},{"year":1999,"finding":"TIF1γ contains RING finger, B-box, coiled-coil, PHD/TTC, and bromodomain structural motifs. Unlike TIF1α, it does not interact with nuclear receptors or HP1 proteins, but exhibits transcriptional silencing activity dependent on a novel TIF1 signature sequence (TSS).","method":"Yeast two-hybrid, GST pull-down, transfection-based reporter assays, deletion mutagenesis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (Y2H, pulldown, reporter assay, mutagenesis) in a single foundational characterization study","pmids":["10022127"],"is_preprint":false},{"year":2010,"finding":"TIF1γ promotes transcription elongation of erythroid genes by physically interacting with the SCL transcription complex and positive elongation factors p-TEFb and FACT, counteracting RNA Pol II pausing. Loss of Pol II-associated factors PAF or DSIF rescued erythroid gene transcription in tif1γ-deficient zebrafish.","method":"Genetic epistasis in zebrafish moonshine mutants, biochemical co-immunoprecipitation, chromatin immunoprecipitation (ChIP) in human CD34+ cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic suppressor screen, reconstituted physical interactions by Co-IP, ChIP validation in primary human cells, multiple orthogonal methods","pmids":["20603019"],"is_preprint":false},{"year":2011,"finding":"The PHD finger-bromodomain of TIF1γ constitutes a multivalent histone-binding module that specifically binds histone H3 tails unmethylated at K4 and R2 and acetylated at key lysines. Histone binding by this module is required for TIF1γ's E3 ubiquitin ligase activity toward Smad4 and its transcriptional repressor activity; histone binding induces the E3 ligase activity.","method":"In vitro histone-binding assays, mutagenesis of PHD finger-bromodomain, ubiquitin ligase assays, transcriptional reporter assays","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of enzymatic activity, mutagenesis, multiple orthogonal functional assays in one rigorous study","pmids":["21726812"],"is_preprint":false},{"year":2011,"finding":"TRIM33 forms macromolecular complexes with TRIM24 and TRIM28 in hepatocytes. Somatic hepatocyte-specific inactivation of any of the three proteins promotes hepatocellular carcinoma in a cell-autonomous manner, and TRIM33 loss potentiates HCC formation upon TRIM24 inactivation.","method":"Protein purification and mass spectrometry (co-purification), conditional knockout mouse models, genetic interaction studies","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-confirmed protein complexes, in vivo genetic epistasis with multiple conditional knockouts","pmids":["21531907"],"is_preprint":false},{"year":2015,"finding":"TRIM33 acts as an E3 ubiquitin ligase that ubiquitylates nuclear β-catenin, promoting its proteasomal degradation in a GSK-3β- and β-TrCP-independent manner. PKCδ-mediated phosphorylation of β-catenin at Ser715 is required for the TRIM33-β-catenin interaction.","method":"Co-immunoprecipitation, ubiquitylation assays, rescue experiments with kinase inhibitors/mutants, in vivo tumor models","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct ubiquitylation assay, Co-IP, mutagenesis of phosphorylation site, in vivo validation; single lab but multiple orthogonal methods","pmids":["25639486"],"is_preprint":false},{"year":2013,"finding":"TRIM33 is dynamically recruited to DNA damage sites in a PARP1- and ALC1-dependent manner. TRIM33 interacts with the chromatin-remodeling enzyme ALC1 after DNA damage and promotes its timely removal from DNA break sites; TRIM33-deficient cells show enhanced sensitivity to DNA damage and prolonged ALC1 retention.","method":"Proteomic analysis, live-cell imaging of TRIM33 recruitment, PARP inhibitor and ALC1 knockdown epistasis, DNA damage sensitivity assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction, live imaging of recruitment, genetic epistasis with defined phenotype; single lab","pmids":["23926104"],"is_preprint":false},{"year":2015,"finding":"TRIM33 is recruited by PU.1 to a conserved 15 kb upstream region (ICE) of the Ifnb1 gene in macrophages. At late phases of LPS activation, TRIM33 bound to ICE controls Ifnb1 enhanceosome loading and represses Ifnb1 transcription by preventing CBP/p300 recruitment.","method":"ChIP-seq, conditional Trim33 knockout in macrophages, chromatin conformation (loop analysis), luciferase/reporter assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq mapping, conditional KO with defined molecular phenotype, multiple orthogonal methods; single lab but rigorous","pmids":["26592194"],"is_preprint":false},{"year":2011,"finding":"TIF1γ forms complexes with TAL1 and PU.1 in adult hematopoietic cells, occupies specific subsets of their DNA binding sites in vivo, and represses their transcriptional activity, thereby regulating adult hematopoiesis.","method":"Co-immunoprecipitation, ChIP in hematopoietic cells, conditional knockout mouse model with transplantation assays","journal":"Cell Stem Cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP at endogenous loci, in vivo conditional KO with defined cellular phenotypes; single lab but multiple orthogonal approaches","pmids":["21474105"],"is_preprint":false},{"year":2014,"finding":"TIF1γ operates as a SUMO E3 ligase for SnoN1 (but not the isoform SnoN2), promoting SnoN1 sumoylation at distinct lysine residues. This sumoylation is required for SnoN1 to suppress TGFβ-induced EMT in mammary epithelial organoids. A 16-amino acid region unique to SnoN1 mediates the TIF1γ interaction.","method":"Interaction proteomics, in vitro SUMO E3 ligase assay, site-directed mutagenesis, 3D organoid EMT model","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of SUMO ligase activity, mutagenesis of substrate sites, functional 3D organoid validation; single lab with multiple orthogonal methods","pmids":["25059663"],"is_preprint":false},{"year":2013,"finding":"TIF1γ requires sumoylation at four sites within its middle (Smad interaction) domain by Ubc9 for its repressive activity on TGFβ signaling. A sumoylation-defective TIF1γ mutant shows reduced inhibition of Smad complexes and impaired limitation of Smad4 binding at the PAI-1 TGFβ target gene promoter.","method":"Co-immunoprecipitation with Ubc9, SUMO site mutagenesis, chromatin immunoprecipitation, TGFβ reporter assays, EMT assays","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of sumoylation sites, ChIP, reporter assays, multiple orthogonal methods; single lab","pmids":["23788427"],"is_preprint":false},{"year":2019,"finding":"TRIM33 functions as an E3 RING ligase that targets HIV-1 integrase (IN) for proteasomal degradation, restricting HIV-1 infection and proviral DNA formation. TRIM33 knockdown increases HIV-1 replication, while overexpression decreases it; knockdown reverts the phenotype of an IN S57A mutation known to impair integration.","method":"RNAi screen against ubiquitin-conjugation machinery, high-content microscopy, overexpression/knockdown with HIV-1 replication assays, genetic epistasis with IN mutant","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — targeted RNAi screen, genetic epistasis with defined molecular substrate, multiple functional assays; replicated across conditions","pmids":["30804369"],"is_preprint":false},{"year":2018,"finding":"Trim33 is recruited to the Il17a and Il10 gene loci in a Smad2-dependent manner and mediates chromatin remodeling at these loci during Th17 differentiation. Trim33 promotes IL-17 expression and suppresses IL-10 expression, contrasting with Smad4 whose loss enhanced IL-10 production.","method":"Conditional T cell-specific Trim33 knockout, ChIP at Il17a and Il10 loci, in vitro Th17 differentiation assays, in vivo autoimmune disease model","journal":"Journal of Experimental Medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined molecular and cellular phenotypes, ChIP at specific loci, in vivo disease validation; single lab, multiple orthogonal methods","pmids":["29930104"],"is_preprint":false},{"year":2016,"finding":"Adenovirus E4-ORF3 acts as a SUMO E3 ligase for TIF1γ in vitro, directly stimulating its sumoylation and poly-SUMO3 chain formation. E4-ORF3 multimerization is required for these activities; E4-ORF3 facilitates both initial SUMO3 conjugation to TIF1γ and chain elongation.","method":"In vitro sumoylation reconstitution with purified E4-ORF3, TIF1γ substrate assays, SUMO chain elongation assays, E4-ORF3 multimerization mutants","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins, mutagenesis of E4-ORF3 multimerization, direct demonstration of SUMO ligase activity; single lab but rigorous biochemistry","pmids":["27247387"],"is_preprint":false},{"year":2018,"finding":"Nuclear c-Abl tyrosine kinase phosphorylates TIF1γ at Tyr-524, -610, and -1048. Replacing these three tyrosines with phenylalanine (3YF) enhances TIF1γ association with Smad3 and strengthens TIF1γ-mediated suppression of TGFβ signaling. EGF-activated c-Abl phosphorylates TIF1γ to desuppress TGFβ/Smad2/3 signaling and synergize with TGFβ in EMT induction.","method":"Tyrosine phosphorylation mapping, site-directed mutagenesis (3YF), knockdown-rescue experiments, Co-IP, TGFβ signaling reporter assays, EMT assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of phosphorylation sites, knockdown-rescue, Co-IP; single lab with multiple orthogonal methods","pmids":["30177833"],"is_preprint":false},{"year":2014,"finding":"Tif1γ controls TGF-β1 receptor (Tgfbr1) turnover in hematopoietic stem cells, regulating their sensitivity to TGFβ signaling and the balance between myeloid-biased and myeloid-lymphoid-balanced HSC populations. Tif1γ-deficient HSCs phenocopy accelerated aging.","method":"Conditional Tif1γ knockout in HSCs, Tgfbr1 receptor turnover assays, flow cytometric analysis of HSC populations, comparison with aged wild-type HSCs","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with mechanistic follow-up on receptor turnover, multiple HSC population phenotypes; single lab","pmids":["25002492"],"is_preprint":false},{"year":2010,"finding":"Ectodermin/Trim33 functions as a Smad4 inhibitor in vivo that limits Nodal responsiveness in mammalian embryos. Genetic ablation of Ecto leads to excessive Nodal activity affecting anterior visceral endoderm Nodal antagonist expression, trophoblast Nodal-dependent stem cell/differentiation balance, and epiblast mesoderm fate allocation.","method":"Conditional and ubiquitous genetic ablation (Cre/loxP), epistasis with Nodal signaling pathway, phenotypic analysis of multiple embryonic territories","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis across multiple embryonic compartments with consistent mechanistic interpretation, replicated in multiple conditional KO contexts","pmids":["20573697"],"is_preprint":false},{"year":2009,"finding":"Tif1γ inactivation cooperates with oncogenic KrasG12D to induce cystic pancreatic tumors (IPMNs) in mice, demonstrating a tumor suppressor function in the pancreas distinct from that of Smad4 (different histological features despite similar pathway context).","method":"Conditional pancreas-specific Tif1γ knockout, compound Pdx1-Cre;LSL-KrasG12D;Tif1γlox/lox mice, histological and IHC analysis","journal":"PLoS Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with genetic epistasis (Kras and Smad4 comparisons), defined histological phenotype distinguishing Tif1γ from Smad4 function","pmids":["19629168"],"is_preprint":false},{"year":2012,"finding":"Tif1γ tumor-suppressor effects in pancreatic carcinogenesis are independent of Smad4, as shown by accelerated tumor progression in Pdx1-Cre;LSL-KrasG12D;Smad4lox/lox;Tif1γlox/lox quadruple mutant mice progressing through IPMN to PDAC.","method":"Compound conditional knockout mice (quadruple mutant), tumor progression analysis","journal":"American Journal of Pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with quadruple conditional knockout, well-defined tumor progression phenotype","pmids":["22469842"],"is_preprint":false},{"year":2015,"finding":"TIF1γ inactivation causes accumulation of chromosomal defects due to attenuation of both spindle assembly checkpoint and post-mitotic checkpoint activities, indicating TIF1γ promotes chromosomal stability.","method":"TIF1γ knockdown/knockout with mitotic checkpoint assays, chromosomal instability measurements, anchorage-independent growth assays, in vivo tumor models","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined mitotic checkpoint phenotype, in vitro and in vivo; single lab","pmids":["26282171"],"is_preprint":false},{"year":2015,"finding":"TRIM33 is recruited to a PU.1-occupied enhancer upstream of the pro-apoptotic gene Bim in B cell leukemia, where it antagonizes PU.1-mediated Bim activation. Deletion of this single enhancer element renders TRIM33 dispensable for leukemia cell survival.","method":"ChIP-seq, conditional TRIM33 deletion, CRISPR/Cas9 enhancer deletion, PU.1 co-occupancy analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, direct enhancer deletion by genome editing with rescue, rigorous causal link between single element and phenotype","pmids":["25919951"],"is_preprint":false},{"year":2020,"finding":"HSPB5 (crystallin alpha B) directly binds TRIM33, reduces its protein level, and impairs the TRIM33/SMAD4 interaction. Loss of TRIM33 in macrophages increases TGFβ1 secretion and sensitizes to BLM-induced fibrosis; TRIM33 acts as a negative regulator of lung fibrosis through the TGFβ/SMAD pathway.","method":"Direct binding assay (in vitro pull-down), co-immunoprecipitation of TRIM33/HSPB5, conditional Trim33 knockout in hematopoietic cells and lung fibroblasts, 3D lung tissue slice ex vivo","journal":"European Respiratory Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated, Co-IP for TRIM33/SMAD4 complex, multiple in vivo and ex vivo models; single lab","pmids":["32184320"],"is_preprint":false},{"year":2021,"finding":"TIF1γ directly controls the transcription of coenzyme Q (CoQ) biosynthesis genes through transcription elongation. Loss of tif1γ reduces CoQ levels, elevates the succinate/α-ketoglutarate ratio, and leads to increased histone methylation, impairing erythroid differentiation. DHODH inhibition or CoQ analog treatment rescues the bloodless phenotype.","method":"Chemical suppressor screen in zebrafish moonshine mutants, metabolic profiling (CoQ levels, succinate/α-KG ratio), ChIP, CoQ analog rescue","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — chemical genetic suppressor screen, direct metabolic measurements, CoQ analog rescue, ChIP; multiple orthogonal methods in one study","pmids":["33986176"],"is_preprint":false},{"year":2022,"finding":"TRIM33 facilitates androgen receptor (AR) chromatin binding and transcriptional output in prostate cancer cells, and protects AR from Skp2-mediated ubiquitination and proteasomal degradation. TRIM33 knockdown sensitizes prostate cancer cells to AR antagonists.","method":"Proteomics (AR-interactor identification), ChIP-seq, co-immunoprecipitation, ubiquitination assays, knockdown with proliferation/apoptosis readouts","journal":"EMBO Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction, ChIP-seq, direct ubiquitination assay; single lab with multiple orthogonal methods","pmids":["35785414"],"is_preprint":false},{"year":2025,"finding":"TRIM33 does not impact AR protein stability (contradicting a prior report), but instead facilitates maximal AR transcriptional activity by interfering with H2BK120 ubiquitination levels at AR-bound chromatin sites.","method":"ChIP-seq, AR protein stability assays, H2BK120 ubiquitination measurements, multiple prostate cancer cell lines","journal":"Communications Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP-seq and H2BK120 ubiquitination measurement; single lab, single study with finding contradicting prior work; moderate confidence pending replication","pmids":["40646276"],"is_preprint":false},{"year":2024,"finding":"The TRIM33 bromodomain is the sole bromodomain (among 28 tested) that binds histone lysine lactylation (Kla) peptides with submicromolar affinity, also binding lysine acetylation. A unique glutamic acid residue in the TRIM33 bromodomain binding pocket confers selective recognition of Kla; mutagenesis of this residue abolishes selectivity.","method":"AlphaScreen bromodomain screen (28 bromodomains), isothermal titration calorimetry, NMR, site-directed mutagenesis, molecular modeling, X-ray crystallography (referenced in adjacent paper)","journal":"ACS Chemical Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ITC and NMR quantitative binding assays, mutagenesis of key residue, molecular modeling; multiple orthogonal biophysical methods in one study","pmids":["39556662"],"is_preprint":false},{"year":2015,"finding":"Trim33 acts as an E3 ubiquitin ligase for A-MYB, regulating its abundance in testis, and binds RLTR10B LTR elements (of MMERVK10C retrotransposons) in a pattern overlapping A-Myb binding sites, thereby silencing this class of young endogenous retroviruses.","method":"ChIP-seq in testis, RNA-seq in haploinsufficient Trim33 mice, A-MYB ubiquitination assay, transgene reporter screen","journal":"PLoS Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, direct E3 ligase assay for A-MYB, RNA-seq phenotype; single lab, multiple methods","pmids":["26624618"],"is_preprint":false},{"year":2020,"finding":"TRIM33 inhibits CBP-mediated FOXO3a acetylation by binding CBP, thereby attenuating FOXO3a ubiquitylation and degradation. This protects osteoblasts from oxidative stress-induced apoptosis; TRIM33 and FOXO3a co-localize in osteoblast nuclei.","method":"Co-immunoprecipitation of TRIM33/CBP, immunofluorescence co-localization, FOXO3a acetylation/ubiquitylation assays, overexpression/knockdown with apoptosis readouts, in vivo ovariectomy model","journal":"Aging Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, direct acetylation/ubiquitylation assays, in vivo model; single lab with multiple orthogonal methods","pmids":["34101965"],"is_preprint":false},{"year":2023,"finding":"TRIM33 ubiquitin ligase targets E2F4 for degradation in unperturbed cells. Under replicative stress, TRIM33-dependent ubiquitination of E2F4 is blunted, allowing transient E2F4 stabilization and recruitment of the DNA helicase Recql to facilitate DNA replication fork progression. Chronic Trim33 deletion leads to genome-wide Recql recruitment, accelerated replication under stress, impaired checkpoint signaling and DNA repair.","method":"Co-immunoprecipitation of E2F4-Recql, E2F4 ubiquitination assays, ChIP-seq, DNA fiber assays (replication fork progression), conditional Trim33 knockout","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct ubiquitination assay, Co-IP, ChIP-seq, DNA fiber assays, multiple genetic models; single lab but multiple orthogonal methods","pmids":["37612308"],"is_preprint":false},{"year":2022,"finding":"TRIM33 interacts with FACT subunit SPT16 at PU.1-bound distal regulatory elements in macrophages. TRIM33 deficiency leads to FACT release, loss of positioned nucleosomes, RNA Pol II recruitment, and bidirectional transcription at these elements, resulting in increased Atp1b3 expression.","method":"ChIP-seq of TRIM33 and SPT16, Co-immunoprecipitation of TRIM33/SPT16, conditional Trim33 KO macrophages, nucleosome positioning analysis","journal":"Epigenetics & Chromatin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, Co-IP, conditional KO with mechanistic follow-up at defined locus; single lab","pmids":["31331374"],"is_preprint":false},{"year":2022,"finding":"TRIM33 co-localizes with PML nuclear bodies (PML-NBs) specifically in mouse embryonic stem cells (mESCs) but not other cell types, in a PML-dependent manner. TRIM33 and PML co-regulate Lefty1/2 expression downstream of Nodal signaling; PML-NB assembly is required for TRIM33 recruitment to these gene loci.","method":"Co-localization imaging (confocal), TurboID proximity labeling, PML knockout epistasis, ChIP, Nodal signaling reporter assays","journal":"EMBO Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling, genetic epistasis with PML KO, ChIP; cell-type specificity demonstrated; single lab","pmids":["36524443"],"is_preprint":false},{"year":2022,"finding":"TRIM33 acts as an E3 ubiquitin ligase that ubiquitylates TFRC (transferrin receptor), targeting it for proteasomal degradation, thereby promoting ferroptosis susceptibility in hepatocellular carcinoma cells.","method":"Immunoprecipitation, immunofluorescence, ubiquitination assay of TFRC by TRIM33, ferroptosis readouts (MDA, Fe2+ levels, mitochondrial superoxide), in vivo xenograft","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ubiquitination assay, Co-IP, in vivo model; single lab with multiple orthogonal methods","pmids":["38909931"],"is_preprint":false},{"year":2024,"finding":"TRIM33 promotes K48-linked polyubiquitination of p53 at the K351 site, leading to its proteasomal degradation, thereby de-repressing downstream glycolytic target genes (GLUT1, HK2, PKM2, LDHA) and promoting aerobic glycolysis in esophageal squamous cell carcinoma.","method":"Co-immunoprecipitation, K48-linked ubiquitination assay, site-directed mutagenesis of p53 K351, in vitro and in vivo tumor growth assays","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct K48-ubiquitination assay, mutagenesis of ubiquitination site on substrate, in vivo validation; single lab","pmids":["39389957"],"is_preprint":false},{"year":2023,"finding":"TRIM21 forms a complex with TIF1γ/TRIM33 in the nucleus and promotes K48-linked ubiquitination of TIF1γ at K5, leading to its degradation, which increases nuclear β-catenin presence and promotes glioblastoma progression.","method":"Tandem Mass Tags/MS substrate identification, Co-IP, luciferase reporter assays, gain/loss of function with RING-finger deletion mutant, in vivo siRNA treatment","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified substrate, Co-IP, direct ubiquitination site mapping; single lab with multiple orthogonal methods","pmids":["37771771"],"is_preprint":false},{"year":2023,"finding":"YOD1 deubiquitinase stabilizes TRIM33 by suppressing its ubiquitination and degradation, thereby maintaining TRIM33-mediated inhibition of the ERK/β-catenin pathway in head and neck squamous cell carcinoma.","method":"Co-immunoprecipitation, ubiquitination assays, YOD1 knockdown/overexpression with TRIM33 stability readout, in vitro and in vivo tumor assays","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional rescue; single lab","pmids":["37573347"],"is_preprint":false},{"year":2022,"finding":"TRIM33 induces K63-linked ubiquitination of Annexin A2 in keratinocytes, promoting Annexin A2 interaction with p50/p65 NF-κB subunits, retaining them in the nucleus and driving expression of NF-κB downstream inflammatory genes in psoriasis.","method":"Immunoprecipitation combined with mass spectrometry (substrate identification), K63-ubiquitination assay, Co-IP of Anxa2/NF-κB, NF-κB target gene expression, overexpression/knockdown assays","journal":"Journal of Dermatological Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified substrate, direct K63-ubiquitination assay, Co-IP; single lab","pmids":["36096861"],"is_preprint":false},{"year":2017,"finding":"In zebrafish embryos, Trim33 is required cell-autonomously for macrophage colonization of the CNS (microglial seeding) and for basal amoeboid motility and inflammatory recruitment of both macrophages and neutrophils; mouse Trim33-deficient bone marrow-derived macrophages show strongly reduced 3D amoeboid mobility in collagen gels.","method":"Trim33-deficient zebrafish embryo imaging, 3D collagen gel motility assays with mouse Trim33 KO BMDMs, bacterial infection recruitment assay","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging in zebrafish, 3D motility assay in mouse cells; two model organisms, defined cellular phenotype; single lab","pmids":["28724755"],"is_preprint":false},{"year":2024,"finding":"TRIM33 promotes transcription of Irf8 in DC progenitors by maintaining CDK9 and Ser2-phosphorylated RNA Pol II levels at the Irf8 gene, facilitating cDC1 differentiation. TRIM33 also directly suppresses PU.1-mediated transcription of Bcl2l11 (Bim) to prevent apoptosis of DCs and progenitors.","method":"Conditional Trim33 knockout (Trim33fl/fl Cre-ERT2), ChIP for CDK9 and Ser2-Pol II at Irf8 locus, ChIP for PU.1/TRIM33 at Bcl2l11 locus, flow cytometry of DC progenitors","journal":"Cellular & Molecular Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO, ChIP at specific gene loci, defined molecular mechanism at Irf8 and Bcl2l11; single lab","pmids":["38822080"],"is_preprint":false},{"year":2020,"finding":"TRIM33 interacts with β-catenin in mESCs but its RING domain does not function as an E3 ubiquitin ligase for β-catenin in this context (neither KO nor overexpression of TRIM33 affects β-catenin protein levels in mESCs). TRIM33 regulates a subset of Wnt target genes (including Mixl1) independently of its RING domain E3 ligase activity.","method":"Co-immunoprecipitation in mESCs, Trim33 knockout and overexpression with β-catenin protein level measurements, Wnt reporter assay, Wnt target gene expression analysis","journal":"Science China Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, KO/OE with negative β-catenin stability result (important negative finding), Wnt gene expression analysis; single lab","pmids":["28844090"],"is_preprint":false},{"year":2017,"finding":"TRIM33 positively regulates osteoblast differentiation through the BMP pathway by forming a TRIM33-Smad1/5 complex that triggers Smad1/5 phosphorylation.","method":"Co-immunoprecipitation of TRIM33-Smad1/5, phospho-Smad1/5 Western blotting, TRIM33 overexpression/knockdown in C3H10T1/2 and MC3T3-E1 cells with osteoblast differentiation markers","journal":"Journal of Cellular Physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and phosphorylation assay, functional differentiation readouts; single lab, single pulldown method plus functional assay","pmids":["28063228"],"is_preprint":false},{"year":2011,"finding":"Adenovirus E4-ORF3 interacts with TIF1γ through its Coiled-Coil domain and relocalizes endogenous TIF1γ into nuclear track structures in infected cells. The C-terminal half of TIF1β interferes with this interaction, explaining differential targeting of TIF1 family members.","method":"Co-immunoprecipitation in vitro and in infected cells, domain mapping with TIF1 chimeras, immunofluorescence of nuclear relocalization","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro Co-IP domain mapping, in vivo relocalization imaging; single lab, multiple orthogonal methods","pmids":["22123502"],"is_preprint":false},{"year":2021,"finding":"TIF1γ binds TBP in competition with TAF15, impedes TAF15/TBP-mediated IL-6 transactivation, and induces multi-mono-ubiquitylation of TAF15, driving its nuclear export. This suppresses EMT and metastasis of lung adenocarcinoma cells.","method":"Co-immunoprecipitation of TIF1γ/TBP and TIF1γ/TAF15, competition assay, ubiquitylation assay of TAF15, nuclear export assay, EMT/invasion assays","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, direct ubiquitylation assay of TAF15, nuclear export assay; single lab with multiple orthogonal methods","pmids":["36261009"],"is_preprint":false},{"year":2020,"finding":"PIAS1 and TIF1γ form a trimeric complex with SnoN to collaboratively promote SnoN SUMOylation. Loss-of-function studies demonstrate that PIAS1 and TIF1γ act in an interdependent (not additive) manner to suppress EMT in breast cell-derived tissue organoids.","method":"Co-immunoprecipitation of trimeric complex, SUMO ligase assays, knockdown of PIAS1 and/or TIF1γ in 3D organoid EMT model","journal":"Cell Death and Differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — trimeric complex Co-IP, in vitro SUMO assay, 3D organoid functional validation; single lab","pmids":["32770107"],"is_preprint":false},{"year":2024,"finding":"TRIM33 loss in multiple myeloma leads to dysregulated ubiquitination of ALC1, impaired non-homologous end joining (NHEJ), accumulation of DNA double strand breaks, and sensitization to PARP inhibitor Olaparib. This effect is synergistic with bortezomib.","method":"TRIM33 knockdown in MM cells, NHEJ efficiency assay, DNA damage (DSB) quantification, ALC1 ubiquitination assay, PARP inhibitor sensitivity assay, co-culture with bone marrow stromal cells","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ALC1 ubiquitination assay, NHEJ assay, mechanistic follow-up on DDR; single lab","pmids":["38627415"],"is_preprint":false},{"year":2022,"finding":"In the context of sepsis, parthenolide (PA) covalently targets TRIM33 via cysteine engagement, functionally binding TRIM33 to reduce Smad4 ubiquitin-dependent degradation, thereby suppressing NF-κB pathway activation and inflammation.","method":"Streamlined cysteine ABPP (activity-based protein profiling) chemoproteomics, proteomics, Co-IP, NF-κB reporter assays, in vivo CLP sepsis model","journal":"Phytomedicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — chemoproteomics hit identification with Co-IP validation, single lab, limited mechanistic depth on TRIM33-Smad4 ubiquitination","pmids":["41702258"],"is_preprint":false}],"current_model":"TRIM33 (TIF1γ) is a multifunctional nuclear E3 ubiquitin/SUMO ligase and chromatin reader that (1) competes with Smad4 for binding to receptor-phosphorylated Smad2/3, thereby branching TGFβ signaling to control cell fate; (2) promotes transcription elongation of lineage-specific genes through physical interaction with p-TEFb, FACT, and the SCL complex; (3) uses its PHD finger-bromodomain—activated by binding unmethylated/acetylated histone H3 tails and, uniquely, histone lysine lactylation—to ubiquitylate Smad4 and repress TGFβ target genes; (4) acts as an E3 ubiquitin ligase for multiple substrates including nuclear β-catenin, HIV-1 integrase, TFRC, TAF15, A-MYB, p53, and E2F4, and as a SUMO E3 ligase for SnoN1; (5) forms regulatory complexes with TRIM24 and TRIM28 to suppress hepatocellular carcinoma; (6) is recruited to specific enhancers by PU.1 to repress Ifnb1 and modulate macrophage-specific inflammatory gene programs; and (7) controls DNA replication fork integrity by regulating E2F4 stability and Recql helicase recruitment under replicative stress."},"narrative":{"mechanistic_narrative":"TRIM33 (TIF1γ) is a multidomain nuclear factor that integrates TGFβ/Nodal/BMP signaling with chromatin regulation to control cell fate decisions, hematopoiesis, and tumor suppression [PMID:16751102, PMID:20573697]. It establishes a distinct branch of TGFβ signaling by selectively binding receptor-phosphorylated Smad2/3 in competition with Smad4, routing the pathway toward differentiation rather than the antiproliferative response [PMID:16751102], and acts in vivo as a Smad4 inhibitor that limits Nodal responsiveness during embryonic patterning [PMID:20573697]. Architecturally TRIM33 carries RING, B-box, coiled-coil, PHD finger, and bromodomain motifs and possesses intrinsic transcriptional silencing activity [PMID:10022127]; its PHD finger–bromodomain forms a multivalent histone-binding module that reads H3 tails unmethylated at K4/R2 and acetylated at key lysines, and this histone engagement licenses its E3 ubiquitin ligase activity toward Smad4 and its repressive output [PMID:21726812]. The bromodomain uniquely recognizes histone lysine lactylation through a distinguishing glutamate in its binding pocket [PMID:39556662]. Beyond chromatin reading, TRIM33 promotes transcription elongation of lineage-specific genes by partnering with the SCL/TAL1 complex and the elongation factors p-TEFb and FACT to relieve RNA Pol II pausing [PMID:20603019, PMID:21474105], a function extended to coenzyme Q biosynthesis genes whose loss perturbs erythroid differentiation through metabolite-driven histone hypermethylation [PMID:33986176]. As an E3 ubiquitin ligase TRIM33 targets a range of substrates—including HIV-1 integrase to restrict infection [PMID:30804369], TFRC to promote ferroptosis [PMID:38909931], p53 to de-repress glycolysis [PMID:39389957], and E2F4 to govern replication fork integrity via Recql recruitment under stress [PMID:37612308]—and acts as a SUMO E3 ligase for SnoN1 to suppress TGFβ-driven EMT [PMID:25059663]. It forms regulatory complexes with TRIM24 and TRIM28 that suppress hepatocellular carcinoma [PMID:21531907] and operates as a tumor suppressor in pancreas independent of Smad4 [PMID:19629168, PMID:22469842]. In immune cells, TRIM33 is recruited by PU.1 to specific enhancers to repress Ifnb1, Bim, and other targets, tuning macrophage, dendritic cell, and lymphocyte programs [PMID:26592194, PMID:25919951, PMID:38822080].","teleology":[{"year":1999,"claim":"Established the domain architecture and intrinsic activity of TIF1γ, distinguishing it from other TIF1 family members.","evidence":"Yeast two-hybrid, GST pull-down, reporter assays and deletion mutagenesis defining RING/B-box/coiled-coil/PHD/bromodomain motifs and a TIF1 signature sequence","pmids":["10022127"],"confidence":"High","gaps":["No physiological substrate or chromatin target identified at this stage","Functional consequence of silencing activity in vivo unknown"]},{"year":2006,"claim":"Defined TIF1γ as a competitor of Smad4 for phospho-Smad2/3, creating a branch point that directs TGFβ signaling toward differentiation.","evidence":"Co-IP and loss-of-function in human hematopoietic stem/progenitor cells with differentiation readouts","pmids":["16751102"],"confidence":"High","gaps":["Molecular basis of selective Smad2/3 recognition not structurally resolved","Whether competition is regulated post-translationally not addressed"]},{"year":2010,"claim":"Resolved how TIF1γ activates lineage genes mechanistically and how it acts as an in vivo Smad4 inhibitor in embryos.","evidence":"Zebrafish moonshine genetic epistasis with elongation factors plus Co-IP/ChIP; conditional Nodal-pathway ablation in mouse embryos","pmids":["20603019","20573697"],"confidence":"High","gaps":["How elongation-promoting and Smad4-inhibitory functions are coordinated unclear","Direct recruitment mechanism to elongation machinery not fully defined"]},{"year":2011,"claim":"Connected chromatin reading to enzymatic output and placed TRIM33 in tumor-suppressive multi-TRIM complexes and hematopoietic TF complexes.","evidence":"In vitro histone binding, ligase and reporter assays (Mol Cell); MS co-purification with conditional KO mice (PNAS); Co-IP/ChIP with TAL1/PU.1 and conditional KO (Cell Stem Cell)","pmids":["21726812","21531907","21474105"],"confidence":"High","gaps":["Stoichiometry and assembly of TRIM24/28/33 complexes unresolved","How histone marks toggle ligase activity structurally undefined"]},{"year":2013,"claim":"Extended TRIM33 function to DNA damage response and post-translational control of its own repressive activity by SUMOylation.","evidence":"Proteomics, live imaging and PARP1/ALC1 epistasis (JBC); SUMO-site mutagenesis with ChIP/reporter assays (J Cell Sci)","pmids":["23926104","23788427"],"confidence":"Medium","gaps":["Whether TRIM33 ubiquitylates ALC1 at this stage not shown","Link between SUMOylation and chromatin recruitment incomplete"]},{"year":2015,"claim":"Diversified TRIM33's substrate repertoire and enhancer-targeted repression, identifying β-catenin ubiquitylation, PU.1-directed Bim repression, Ifnb1 control, and a chromosomal-stability role.","evidence":"Ubiquitylation/Co-IP with kinase mutants (Nat Commun); ChIP-seq with CRISPR enhancer deletion (eLife); ChIP-seq/conditional KO in macrophages (Nat Commun); mitotic checkpoint assays (Cancer Res)","pmids":["25639486","25919951","26592194","26282171"],"confidence":"High","gaps":["Generalizability of β-catenin ubiquitylation across cell types untested (later contradicted in mESCs)","How PU.1 recruits TRIM33 to specific enhancers undefined"]},{"year":2015,"claim":"Established SUMO ligase activity toward SnoN1 and a testis-specific role silencing endogenous retroviruses via A-MYB ubiquitylation.","evidence":"In vitro SUMO ligase and organoid EMT assays (JBC); ChIP-seq, RNA-seq and A-MYB ubiquitination in testis (PLoS Genet)","pmids":["25059663","26624618"],"confidence":"High","gaps":["Isoform selectivity determinants for SnoN1 vs SnoN2 only partly mapped","In vivo consequence of ERV de-silencing on fertility not fully quantified"]},{"year":2017,"claim":"Broadened TRIM33's signaling reach to BMP-driven osteoblast differentiation, PML-body localization in stem cells, and myeloid cell motility.","evidence":"Co-IP/phospho-Smad1/5 assays in osteoblast lines; zebrafish imaging and 3D motility assays in macrophages","pmids":["28063228","28724755"],"confidence":"Medium","gaps":["Mechanism of Smad1/5 phosphorylation promotion by TRIM33 unclear","Molecular driver of amoeboid motility defect not identified"]},{"year":2019,"claim":"Showed TRIM33 RING-ligase activity restricts viral integration and contributes negatively to fibrotic and Th17/Treg-type immune programs.","evidence":"RNAi screen with HIV-1 replication and IN-mutant epistasis (Nat Commun); conditional T-cell KO with ChIP and autoimmune model (JEM)","pmids":["30804369","29930104"],"confidence":"High","gaps":["Direct ubiquitin transfer to integrase not biochemically reconstituted","How Smad2-dependent recruitment to Il17a/Il10 loci occurs unresolved"]},{"year":2022,"claim":"Linked TRIM33 transcription-elongation control to coenzyme Q metabolism and detailed FACT-dependent enhancer regulation and PML-body co-regulation of Nodal targets.","evidence":"Chemical suppressor screen with metabolic profiling and CoQ rescue (Science); ChIP-seq/Co-IP with SPT16 (Epigenetics Chromatin); TurboID and PML-KO epistasis (EMBO J)","pmids":["33986176","31331374","36524443"],"confidence":"High","gaps":["Direct vs indirect control of CoQ genes via metabolite feedback hard to separate","Cell-type specificity of PML-body recruitment mechanism undefined"]},{"year":2023,"claim":"Established E2F4/Recql-dependent control of replication fork integrity and identified upstream regulators (TRIM21, YOD1) governing TRIM33 stability.","evidence":"E2F4 ubiquitination, Co-IP, ChIP-seq and DNA fiber assays with conditional KO (Nat Commun); MS/Co-IP/ubiquitin-site mapping (Theranostics, Cell Death Dis)","pmids":["37612308","37771771","37573347"],"confidence":"High","gaps":["How replicative stress blunts E2F4 ubiquitylation mechanistically unclear","Interplay of TRIM21 degradation and YOD1 stabilization not jointly studied"]},{"year":2024,"claim":"Defined the bromodomain's unique lactyl-lysine recognition and expanded substrate/target roles across p53-glycolysis, AR transcription, NHEJ, and dendritic-cell programs.","evidence":"ITC/NMR/mutagenesis bromodomain screen (ACS Chem Biol); K48-ubiquitination of p53 (Cell Death Dis); ChIP-seq/H2BK120ub (Commun Biol); ALC1-ubiquitination NHEJ assays (Sci Rep); conditional KO with ChIP at Irf8/Bcl2l11 (CMI)","pmids":["39556662","39389957","40646276","38627415","38822080"],"confidence":"Medium","gaps":["Whether TRIM33 affects AR protein stability remains contradictory across studies (#23 vs #24)","Physiological writers/erasers of the lactyl mark read by TRIM33 unknown"]},{"year":null,"claim":"How TRIM33's many enzymatic activities (ubiquitin and SUMO ligase) and chromatin-reading functions are selectively deployed across cell types and substrates remains the central open question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model linking histone-mark recognition to substrate choice","Determinants of context-specific substrate selection (β-catenin, p53, TFRC, E2F4, AR) undefined","Cell-type-specific contradictory phenotypes (e.g. β-catenin, AR) unreconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,5,11,28,31,32]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[3,9,11,28,31,32]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3,25]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,7,8]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[8,26]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,27,33]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2,8,28]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[30]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,16,39]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,7,8,22]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[6,28,43]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,11,12,37]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,17,18,32]}],"complexes":["TRIM24/TRIM28/TRIM33 complex","SCL/TAL1 complex","PIAS1-TIF1γ-SnoN SUMOylation complex"],"partners":["SMAD4","SMAD2/3","PU.1","TAL1","TRIM24","TRIM28","SPT16","TRIM21"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UPN9","full_name":"E3 ubiquitin-protein ligase TRIM33","aliases":["Ectodermin homolog","RET-fused gene 7 protein","Protein Rfg7","RING-type E3 ubiquitin transferase TRIM33","Transcription intermediary factor 1-gamma","TIF1-gamma","Tripartite motif-containing protein 33"],"length_aa":1127,"mass_kda":122.5,"function":"Acts as an E3 ubiquitin-protein ligase. Promotes SMAD4 ubiquitination, nuclear exclusion and degradation via the ubiquitin proteasome pathway. According to PubMed:16751102, does not promote a decrease in the level of endogenous SMAD4. May act as a transcriptional repressor. Inhibits the transcriptional response to TGF-beta/BMP signaling cascade. Plays a role in the control of cell proliferation. Its association with SMAD2 and SMAD3 stimulates erythroid differentiation of hematopoietic stem/progenitor (By similarity). Monoubiquitinates SMAD4 and acts as an inhibitor of SMAD4-dependent TGF-beta/BMP signaling cascade (Monoubiquitination of SMAD4 hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UPN9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM33","classification":"Not Classified","n_dependent_lines":39,"n_total_lines":1208,"dependency_fraction":0.03228476821192053},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000197323","cell_line_id":"CID001293","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"nuclear_punctae","grade":2}],"interactors":[{"gene":"TRIM24","stoichiometry":10.0},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"TRIM28","stoichiometry":0.2},{"gene":"JUN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001293","total_profiled":1310},"omim":[{"mim_id":"621311","title":"DEVELOPMENTAL DYSPLASIA OF THE HIP 4; DDH4","url":"https://www.omim.org/entry/621311"},{"mim_id":"617354","title":"CHROMOBOX 8; CBX8","url":"https://www.omim.org/entry/617354"},{"mim_id":"612000","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 66; TRIM66","url":"https://www.omim.org/entry/612000"},{"mim_id":"605769","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 33; TRIM33","url":"https://www.omim.org/entry/605769"},{"mim_id":"603149","title":"INTERLEUKIN 17A; IL17A","url":"https://www.omim.org/entry/603149"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRIM33"},"hgnc":{"alias_symbol":["TIF1GAMMA","FLJ11429","KIAA1113","TIFGAMMA","RFG7","TF1G","TIF1G","PTC7"],"prev_symbol":[]},"alphafold":{"accession":"Q9UPN9","domains":[{"cath_id":"3.30.40","chopping":"120-203","consensus_level":"medium","plddt":75.8813,"start":120,"end":203},{"cath_id":"-","chopping":"216-264","consensus_level":"medium","plddt":84.8016,"start":216,"end":264},{"cath_id":"-","chopping":"325-456","consensus_level":"high","plddt":90.1011,"start":325,"end":456},{"cath_id":"1.20.920.10","chopping":"901-945_958-1051_1058-1082","consensus_level":"medium","plddt":87.7222,"start":901,"end":1082}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPN9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPN9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPN9-F1-predicted_aligned_error_v6.png","plddt_mean":60.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM33","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM33"},"sequence":{"accession":"Q9UPN9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UPN9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UPN9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPN9"}},"corpus_meta":[{"pmid":"16751102","id":"PMC_16751102","title":"Hematopoiesis 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In hematopoietic cells, Smad2/3-TIF1γ mediates erythroid differentiation while Smad2/3-Smad4 mediates the antiproliferative response.\",\n      \"method\": \"Co-immunoprecipitation, cell-based TGFβ signaling assays, loss-of-function in human hematopoietic stem/progenitor cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP across multiple cell types, genetic loss-of-function with defined phenotypic readouts, replicated in multiple cell lineages\",\n      \"pmids\": [\"16751102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"TIF1γ contains RING finger, B-box, coiled-coil, PHD/TTC, and bromodomain structural motifs. Unlike TIF1α, it does not interact with nuclear receptors or HP1 proteins, but exhibits transcriptional silencing activity dependent on a novel TIF1 signature sequence (TSS).\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, transfection-based reporter assays, deletion mutagenesis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (Y2H, pulldown, reporter assay, mutagenesis) in a single foundational characterization study\",\n      \"pmids\": [\"10022127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TIF1γ promotes transcription elongation of erythroid genes by physically interacting with the SCL transcription complex and positive elongation factors p-TEFb and FACT, counteracting RNA Pol II pausing. Loss of Pol II-associated factors PAF or DSIF rescued erythroid gene transcription in tif1γ-deficient zebrafish.\",\n      \"method\": \"Genetic epistasis in zebrafish moonshine mutants, biochemical co-immunoprecipitation, chromatin immunoprecipitation (ChIP) in human CD34+ cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic suppressor screen, reconstituted physical interactions by Co-IP, ChIP validation in primary human cells, multiple orthogonal methods\",\n      \"pmids\": [\"20603019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The PHD finger-bromodomain of TIF1γ constitutes a multivalent histone-binding module that specifically binds histone H3 tails unmethylated at K4 and R2 and acetylated at key lysines. Histone binding by this module is required for TIF1γ's E3 ubiquitin ligase activity toward Smad4 and its transcriptional repressor activity; histone binding induces the E3 ligase activity.\",\n      \"method\": \"In vitro histone-binding assays, mutagenesis of PHD finger-bromodomain, ubiquitin ligase assays, transcriptional reporter assays\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of enzymatic activity, mutagenesis, multiple orthogonal functional assays in one rigorous study\",\n      \"pmids\": [\"21726812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRIM33 forms macromolecular complexes with TRIM24 and TRIM28 in hepatocytes. Somatic hepatocyte-specific inactivation of any of the three proteins promotes hepatocellular carcinoma in a cell-autonomous manner, and TRIM33 loss potentiates HCC formation upon TRIM24 inactivation.\",\n      \"method\": \"Protein purification and mass spectrometry (co-purification), conditional knockout mouse models, genetic interaction studies\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-confirmed protein complexes, in vivo genetic epistasis with multiple conditional knockouts\",\n      \"pmids\": [\"21531907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM33 acts as an E3 ubiquitin ligase that ubiquitylates nuclear β-catenin, promoting its proteasomal degradation in a GSK-3β- and β-TrCP-independent manner. PKCδ-mediated phosphorylation of β-catenin at Ser715 is required for the TRIM33-β-catenin interaction.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, rescue experiments with kinase inhibitors/mutants, in vivo tumor models\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct ubiquitylation assay, Co-IP, mutagenesis of phosphorylation site, in vivo validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25639486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRIM33 is dynamically recruited to DNA damage sites in a PARP1- and ALC1-dependent manner. TRIM33 interacts with the chromatin-remodeling enzyme ALC1 after DNA damage and promotes its timely removal from DNA break sites; TRIM33-deficient cells show enhanced sensitivity to DNA damage and prolonged ALC1 retention.\",\n      \"method\": \"Proteomic analysis, live-cell imaging of TRIM33 recruitment, PARP inhibitor and ALC1 knockdown epistasis, DNA damage sensitivity assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction, live imaging of recruitment, genetic epistasis with defined phenotype; single lab\",\n      \"pmids\": [\"23926104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM33 is recruited by PU.1 to a conserved 15 kb upstream region (ICE) of the Ifnb1 gene in macrophages. At late phases of LPS activation, TRIM33 bound to ICE controls Ifnb1 enhanceosome loading and represses Ifnb1 transcription by preventing CBP/p300 recruitment.\",\n      \"method\": \"ChIP-seq, conditional Trim33 knockout in macrophages, chromatin conformation (loop analysis), luciferase/reporter assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq mapping, conditional KO with defined molecular phenotype, multiple orthogonal methods; single lab but rigorous\",\n      \"pmids\": [\"26592194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TIF1γ forms complexes with TAL1 and PU.1 in adult hematopoietic cells, occupies specific subsets of their DNA binding sites in vivo, and represses their transcriptional activity, thereby regulating adult hematopoiesis.\",\n      \"method\": \"Co-immunoprecipitation, ChIP in hematopoietic cells, conditional knockout mouse model with transplantation assays\",\n      \"journal\": \"Cell Stem Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP at endogenous loci, in vivo conditional KO with defined cellular phenotypes; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"21474105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TIF1γ operates as a SUMO E3 ligase for SnoN1 (but not the isoform SnoN2), promoting SnoN1 sumoylation at distinct lysine residues. This sumoylation is required for SnoN1 to suppress TGFβ-induced EMT in mammary epithelial organoids. A 16-amino acid region unique to SnoN1 mediates the TIF1γ interaction.\",\n      \"method\": \"Interaction proteomics, in vitro SUMO E3 ligase assay, site-directed mutagenesis, 3D organoid EMT model\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of SUMO ligase activity, mutagenesis of substrate sites, functional 3D organoid validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25059663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TIF1γ requires sumoylation at four sites within its middle (Smad interaction) domain by Ubc9 for its repressive activity on TGFβ signaling. A sumoylation-defective TIF1γ mutant shows reduced inhibition of Smad complexes and impaired limitation of Smad4 binding at the PAI-1 TGFβ target gene promoter.\",\n      \"method\": \"Co-immunoprecipitation with Ubc9, SUMO site mutagenesis, chromatin immunoprecipitation, TGFβ reporter assays, EMT assays\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of sumoylation sites, ChIP, reporter assays, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"23788427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM33 functions as an E3 RING ligase that targets HIV-1 integrase (IN) for proteasomal degradation, restricting HIV-1 infection and proviral DNA formation. TRIM33 knockdown increases HIV-1 replication, while overexpression decreases it; knockdown reverts the phenotype of an IN S57A mutation known to impair integration.\",\n      \"method\": \"RNAi screen against ubiquitin-conjugation machinery, high-content microscopy, overexpression/knockdown with HIV-1 replication assays, genetic epistasis with IN mutant\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — targeted RNAi screen, genetic epistasis with defined molecular substrate, multiple functional assays; replicated across conditions\",\n      \"pmids\": [\"30804369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Trim33 is recruited to the Il17a and Il10 gene loci in a Smad2-dependent manner and mediates chromatin remodeling at these loci during Th17 differentiation. Trim33 promotes IL-17 expression and suppresses IL-10 expression, contrasting with Smad4 whose loss enhanced IL-10 production.\",\n      \"method\": \"Conditional T cell-specific Trim33 knockout, ChIP at Il17a and Il10 loci, in vitro Th17 differentiation assays, in vivo autoimmune disease model\",\n      \"journal\": \"Journal of Experimental Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined molecular and cellular phenotypes, ChIP at specific loci, in vivo disease validation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29930104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Adenovirus E4-ORF3 acts as a SUMO E3 ligase for TIF1γ in vitro, directly stimulating its sumoylation and poly-SUMO3 chain formation. E4-ORF3 multimerization is required for these activities; E4-ORF3 facilitates both initial SUMO3 conjugation to TIF1γ and chain elongation.\",\n      \"method\": \"In vitro sumoylation reconstitution with purified E4-ORF3, TIF1γ substrate assays, SUMO chain elongation assays, E4-ORF3 multimerization mutants\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins, mutagenesis of E4-ORF3 multimerization, direct demonstration of SUMO ligase activity; single lab but rigorous biochemistry\",\n      \"pmids\": [\"27247387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nuclear c-Abl tyrosine kinase phosphorylates TIF1γ at Tyr-524, -610, and -1048. Replacing these three tyrosines with phenylalanine (3YF) enhances TIF1γ association with Smad3 and strengthens TIF1γ-mediated suppression of TGFβ signaling. EGF-activated c-Abl phosphorylates TIF1γ to desuppress TGFβ/Smad2/3 signaling and synergize with TGFβ in EMT induction.\",\n      \"method\": \"Tyrosine phosphorylation mapping, site-directed mutagenesis (3YF), knockdown-rescue experiments, Co-IP, TGFβ signaling reporter assays, EMT assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of phosphorylation sites, knockdown-rescue, Co-IP; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30177833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Tif1γ controls TGF-β1 receptor (Tgfbr1) turnover in hematopoietic stem cells, regulating their sensitivity to TGFβ signaling and the balance between myeloid-biased and myeloid-lymphoid-balanced HSC populations. Tif1γ-deficient HSCs phenocopy accelerated aging.\",\n      \"method\": \"Conditional Tif1γ knockout in HSCs, Tgfbr1 receptor turnover assays, flow cytometric analysis of HSC populations, comparison with aged wild-type HSCs\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with mechanistic follow-up on receptor turnover, multiple HSC population phenotypes; single lab\",\n      \"pmids\": [\"25002492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Ectodermin/Trim33 functions as a Smad4 inhibitor in vivo that limits Nodal responsiveness in mammalian embryos. Genetic ablation of Ecto leads to excessive Nodal activity affecting anterior visceral endoderm Nodal antagonist expression, trophoblast Nodal-dependent stem cell/differentiation balance, and epiblast mesoderm fate allocation.\",\n      \"method\": \"Conditional and ubiquitous genetic ablation (Cre/loxP), epistasis with Nodal signaling pathway, phenotypic analysis of multiple embryonic territories\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis across multiple embryonic compartments with consistent mechanistic interpretation, replicated in multiple conditional KO contexts\",\n      \"pmids\": [\"20573697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Tif1γ inactivation cooperates with oncogenic KrasG12D to induce cystic pancreatic tumors (IPMNs) in mice, demonstrating a tumor suppressor function in the pancreas distinct from that of Smad4 (different histological features despite similar pathway context).\",\n      \"method\": \"Conditional pancreas-specific Tif1γ knockout, compound Pdx1-Cre;LSL-KrasG12D;Tif1γlox/lox mice, histological and IHC analysis\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with genetic epistasis (Kras and Smad4 comparisons), defined histological phenotype distinguishing Tif1γ from Smad4 function\",\n      \"pmids\": [\"19629168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Tif1γ tumor-suppressor effects in pancreatic carcinogenesis are independent of Smad4, as shown by accelerated tumor progression in Pdx1-Cre;LSL-KrasG12D;Smad4lox/lox;Tif1γlox/lox quadruple mutant mice progressing through IPMN to PDAC.\",\n      \"method\": \"Compound conditional knockout mice (quadruple mutant), tumor progression analysis\",\n      \"journal\": \"American Journal of Pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with quadruple conditional knockout, well-defined tumor progression phenotype\",\n      \"pmids\": [\"22469842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TIF1γ inactivation causes accumulation of chromosomal defects due to attenuation of both spindle assembly checkpoint and post-mitotic checkpoint activities, indicating TIF1γ promotes chromosomal stability.\",\n      \"method\": \"TIF1γ knockdown/knockout with mitotic checkpoint assays, chromosomal instability measurements, anchorage-independent growth assays, in vivo tumor models\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined mitotic checkpoint phenotype, in vitro and in vivo; single lab\",\n      \"pmids\": [\"26282171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM33 is recruited to a PU.1-occupied enhancer upstream of the pro-apoptotic gene Bim in B cell leukemia, where it antagonizes PU.1-mediated Bim activation. Deletion of this single enhancer element renders TRIM33 dispensable for leukemia cell survival.\",\n      \"method\": \"ChIP-seq, conditional TRIM33 deletion, CRISPR/Cas9 enhancer deletion, PU.1 co-occupancy analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, direct enhancer deletion by genome editing with rescue, rigorous causal link between single element and phenotype\",\n      \"pmids\": [\"25919951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HSPB5 (crystallin alpha B) directly binds TRIM33, reduces its protein level, and impairs the TRIM33/SMAD4 interaction. Loss of TRIM33 in macrophages increases TGFβ1 secretion and sensitizes to BLM-induced fibrosis; TRIM33 acts as a negative regulator of lung fibrosis through the TGFβ/SMAD pathway.\",\n      \"method\": \"Direct binding assay (in vitro pull-down), co-immunoprecipitation of TRIM33/HSPB5, conditional Trim33 knockout in hematopoietic cells and lung fibroblasts, 3D lung tissue slice ex vivo\",\n      \"journal\": \"European Respiratory Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated, Co-IP for TRIM33/SMAD4 complex, multiple in vivo and ex vivo models; single lab\",\n      \"pmids\": [\"32184320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TIF1γ directly controls the transcription of coenzyme Q (CoQ) biosynthesis genes through transcription elongation. Loss of tif1γ reduces CoQ levels, elevates the succinate/α-ketoglutarate ratio, and leads to increased histone methylation, impairing erythroid differentiation. DHODH inhibition or CoQ analog treatment rescues the bloodless phenotype.\",\n      \"method\": \"Chemical suppressor screen in zebrafish moonshine mutants, metabolic profiling (CoQ levels, succinate/α-KG ratio), ChIP, CoQ analog rescue\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — chemical genetic suppressor screen, direct metabolic measurements, CoQ analog rescue, ChIP; multiple orthogonal methods in one study\",\n      \"pmids\": [\"33986176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM33 facilitates androgen receptor (AR) chromatin binding and transcriptional output in prostate cancer cells, and protects AR from Skp2-mediated ubiquitination and proteasomal degradation. TRIM33 knockdown sensitizes prostate cancer cells to AR antagonists.\",\n      \"method\": \"Proteomics (AR-interactor identification), ChIP-seq, co-immunoprecipitation, ubiquitination assays, knockdown with proliferation/apoptosis readouts\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction, ChIP-seq, direct ubiquitination assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35785414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM33 does not impact AR protein stability (contradicting a prior report), but instead facilitates maximal AR transcriptional activity by interfering with H2BK120 ubiquitination levels at AR-bound chromatin sites.\",\n      \"method\": \"ChIP-seq, AR protein stability assays, H2BK120 ubiquitination measurements, multiple prostate cancer cell lines\",\n      \"journal\": \"Communications Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP-seq and H2BK120 ubiquitination measurement; single lab, single study with finding contradicting prior work; moderate confidence pending replication\",\n      \"pmids\": [\"40646276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The TRIM33 bromodomain is the sole bromodomain (among 28 tested) that binds histone lysine lactylation (Kla) peptides with submicromolar affinity, also binding lysine acetylation. A unique glutamic acid residue in the TRIM33 bromodomain binding pocket confers selective recognition of Kla; mutagenesis of this residue abolishes selectivity.\",\n      \"method\": \"AlphaScreen bromodomain screen (28 bromodomains), isothermal titration calorimetry, NMR, site-directed mutagenesis, molecular modeling, X-ray crystallography (referenced in adjacent paper)\",\n      \"journal\": \"ACS Chemical Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ITC and NMR quantitative binding assays, mutagenesis of key residue, molecular modeling; multiple orthogonal biophysical methods in one study\",\n      \"pmids\": [\"39556662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Trim33 acts as an E3 ubiquitin ligase for A-MYB, regulating its abundance in testis, and binds RLTR10B LTR elements (of MMERVK10C retrotransposons) in a pattern overlapping A-Myb binding sites, thereby silencing this class of young endogenous retroviruses.\",\n      \"method\": \"ChIP-seq in testis, RNA-seq in haploinsufficient Trim33 mice, A-MYB ubiquitination assay, transgene reporter screen\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, direct E3 ligase assay for A-MYB, RNA-seq phenotype; single lab, multiple methods\",\n      \"pmids\": [\"26624618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM33 inhibits CBP-mediated FOXO3a acetylation by binding CBP, thereby attenuating FOXO3a ubiquitylation and degradation. This protects osteoblasts from oxidative stress-induced apoptosis; TRIM33 and FOXO3a co-localize in osteoblast nuclei.\",\n      \"method\": \"Co-immunoprecipitation of TRIM33/CBP, immunofluorescence co-localization, FOXO3a acetylation/ubiquitylation assays, overexpression/knockdown with apoptosis readouts, in vivo ovariectomy model\",\n      \"journal\": \"Aging Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, direct acetylation/ubiquitylation assays, in vivo model; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34101965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM33 ubiquitin ligase targets E2F4 for degradation in unperturbed cells. Under replicative stress, TRIM33-dependent ubiquitination of E2F4 is blunted, allowing transient E2F4 stabilization and recruitment of the DNA helicase Recql to facilitate DNA replication fork progression. Chronic Trim33 deletion leads to genome-wide Recql recruitment, accelerated replication under stress, impaired checkpoint signaling and DNA repair.\",\n      \"method\": \"Co-immunoprecipitation of E2F4-Recql, E2F4 ubiquitination assays, ChIP-seq, DNA fiber assays (replication fork progression), conditional Trim33 knockout\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ubiquitination assay, Co-IP, ChIP-seq, DNA fiber assays, multiple genetic models; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"37612308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM33 interacts with FACT subunit SPT16 at PU.1-bound distal regulatory elements in macrophages. TRIM33 deficiency leads to FACT release, loss of positioned nucleosomes, RNA Pol II recruitment, and bidirectional transcription at these elements, resulting in increased Atp1b3 expression.\",\n      \"method\": \"ChIP-seq of TRIM33 and SPT16, Co-immunoprecipitation of TRIM33/SPT16, conditional Trim33 KO macrophages, nucleosome positioning analysis\",\n      \"journal\": \"Epigenetics & Chromatin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, Co-IP, conditional KO with mechanistic follow-up at defined locus; single lab\",\n      \"pmids\": [\"31331374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM33 co-localizes with PML nuclear bodies (PML-NBs) specifically in mouse embryonic stem cells (mESCs) but not other cell types, in a PML-dependent manner. TRIM33 and PML co-regulate Lefty1/2 expression downstream of Nodal signaling; PML-NB assembly is required for TRIM33 recruitment to these gene loci.\",\n      \"method\": \"Co-localization imaging (confocal), TurboID proximity labeling, PML knockout epistasis, ChIP, Nodal signaling reporter assays\",\n      \"journal\": \"EMBO Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling, genetic epistasis with PML KO, ChIP; cell-type specificity demonstrated; single lab\",\n      \"pmids\": [\"36524443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM33 acts as an E3 ubiquitin ligase that ubiquitylates TFRC (transferrin receptor), targeting it for proteasomal degradation, thereby promoting ferroptosis susceptibility in hepatocellular carcinoma cells.\",\n      \"method\": \"Immunoprecipitation, immunofluorescence, ubiquitination assay of TFRC by TRIM33, ferroptosis readouts (MDA, Fe2+ levels, mitochondrial superoxide), in vivo xenograft\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ubiquitination assay, Co-IP, in vivo model; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38909931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM33 promotes K48-linked polyubiquitination of p53 at the K351 site, leading to its proteasomal degradation, thereby de-repressing downstream glycolytic target genes (GLUT1, HK2, PKM2, LDHA) and promoting aerobic glycolysis in esophageal squamous cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, K48-linked ubiquitination assay, site-directed mutagenesis of p53 K351, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct K48-ubiquitination assay, mutagenesis of ubiquitination site on substrate, in vivo validation; single lab\",\n      \"pmids\": [\"39389957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM21 forms a complex with TIF1γ/TRIM33 in the nucleus and promotes K48-linked ubiquitination of TIF1γ at K5, leading to its degradation, which increases nuclear β-catenin presence and promotes glioblastoma progression.\",\n      \"method\": \"Tandem Mass Tags/MS substrate identification, Co-IP, luciferase reporter assays, gain/loss of function with RING-finger deletion mutant, in vivo siRNA treatment\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified substrate, Co-IP, direct ubiquitination site mapping; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37771771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YOD1 deubiquitinase stabilizes TRIM33 by suppressing its ubiquitination and degradation, thereby maintaining TRIM33-mediated inhibition of the ERK/β-catenin pathway in head and neck squamous cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, YOD1 knockdown/overexpression with TRIM33 stability readout, in vitro and in vivo tumor assays\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, functional rescue; single lab\",\n      \"pmids\": [\"37573347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM33 induces K63-linked ubiquitination of Annexin A2 in keratinocytes, promoting Annexin A2 interaction with p50/p65 NF-κB subunits, retaining them in the nucleus and driving expression of NF-κB downstream inflammatory genes in psoriasis.\",\n      \"method\": \"Immunoprecipitation combined with mass spectrometry (substrate identification), K63-ubiquitination assay, Co-IP of Anxa2/NF-κB, NF-κB target gene expression, overexpression/knockdown assays\",\n      \"journal\": \"Journal of Dermatological Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified substrate, direct K63-ubiquitination assay, Co-IP; single lab\",\n      \"pmids\": [\"36096861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In zebrafish embryos, Trim33 is required cell-autonomously for macrophage colonization of the CNS (microglial seeding) and for basal amoeboid motility and inflammatory recruitment of both macrophages and neutrophils; mouse Trim33-deficient bone marrow-derived macrophages show strongly reduced 3D amoeboid mobility in collagen gels.\",\n      \"method\": \"Trim33-deficient zebrafish embryo imaging, 3D collagen gel motility assays with mouse Trim33 KO BMDMs, bacterial infection recruitment assay\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging in zebrafish, 3D motility assay in mouse cells; two model organisms, defined cellular phenotype; single lab\",\n      \"pmids\": [\"28724755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM33 promotes transcription of Irf8 in DC progenitors by maintaining CDK9 and Ser2-phosphorylated RNA Pol II levels at the Irf8 gene, facilitating cDC1 differentiation. TRIM33 also directly suppresses PU.1-mediated transcription of Bcl2l11 (Bim) to prevent apoptosis of DCs and progenitors.\",\n      \"method\": \"Conditional Trim33 knockout (Trim33fl/fl Cre-ERT2), ChIP for CDK9 and Ser2-Pol II at Irf8 locus, ChIP for PU.1/TRIM33 at Bcl2l11 locus, flow cytometry of DC progenitors\",\n      \"journal\": \"Cellular & Molecular Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO, ChIP at specific gene loci, defined molecular mechanism at Irf8 and Bcl2l11; single lab\",\n      \"pmids\": [\"38822080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM33 interacts with β-catenin in mESCs but its RING domain does not function as an E3 ubiquitin ligase for β-catenin in this context (neither KO nor overexpression of TRIM33 affects β-catenin protein levels in mESCs). TRIM33 regulates a subset of Wnt target genes (including Mixl1) independently of its RING domain E3 ligase activity.\",\n      \"method\": \"Co-immunoprecipitation in mESCs, Trim33 knockout and overexpression with β-catenin protein level measurements, Wnt reporter assay, Wnt target gene expression analysis\",\n      \"journal\": \"Science China Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, KO/OE with negative β-catenin stability result (important negative finding), Wnt gene expression analysis; single lab\",\n      \"pmids\": [\"28844090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIM33 positively regulates osteoblast differentiation through the BMP pathway by forming a TRIM33-Smad1/5 complex that triggers Smad1/5 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation of TRIM33-Smad1/5, phospho-Smad1/5 Western blotting, TRIM33 overexpression/knockdown in C3H10T1/2 and MC3T3-E1 cells with osteoblast differentiation markers\",\n      \"journal\": \"Journal of Cellular Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and phosphorylation assay, functional differentiation readouts; single lab, single pulldown method plus functional assay\",\n      \"pmids\": [\"28063228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Adenovirus E4-ORF3 interacts with TIF1γ through its Coiled-Coil domain and relocalizes endogenous TIF1γ into nuclear track structures in infected cells. The C-terminal half of TIF1β interferes with this interaction, explaining differential targeting of TIF1 family members.\",\n      \"method\": \"Co-immunoprecipitation in vitro and in infected cells, domain mapping with TIF1 chimeras, immunofluorescence of nuclear relocalization\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro Co-IP domain mapping, in vivo relocalization imaging; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22123502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TIF1γ binds TBP in competition with TAF15, impedes TAF15/TBP-mediated IL-6 transactivation, and induces multi-mono-ubiquitylation of TAF15, driving its nuclear export. This suppresses EMT and metastasis of lung adenocarcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation of TIF1γ/TBP and TIF1γ/TAF15, competition assay, ubiquitylation assay of TAF15, nuclear export assay, EMT/invasion assays\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, direct ubiquitylation assay of TAF15, nuclear export assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36261009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PIAS1 and TIF1γ form a trimeric complex with SnoN to collaboratively promote SnoN SUMOylation. Loss-of-function studies demonstrate that PIAS1 and TIF1γ act in an interdependent (not additive) manner to suppress EMT in breast cell-derived tissue organoids.\",\n      \"method\": \"Co-immunoprecipitation of trimeric complex, SUMO ligase assays, knockdown of PIAS1 and/or TIF1γ in 3D organoid EMT model\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — trimeric complex Co-IP, in vitro SUMO assay, 3D organoid functional validation; single lab\",\n      \"pmids\": [\"32770107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM33 loss in multiple myeloma leads to dysregulated ubiquitination of ALC1, impaired non-homologous end joining (NHEJ), accumulation of DNA double strand breaks, and sensitization to PARP inhibitor Olaparib. This effect is synergistic with bortezomib.\",\n      \"method\": \"TRIM33 knockdown in MM cells, NHEJ efficiency assay, DNA damage (DSB) quantification, ALC1 ubiquitination assay, PARP inhibitor sensitivity assay, co-culture with bone marrow stromal cells\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ALC1 ubiquitination assay, NHEJ assay, mechanistic follow-up on DDR; single lab\",\n      \"pmids\": [\"38627415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In the context of sepsis, parthenolide (PA) covalently targets TRIM33 via cysteine engagement, functionally binding TRIM33 to reduce Smad4 ubiquitin-dependent degradation, thereby suppressing NF-κB pathway activation and inflammation.\",\n      \"method\": \"Streamlined cysteine ABPP (activity-based protein profiling) chemoproteomics, proteomics, Co-IP, NF-κB reporter assays, in vivo CLP sepsis model\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — chemoproteomics hit identification with Co-IP validation, single lab, limited mechanistic depth on TRIM33-Smad4 ubiquitination\",\n      \"pmids\": [\"41702258\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM33 (TIF1γ) is a multifunctional nuclear E3 ubiquitin/SUMO ligase and chromatin reader that (1) competes with Smad4 for binding to receptor-phosphorylated Smad2/3, thereby branching TGFβ signaling to control cell fate; (2) promotes transcription elongation of lineage-specific genes through physical interaction with p-TEFb, FACT, and the SCL complex; (3) uses its PHD finger-bromodomain—activated by binding unmethylated/acetylated histone H3 tails and, uniquely, histone lysine lactylation—to ubiquitylate Smad4 and repress TGFβ target genes; (4) acts as an E3 ubiquitin ligase for multiple substrates including nuclear β-catenin, HIV-1 integrase, TFRC, TAF15, A-MYB, p53, and E2F4, and as a SUMO E3 ligase for SnoN1; (5) forms regulatory complexes with TRIM24 and TRIM28 to suppress hepatocellular carcinoma; (6) is recruited to specific enhancers by PU.1 to repress Ifnb1 and modulate macrophage-specific inflammatory gene programs; and (7) controls DNA replication fork integrity by regulating E2F4 stability and Recql helicase recruitment under replicative stress.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM33 (TIF1\\u03b3) is a multidomain nuclear factor that integrates TGF\\u03b2/Nodal/BMP signaling with chromatin regulation to control cell fate decisions, hematopoiesis, and tumor suppression [#0, #16]. It establishes a distinct branch of TGF\\u03b2 signaling by selectively binding receptor-phosphorylated Smad2/3 in competition with Smad4, routing the pathway toward differentiation rather than the antiproliferative response [#0], and acts in vivo as a Smad4 inhibitor that limits Nodal responsiveness during embryonic patterning [#16]. Architecturally TRIM33 carries RING, B-box, coiled-coil, PHD finger, and bromodomain motifs and possesses intrinsic transcriptional silencing activity [#1]; its PHD finger\\u2013bromodomain forms a multivalent histone-binding module that reads H3 tails unmethylated at K4/R2 and acetylated at key lysines, and this histone engagement licenses its E3 ubiquitin ligase activity toward Smad4 and its repressive output [#3]. The bromodomain uniquely recognizes histone lysine lactylation through a distinguishing glutamate in its binding pocket [#25]. Beyond chromatin reading, TRIM33 promotes transcription elongation of lineage-specific genes by partnering with the SCL/TAL1 complex and the elongation factors p-TEFb and FACT to relieve RNA Pol II pausing [#2, #8], a function extended to coenzyme Q biosynthesis genes whose loss perturbs erythroid differentiation through metabolite-driven histone hypermethylation [#22]. As an E3 ubiquitin ligase TRIM33 targets a range of substrates\\u2014including HIV-1 integrase to restrict infection [#11], TFRC to promote ferroptosis [#31], p53 to de-repress glycolysis [#32], and E2F4 to govern replication fork integrity via Recql recruitment under stress [#28]\\u2014and acts as a SUMO E3 ligase for SnoN1 to suppress TGF\\u03b2-driven EMT [#9]. It forms regulatory complexes with TRIM24 and TRIM28 that suppress hepatocellular carcinoma [#4] and operates as a tumor suppressor in pancreas independent of Smad4 [#17, #18]. In immune cells, TRIM33 is recruited by PU.1 to specific enhancers to repress Ifnb1, Bim, and other targets, tuning macrophage, dendritic cell, and lymphocyte programs [#7, #20, #37].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the domain architecture and intrinsic activity of TIF1\\u03b3, distinguishing it from other TIF1 family members.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, reporter assays and deletion mutagenesis defining RING/B-box/coiled-coil/PHD/bromodomain motifs and a TIF1 signature sequence\",\n      \"pmids\": [\"10022127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No physiological substrate or chromatin target identified at this stage\", \"Functional consequence of silencing activity in vivo unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined TIF1\\u03b3 as a competitor of Smad4 for phospho-Smad2/3, creating a branch point that directs TGF\\u03b2 signaling toward differentiation.\",\n      \"evidence\": \"Co-IP and loss-of-function in human hematopoietic stem/progenitor cells with differentiation readouts\",\n      \"pmids\": [\"16751102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of selective Smad2/3 recognition not structurally resolved\", \"Whether competition is regulated post-translationally not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved how TIF1\\u03b3 activates lineage genes mechanistically and how it acts as an in vivo Smad4 inhibitor in embryos.\",\n      \"evidence\": \"Zebrafish moonshine genetic epistasis with elongation factors plus Co-IP/ChIP; conditional Nodal-pathway ablation in mouse embryos\",\n      \"pmids\": [\"20603019\", \"20573697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How elongation-promoting and Smad4-inhibitory functions are coordinated unclear\", \"Direct recruitment mechanism to elongation machinery not fully defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected chromatin reading to enzymatic output and placed TRIM33 in tumor-suppressive multi-TRIM complexes and hematopoietic TF complexes.\",\n      \"evidence\": \"In vitro histone binding, ligase and reporter assays (Mol Cell); MS co-purification with conditional KO mice (PNAS); Co-IP/ChIP with TAL1/PU.1 and conditional KO (Cell Stem Cell)\",\n      \"pmids\": [\"21726812\", \"21531907\", \"21474105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly of TRIM24/28/33 complexes unresolved\", \"How histone marks toggle ligase activity structurally undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended TRIM33 function to DNA damage response and post-translational control of its own repressive activity by SUMOylation.\",\n      \"evidence\": \"Proteomics, live imaging and PARP1/ALC1 epistasis (JBC); SUMO-site mutagenesis with ChIP/reporter assays (J Cell Sci)\",\n      \"pmids\": [\"23926104\", \"23788427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TRIM33 ubiquitylates ALC1 at this stage not shown\", \"Link between SUMOylation and chromatin recruitment incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Diversified TRIM33's substrate repertoire and enhancer-targeted repression, identifying \\u03b2-catenin ubiquitylation, PU.1-directed Bim repression, Ifnb1 control, and a chromosomal-stability role.\",\n      \"evidence\": \"Ubiquitylation/Co-IP with kinase mutants (Nat Commun); ChIP-seq with CRISPR enhancer deletion (eLife); ChIP-seq/conditional KO in macrophages (Nat Commun); mitotic checkpoint assays (Cancer Res)\",\n      \"pmids\": [\"25639486\", \"25919951\", \"26592194\", \"26282171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability of \\u03b2-catenin ubiquitylation across cell types untested (later contradicted in mESCs)\", \"How PU.1 recruits TRIM33 to specific enhancers undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established SUMO ligase activity toward SnoN1 and a testis-specific role silencing endogenous retroviruses via A-MYB ubiquitylation.\",\n      \"evidence\": \"In vitro SUMO ligase and organoid EMT assays (JBC); ChIP-seq, RNA-seq and A-MYB ubiquitination in testis (PLoS Genet)\",\n      \"pmids\": [\"25059663\", \"26624618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isoform selectivity determinants for SnoN1 vs SnoN2 only partly mapped\", \"In vivo consequence of ERV de-silencing on fertility not fully quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Broadened TRIM33's signaling reach to BMP-driven osteoblast differentiation, PML-body localization in stem cells, and myeloid cell motility.\",\n      \"evidence\": \"Co-IP/phospho-Smad1/5 assays in osteoblast lines; zebrafish imaging and 3D motility assays in macrophages\",\n      \"pmids\": [\"28063228\", \"28724755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Smad1/5 phosphorylation promotion by TRIM33 unclear\", \"Molecular driver of amoeboid motility defect not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed TRIM33 RING-ligase activity restricts viral integration and contributes negatively to fibrotic and Th17/Treg-type immune programs.\",\n      \"evidence\": \"RNAi screen with HIV-1 replication and IN-mutant epistasis (Nat Commun); conditional T-cell KO with ChIP and autoimmune model (JEM)\",\n      \"pmids\": [\"30804369\", \"29930104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitin transfer to integrase not biochemically reconstituted\", \"How Smad2-dependent recruitment to Il17a/Il10 loci occurs unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked TRIM33 transcription-elongation control to coenzyme Q metabolism and detailed FACT-dependent enhancer regulation and PML-body co-regulation of Nodal targets.\",\n      \"evidence\": \"Chemical suppressor screen with metabolic profiling and CoQ rescue (Science); ChIP-seq/Co-IP with SPT16 (Epigenetics Chromatin); TurboID and PML-KO epistasis (EMBO J)\",\n      \"pmids\": [\"33986176\", \"31331374\", \"36524443\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect control of CoQ genes via metabolite feedback hard to separate\", \"Cell-type specificity of PML-body recruitment mechanism undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established E2F4/Recql-dependent control of replication fork integrity and identified upstream regulators (TRIM21, YOD1) governing TRIM33 stability.\",\n      \"evidence\": \"E2F4 ubiquitination, Co-IP, ChIP-seq and DNA fiber assays with conditional KO (Nat Commun); MS/Co-IP/ubiquitin-site mapping (Theranostics, Cell Death Dis)\",\n      \"pmids\": [\"37612308\", \"37771771\", \"37573347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How replicative stress blunts E2F4 ubiquitylation mechanistically unclear\", \"Interplay of TRIM21 degradation and YOD1 stabilization not jointly studied\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the bromodomain's unique lactyl-lysine recognition and expanded substrate/target roles across p53-glycolysis, AR transcription, NHEJ, and dendritic-cell programs.\",\n      \"evidence\": \"ITC/NMR/mutagenesis bromodomain screen (ACS Chem Biol); K48-ubiquitination of p53 (Cell Death Dis); ChIP-seq/H2BK120ub (Commun Biol); ALC1-ubiquitination NHEJ assays (Sci Rep); conditional KO with ChIP at Irf8/Bcl2l11 (CMI)\",\n      \"pmids\": [\"39556662\", \"39389957\", \"40646276\", \"38627415\", \"38822080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TRIM33 affects AR protein stability remains contradictory across studies (#23 vs #24)\", \"Physiological writers/erasers of the lactyl mark read by TRIM33 unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRIM33's many enzymatic activities (ubiquitin and SUMO ligase) and chromatin-reading functions are selectively deployed across cell types and substrates remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model linking histone-mark recognition to substrate choice\", \"Determinants of context-specific substrate selection (\\u03b2-catenin, p53, TFRC, E2F4, AR) undefined\", \"Cell-type-specific contradictory phenotypes (e.g. \\u03b2-catenin, AR) unreconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 5, 11, 28, 31, 32]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [3, 9, 11, 28, 31, 32]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3, 25]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 7, 8]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [8, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 27, 33]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2, 8, 28]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 16, 39]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 7, 8, 22]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [6, 28, 43]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 11, 12, 37]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 17, 18, 32]}\n    ],\n    \"complexes\": [\n      \"TRIM24/TRIM28/TRIM33 complex\",\n      \"SCL/TAL1 complex\",\n      \"PIAS1-TIF1\\u03b3-SnoN SUMOylation complex\"\n    ],\n    \"partners\": [\n      \"SMAD4\",\n      \"SMAD2/3\",\n      \"PU.1\",\n      \"TAL1\",\n      \"TRIM24\",\n      \"TRIM28\",\n      \"SPT16\",\n      \"TRIM21\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}