{"gene":"TRIM33","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2006,"finding":"TIF1γ (TRIM33) selectively binds receptor-phosphorylated Smad2/3 in competition with Smad4, forming a distinct effector arm of the TGFβ pathway. In human hematopoietic cells, TIF1γ mediates erythroid differentiation response while Smad4 mediates the antiproliferative response downstream of TGFβ.","method":"Co-immunoprecipitation, GST pulldown, siRNA knockdown in human hematopoietic stem/progenitor cells with functional differentiation and proliferation readouts","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal Co-IP, functional rescue experiments, replicated concept across multiple labs","pmids":["16751102"],"is_preprint":false},{"year":1999,"finding":"TIF1γ contains RING finger, B-box, coiled-coil, PHD/TTC, and bromodomain architecture. Unlike TIF1α, it does not interact with nuclear receptors or HP1 proteins; unlike TIF1β, it does not interact with the KRAB silencing domain. Deletion of the TIF1 signature sequence (TSS) abrogates its transcriptional repression activity.","method":"Yeast two-hybrid, GST pulldown, domain-deletion transfection reporter assays in mammalian cells","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 — multiple in vitro binding assays plus mutagenesis, foundational characterization paper","pmids":["10022127"],"is_preprint":false},{"year":2010,"finding":"TIF1γ controls erythroid cell fate by promoting transcription elongation: it physically interacts with the blood-specific SCL transcription complex and positive elongation factors p-TEFb and FACT, and recruits them to erythroid genes to counteract RNA Pol II pausing. Loss-of-function of Pol II-associated factors PAF or DSIF rescued erythroid transcription in tif1γ-deficient zebrafish.","method":"Genetic epistasis in zebrafish moonshine mutants, co-immunoprecipitation of TIF1γ with SCL complex/p-TEFb/FACT, ChIP in human CD34+ cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — genetic epistasis plus biochemical interactions plus ChIP in primary human cells, replicated in mouse (PMID 23159334)","pmids":["20603019"],"is_preprint":false},{"year":2011,"finding":"The PHD finger-bromodomain of TIF1γ/TRIM33 constitutes a multivalent histone-binding module that specifically recognizes histone H3 tails unmethylated at K4 and R2 and acetylated at key lysines. This chromatin binding activates TIF1γ's E3 ubiquitin ligase activity toward Smad4 and its transcriptional repressor activity.","method":"Histone peptide binding assays, in vitro ubiquitination assays, PHD-bromodomain mutagenesis, chromatin immunoprecipitation","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of ubiquitin ligase activity with mutagenesis showing histone-binding requirement; mechanistically rigorous single study","pmids":["21726812"],"is_preprint":false},{"year":2011,"finding":"TRIM24, TRIM28, and TRIM33 physically associate to form at least two macromolecular complexes (TRIM24-TRIM33 and TRIM24-TRIM28-TRIM33), and somatic hepatocyte-specific inactivation of any of these three proteins promotes hepatocellular carcinoma in mice in a cell-autonomous manner.","method":"Protein purification and mass spectrometry, conditional knockout mouse models with HCC phenotype assessment","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 — MS-confirmed complex plus multiple conditional KO mouse models with defined tumor phenotype","pmids":["21531907"],"is_preprint":false},{"year":2011,"finding":"TIF1γ forms complexes with TAL1 or PU.1 in hematopoietic cells, occupies specific subsets of their DNA binding sites in vivo, and represses their transcriptional activity, regulating adult hematopoietic stem cell function.","method":"Co-immunoprecipitation, ChIP, conditional knockout mouse models with HSC transplantation and differentiation assays","journal":"Cell Stem Cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, and KO mouse with defined cellular phenotypes","pmids":["21474105"],"is_preprint":false},{"year":2015,"finding":"TRIM33, acting as an E3 ubiquitin ligase, targets nuclear β-catenin for degradation in a GSK-3β- and β-TrCP-independent manner. Protein kinase Cδ phosphorylates β-catenin at Ser715, which is required for the TRIM33-β-catenin interaction and subsequent ubiquitination.","method":"Co-immunoprecipitation, in vitro ubiquitination assays, PKCδ kinase assays, knockdown/overexpression with tumor growth readouts","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro ubiquitination reconstitution, identified phosphorylation requirement, validated in vivo tumor models","pmids":["25639486"],"is_preprint":false},{"year":2013,"finding":"TRIM33 is recruited to DNA damage sites in a PARP1- and ALC1-dependent manner, and interacts with ALC1 after DNA damage. TRIM33-deficient cells show enhanced sensitivity to DNA damage and prolonged ALC1 retention at damage sites; overexpression of TRIM33 alleviates DNA repair defects caused by ALC1 overexpression.","method":"Proteomic analysis (AP-MS), live-cell imaging of TRIM33 recruitment to laser damage sites, siRNA knockdown with DNA damage sensitivity assays","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 — MS-identified interaction, live imaging of recruitment, functional epistasis with KD and OE","pmids":["23926104"],"is_preprint":false},{"year":2015,"finding":"TRIM33 prevents apoptosis in B lymphoblastic leukemia by associating with a single PU.1-bound enhancer upstream of the pro-apoptotic gene Bim; TRIM33 is recruited by PU.1 to this enhancer and antagonizes PU.1 function. Deletion of this enhancer renders TRIM33 dispensable for leukemia cell survival.","method":"ChIP-seq, enhancer deletion by genome editing, shRNA knockdown with apoptosis readout","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — ChIP-seq genome-wide mapping plus enhancer deletion functional rescue, mechanistically rigorous","pmids":["25919951"],"is_preprint":false},{"year":2015,"finding":"TRIM33 switches off Ifnb1 transcription during late-phase macrophage activation by being recruited by PU.1 to a conserved Ifnb1 Control Element (ICE) 15 kb upstream of Ifnb1. At ICE, TRIM33 regulates enhanceosome loading, controls chromatin structure, and represses Ifnb1 transcription by preventing recruitment of CBP/p300.","method":"ChIP, ChIP-seq, 3C/4C chromatin interaction assays, TRIM33 KO macrophages with LPS stimulation, ChIP for CBP/p300","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — ChIP-seq, chromatin looping, KO with defined molecular mechanism (CBP/p300 exclusion), macrophage-specific","pmids":["26592194"],"is_preprint":false},{"year":2019,"finding":"TRIM33 (E3 RING ligase) promotes degradation of HIV-1 integrase via the ubiquitin-proteasome system. TRIM33 knockdown in CD4+ cells increases HIV-1 replication and proviral DNA formation; overexpression has opposite effects.","method":"RNAi screen against ubiquitin machinery components, high-content microscopy, TRIM33 KD and OE with HIV infection assays, proviral DNA quantification","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — systematic RNAi screen plus KD/OE functional validation with specific viral integration readout","pmids":["30804369"],"is_preprint":false},{"year":2014,"finding":"TIF1γ operates as a SUMO E3 ligase (not only a ubiquitin E3 ligase) that promotes sumoylation of SnoN1 at distinct lysine residues via a 16-amino acid peptide unique to SnoN1 (not SnoN2). TIF1γ-induced SnoN1 sumoylation is required to suppress TGFβ-induced EMT in 3D mammary epithelial organoids.","method":"Interaction proteomics, in vitro sumoylation assays, domain mapping, 3D NMuMG organoid EMT assay","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of SUMO E3 ligase activity with domain mapping and functional 3D organoid validation","pmids":["25059663"],"is_preprint":false},{"year":2013,"finding":"TIF1γ sumoylation is required for its repressive activity on TGFβ signaling. TIF1γ interacts with Ubc9 (the SUMO-conjugating enzyme) and is sumoylated at four functional sites within its middle domain (the Smad interaction domain). A sumoylation-defective mutant significantly reduces TIF1γ inhibition of Smad complexes and Smad4 binding to the PAI-1 promoter.","method":"Co-immunoprecipitation, site-directed mutagenesis of sumoylation sites, ChIP on PAI-1 promoter, EMT assay in mammary epithelial cells","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis plus ChIP plus functional EMT assay","pmids":["23788427"],"is_preprint":false},{"year":2018,"finding":"Nuclear c-Abl tyrosine kinase phosphorylates TIF1γ/TRIM33 at Tyr-524, Tyr-610, and Tyr-1048, which reduces TIF1γ association with Smad3 and de-suppresses TGFβ signaling. EGF activates c-Abl to increase TIF1γ tyrosine phosphorylation, synergizing with TGFβ to provoke EMT.","method":"Phosphorylation site identification, triple tyrosine-to-phenylalanine (3YF) mutant rescue experiments, co-immunoprecipitation of TIF1γ with Smad3, EGF stimulation assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis defining specific phosphorylation sites, functional rescue experiments, kinase-substrate relationship established","pmids":["30177833"],"is_preprint":false},{"year":2018,"finding":"TRIM33 is required for Th17 cell proinflammatory function: it associates with Smad2 and is recruited to the Il17a and Il10 gene loci in a Smad2-dependent manner, mediating chromatin remodeling during Th17 differentiation to induce IL-17 and suppress IL-10 expression.","method":"Conditional T cell-specific TRIM33 KO mice, ChIP at Il17a and Il10 loci, in vitro Th17 differentiation assays, autoimmune disease model","journal":"Journal of Experimental Medicine","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined phenotype, ChIP showing locus-specific recruitment, Smad2-dependence established","pmids":["29930104"],"is_preprint":false},{"year":2016,"finding":"Adenovirus E4-ORF3 protein acts as a SUMO E3 ligase for TIF1γ sumoylation and can extend poly-SUMO3 chains in vitro; E4-ORF3 self-assembly (multimerization) is required for these activities. E4-ORF3 binds TIF1γ through the Coiled-Coil domain and relocalizes it to nuclear track structures in infected cells.","method":"In vitro sumoylation reconstitution with purified E4-ORF3 and TIF1γ, SUMO chain elongation assays, E4-ORF3 multimerization mutants, co-immunoprecipitation","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 — purified protein in vitro reconstitution demonstrating SUMO E3 ligase activity plus mutagenesis","pmids":["27247387"],"is_preprint":false},{"year":2020,"finding":"TRIM33 directly associates with HSPB5 (crystallin alpha B), which diminishes TRIM33 protein level and impairs TRIM33/SMAD4 interaction. TRIM33 acts as a negative regulator of TGFβ1/SMAD signaling in lung fibroblasts and macrophages; its loss increases TGFβ1 secretion and downstream fibrogenic gene expression.","method":"Direct binding assay (HSPB5-TRIM33), co-immunoprecipitation, conditional KO mouse with bleomycin-induced fibrosis, primary cell cultures","journal":"European Respiratory Journal","confidence":"High","confidence_rationale":"Tier 2 — direct binding demonstrated, conditional KO with defined fibrosis phenotype, mechanistic link to SMAD4 interaction","pmids":["32184320"],"is_preprint":false},{"year":2014,"finding":"Tif1γ controls TGFβ1 receptor (Tgfbr1) turnover: Tif1γ-deficient HSCs have elevated Tgfbr1 levels and increased TGFβ sensitivity. Two HSC populations discriminated by Tgfbr1 expression level (myeloid-biased Tgfbr1-high vs. balanced Tgfbr1-low) are regulated by Tif1γ.","method":"Conditional HSC-specific Tif1γ KO mice, flow cytometry, aging phenotype analysis, Tgfbr1 expression and TGFβ signaling assays","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with defined phenotype; Tgfbr1 regulation proposed but mechanism of how Tif1γ controls receptor turnover not fully biochemically defined","pmids":["25002492"],"is_preprint":false},{"year":2022,"finding":"TRIM33 facilitates androgen receptor (AR) chromatin binding and directly regulates AR-driven transcription in prostate cancer. TRIM33 also protects AR from Skp2-mediated ubiquitination and proteasomal degradation.","method":"Proteomics to identify TRIM33 as AR interactor, Co-IP, ChIP-seq for AR with TRIM33 KD, ubiquitination assays with Skp2","journal":"EMBO Reports","confidence":"High","confidence_rationale":"Tier 2 — proteomics-identified interaction, ChIP-seq, ubiquitination assay defining Skp2 as the E3 ligase blocked by TRIM33","pmids":["35785414"],"is_preprint":false},{"year":2015,"finding":"TIF1γ inhibits TGFβ-induced EMT in mammary epithelial cells by competing with Smad4 for binding to Smad2/3, and directly binds and represses the PAI-1 (plasminogen activator inhibitor 1) promoter.","method":"siRNA knockdown of TIF1γ or Smad4, microarray analysis of TIF1γ target genes, ChIP on PAI-1 promoter, EMT assays","journal":"EMBO Reports","confidence":"High","confidence_rationale":"Tier 2 — ChIP demonstrating direct promoter occupancy, genetic manipulation with defined EMT phenotype","pmids":["21597466"],"is_preprint":false},{"year":2021,"finding":"TIF1γ directly controls coenzyme Q (CoQ) synthesis gene expression through transcription elongation, and CoQ levels regulate mitochondrial respiration. Loss of tif1γ reduces CoQ levels and increases the succinate/α-ketoglutarate ratio, leading to increased histone methylation and impaired erythroid differentiation.","method":"Chemical suppressor screen in zebrafish tif1γ mutants, metabolomics (CoQ measurement), histone methylation assays, CoQ analog rescue of bloodless phenotype","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 — chemical genetic screen, metabolite rescue, mechanistic link between transcription elongation factor and metabolic output","pmids":["33986176"],"is_preprint":false},{"year":2024,"finding":"The TRIM33 bromodomain is the sole bromodomain (among 28 tested) that binds histone lysine lactylation (Kla) peptides. A unique glutamic acid residue within the TRIM33 bromodomain binding pocket confers specificity for Kla over other modifications; mutagenesis of this glutamic acid eliminates Kla binding.","method":"AlphaScreen assay of 28 bromodomains, isothermal titration calorimetry, protein-detected NMR, site-directed mutagenesis, molecular modeling","journal":"ACS Chemical Biology","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal biophysical methods plus mutagenesis identifying the critical residue for Kla specificity","pmids":["39556662"],"is_preprint":false},{"year":2019,"finding":"In macrophages, TRIM33 interacts with FACT subunit SPT16 at PU.1-bound distal regulatory elements. TRIM33 deficiency leads to FACT release, loss of positioned nucleosomes, RNA Pol II recruitment and bidirectional transcription at these elements, and increased gene expression.","method":"ChIP-seq for SPT16 and TRIM33, co-immunoprecipitation of TRIM33 with SPT16, ChIP for RNA Pol II and histone marks in TRIM33 KO macrophages, 3C chromatin interaction","journal":"Epigenetics & Chromatin","confidence":"High","confidence_rationale":"Tier 2 — ChIP-seq, Co-IP, functional consequence of KO on chromatin structure and transcription","pmids":["31331374"],"is_preprint":false},{"year":2017,"finding":"In zebrafish, Trim33 deficiency causes primitive macrophages to fail to colonize the CNS to become microglia; both macrophages and neutrophils display reduced basal interstitial motility and fail to respond to inflammatory recruitment signals. Mouse Trim33-deficient bone marrow-derived macrophages show strongly reduced 3D amoeboid mobility in collagen gels.","method":"Trim33-deficient zebrafish embryo live imaging, bacterial infection assays, 3D collagen gel motility assay for mouse BMDMs","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 2 — live imaging in zebrafish and mouse BMDM motility assays defining a non-TGFβ function in cell migration","pmids":["28724755"],"is_preprint":false},{"year":2015,"finding":"TIF1γ inactivation causes chromosomal defects due to attenuation of the spindle assembly checkpoint and the post-mitotic checkpoint, resulting in loss of contact growth inhibition and increased anchorage-independent growth.","method":"TIF1γ siRNA knockdown, mitotic checkpoint assays, chromosomal instability quantification, soft agar and in vivo tumor growth assays","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined mitotic checkpoint phenotype; mechanistic detail on how TIF1γ regulates checkpoints not fully biochemically defined","pmids":["26282171"],"is_preprint":false},{"year":2023,"finding":"TRIM33 ubiquitin ligase targets E2f4 for degradation in unperturbed cells, limiting E2f4 genomic binding and interactions with DNA helicase Recql. Replicative stress blunts TRIM33-dependent ubiquitination of E2f4, stimulating transient Recql recruitment to chromatin and facilitating recovery of DNA synthesis.","method":"TRIM33 deletion in mouse cells, ubiquitination assays for E2f4, ChIP-seq for E2f4 and Recql, DNA fiber assays for replication fork progression, Myc-overexpression tumor model","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1-2 — ubiquitination assays, ChIP-seq, DNA fiber analysis, genetic interaction with Myc in tumor model","pmids":["37612308"],"is_preprint":false},{"year":2022,"finding":"TRIM33 promotes K63-linked ubiquitination of Annexin A2 (Anxa2) in keratinocytes, which promotes Anxa2 interaction with p50/p65 NF-κB subunits, favors nuclear retention of p50/p65, and drives expression of NF-κB downstream inflammatory genes.","method":"Immunoprecipitation-mass spectrometry to identify Anxa2 as TRIM33 substrate, K63-ubiquitination assay, co-immunoprecipitation of Anxa2 with NF-κB subunits, nuclear fractionation","journal":"Journal of Dermatological Science","confidence":"Medium","confidence_rationale":"Tier 2 — MS-identified substrate, ubiquitination assay, Co-IP; single lab study","pmids":["36096861"],"is_preprint":false},{"year":2020,"finding":"TRIM33 protects osteoblasts from oxidative stress-induced apoptosis by binding CBP and restraining CBP-mediated FOXO3a acetylation, thereby attenuating FOXO3a ubiquitylation and degradation. TRIM33 and FOXO3a co-localize in osteoblast nuclei.","method":"Co-immunoprecipitation of TRIM33 with CBP and FOXO3a, immunofluorescence co-localization, FOXO3a acetylation and ubiquitination assays, OVX mouse model","journal":"Aging Cell","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with functional assays; mechanism via CBP inhibition is from single lab","pmids":["34101965"],"is_preprint":false},{"year":2024,"finding":"TRIM33 promotes K48-linked polyubiquitination and proteasomal degradation of p53 at the K351 site in esophageal squamous cell carcinoma, leading to upregulation of glycolysis target genes GLUT1, HK2, PKM2, and LDHA.","method":"Co-immunoprecipitation, in vitro/cell-based ubiquitination assays with K48-linkage specificity, K351 site mutagenesis, glycolysis assays, xenograft model","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 1-2 — ubiquitination assay with site mutagenesis; single lab study","pmids":["39389957"],"is_preprint":false},{"year":2022,"finding":"TRIM33 co-localizes with promyelocytic leukemia nuclear bodies (PML-NBs) specifically in mouse ESCs, and this localization depends on PML. TRIM33 and PML co-regulate Lefty1/2 expression, with PML-NBs directly associating with Lefty1/2 gene loci and required for TRIM33 recruitment to these loci.","method":"Co-localization imaging, TurboID proximity-labeling proteomics, PML KO in mESCs, ChIP, 4C-seq","journal":"EMBO Journal","confidence":"High","confidence_rationale":"Tier 2 — proximity labeling proteomics, KO functional validation, chromatin interaction mapping","pmids":["36524443"],"is_preprint":false},{"year":2017,"finding":"TRIM33 has E3 ubiquitin ligase activity toward A-MYB, regulating its abundance in the testis. ChIP-seq in mouse testis reveals TRIM33 is enriched at RLTR10B LTR elements of MMERVK10C retrotransposons, and Trim33 haploinsufficiency increases expression of genes transcribed from upstream RLTR10B.","method":"ChIP-seq in mouse testis, RNA-seq, A-MYB ubiquitination assay","journal":"PLoS Genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP-seq plus ubiquitination assay; A-MYB as substrate is novel and from single study","pmids":["26624618"],"is_preprint":false},{"year":2022,"finding":"TRIM33 interacts with TFRC (transferrin receptor) and promotes its E3 ligase-dependent ubiquitination and degradation, thereby inducing cellular ferroptosis in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, ferroptosis markers (MDA, Fe2+, mitochondrial superoxide), xenograft model","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and ubiquitination assay with functional ferroptosis readout; single lab","pmids":["38909931"],"is_preprint":false},{"year":2020,"finding":"PIAS1 and TIF1γ collaborate as SUMO E3 ligases forming a trimeric complex with SnoN to promote SnoN SUMOylation in an interdependent manner, suppressing EMT in breast organoids.","method":"Co-immunoprecipitation of trimeric SnoN-TIF1γ-PIAS1 complex, in vitro SUMOylation assays, loss-of-function studies in 3D breast organoid EMT assay","journal":"Cell Death and Differentiation","confidence":"High","confidence_rationale":"Tier 1-2 — trimeric complex Co-IP, in vitro SUMO assay, functional 3D organoid validation","pmids":["32770107"],"is_preprint":false},{"year":2022,"finding":"TIF1γ binds to TBP in competition with TAF15 and impedes TAF15/TBP-mediated IL-6 transactivation. TIF1γ also modifies TAF15 through multi-mono-ubiquitylation and drives nuclear export of TAF15, thereby inhibiting EMT and metastasis of lung adenocarcinoma cells.","method":"Co-immunoprecipitation of TIF1γ-TBP and TIF1γ-TAF15 interactions, ubiquitination assay for TAF15, nuclear/cytoplasmic fractionation, IL-6 luciferase reporter, EMT and metastasis assays","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ubiquitination assay, functional EMT assay; single lab study","pmids":["36261009"],"is_preprint":false},{"year":2024,"finding":"TRIM33 is an essential regulator of the entire DC lineage: conditional deletion causes rapid loss of DC progenitors, pDCs, and cDC1s. Trim33-deficient Flt3+ progenitors up-regulate pro-inflammatory and macrophage-specific genes but fail to induce the DC differentiation program, placing TRIM33 upstream of IRF8-driven DC commitment.","method":"Genome-wide CRISPR-Cas9 screen for Flt3L-driven DC differentiation, conditional Trim33 KO mice, RNA-seq of progenitors","journal":"Science Immunology","confidence":"High","confidence_rationale":"Tier 2 — genome-wide screen plus conditional KO in vivo with defined lineage phenotype and transcriptional mechanism","pmids":["38608038"],"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 Irf8 gene sites (consistent with a transcription elongation function). TRIM33 also directly suppresses PU.1-mediated transcription of Bcl2l11 (Bim) to prevent DC apoptosis.","method":"ChIP for CDK9 and S2-phospho-Pol II at Irf8 locus, ChIP for TRIM33 and PU.1 at Bcl2l11, conditional KO mice, differentiation and apoptosis assays","journal":"Cellular & Molecular Immunology","confidence":"High","confidence_rationale":"Tier 2 — ChIP defining transcription elongation mechanism at specific loci, conditional KO functional validation","pmids":["38822080"],"is_preprint":false},{"year":2017,"finding":"TRIM33 is essential for the production of small peritoneal macrophages, monocytes, and bone marrow-derived macrophages. In mature myeloid cells, TRIM33 ChIP-seq reveals binding near inflammatory response genes; TRIM33 loss impairs repression of late LPS activation pathways and causes high LPS sensitivity in vivo.","method":"ChIP-seq in immature and mature myeloid cell lines, conditional KO mice with in vivo LPS challenge, macrophage production assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-seq plus conditional KO with defined immune phenotype; mechanism not fully biochemically reconstituted","pmids":["27974684"],"is_preprint":false},{"year":2023,"finding":"TRIM21 E3 ubiquitin ligase forms a complex with TIF1γ in the nucleus and promotes K48-linked ubiquitination of TIF1γ at K5, leading to TIF1γ degradation and consequent increase in nuclear β-catenin presence in glioblastoma.","method":"TMT/MS to identify TRIM21 substrates including TIF1γ, Co-IP, K48-ubiquitination assay at K5, luciferase reporter for β-catenin, RING-finger deletion mutant, xenograft model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — MS, Co-IP, site-specific ubiquitination assay; single lab","pmids":["37771771"],"is_preprint":false},{"year":2023,"finding":"YOD1 deubiquitinase stabilizes TRIM33 by suppressing its ubiquitination and degradation, thereby inhibiting ERK/β-catenin pathway activation in head and neck squamous cell carcinoma.","method":"Co-immunoprecipitation of YOD1 with TRIM33, ubiquitination assay showing YOD1 reduces TRIM33 ubiquitination, KD/OE functional assays with ERK/β-catenin pathway readout","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and ubiquitination assay with functional pathway readout; single lab","pmids":["37573347"],"is_preprint":false},{"year":2025,"finding":"TRIM33 loss reduces H2BK120 ubiquitination levels and decreases AR transcriptional output without affecting AR protein stability, suggesting TRIM33 facilitates maximal AR activity through chromatin modification rather than AR stabilization.","method":"Co-immunoprecipitation and ChIP-seq across prostate cancer cell lines, H2BK120 ubiquitination measurement, AR stability assays with TRIM33 KD","journal":"Communications Biology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-seq, chromatin mark measurement, functional transcriptomic output; single study contrasting earlier stabilization claims","pmids":["40646276"],"is_preprint":false},{"year":2017,"finding":"TRIM33 positively regulates osteoblast differentiation through the BMP pathway by forming a TRIM33-Smad1/5 complex; this interaction triggers phosphorylation of Smad1/5 and promotes BMP-driven differentiation.","method":"Co-immunoprecipitation of TRIM33 with Smad1/5, phospho-Smad1/5 assay, TRIM33 overexpression/knockdown with ALP, Runx2, osteocalcin readouts, cell cycle assays","journal":"Journal of Cellular Physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP plus functional differentiation assay; mechanistic detail on how TRIM33 activates Smad1/5 phosphorylation not fully established","pmids":["28063228"],"is_preprint":false}],"current_model":"TRIM33 (TIF1γ) is a multifunctional nuclear E3 ubiquitin/SUMO ligase and chromatin reader that regulates TGFβ/Nodal/BMP signaling by competitively binding receptor-phosphorylated Smad2/3 away from Smad4, ubiquitinating Smad4 only upon recruitment to chromatin via its PHD finger-bromodomain (which recognizes unmodified H3K4/H3R2 and acetylated H3 lysines, and also histone lysine lactylation), promotes transcription elongation at lineage-specific genes through interactions with p-TEFb and FACT, acts as a SUMO E3 ligase for SnoN1 to suppress EMT, targets multiple substrates (nuclear β-catenin, HIV integrase, TFRC, E2f4, p53, A-MYB, AR-protective against Skp2) for ubiquitin-mediated degradation, is recruited to specific genomic regulatory elements by lineage-determining transcription factors (PU.1, TAL1, AR), participates in PARP-dependent DNA damage response by regulating ALC1 activity, and controls mitotic fidelity and replication fork progression."},"narrative":{"teleology":[{"year":1999,"claim":"Establishing TRIM33's domain architecture (RING, B-box, coiled-coil, PHD, bromodomain) and intrinsic transcriptional repression activity distinguished it from paralogs TIF1α and TIF1β and set the framework for all subsequent functional studies.","evidence":"Yeast two-hybrid, GST pulldown, and domain-deletion reporter assays in mammalian cells","pmids":["10022127"],"confidence":"High","gaps":["No endogenous target genes identified","No E3 ligase activity tested","Physiological role unknown"]},{"year":2006,"claim":"Demonstrating that TIF1γ competitively binds phospho-Smad2/3 away from Smad4 revealed a bifurcation of TGF-β signaling into distinct effector arms—TIF1γ for differentiation and Smad4 for growth arrest—answering how a single pathway drives divergent cell-fate outcomes.","evidence":"Reciprocal Co-IP, GST pulldown, siRNA knockdown in human hematopoietic stem/progenitor cells with erythroid differentiation and proliferation readouts","pmids":["16751102"],"confidence":"High","gaps":["Chromatin-level mechanism of TIF1γ-Smad target gene selection unknown","Whether TIF1γ possesses E3 ligase activity toward Smads not yet tested"]},{"year":2010,"claim":"Identifying TIF1γ as a transcription elongation factor—through physical interaction with p-TEFb and FACT and genetic epistasis with pausing regulators—explained how it activates blood-specific genes beyond simply modulating Smad signaling.","evidence":"Genetic epistasis in zebrafish moonshine mutants, Co-IP of TIF1γ with SCL/p-TEFb/FACT, ChIP in human CD34+ cells","pmids":["20603019"],"confidence":"High","gaps":["Whether elongation function is general or restricted to erythroid loci","Direct biochemical mechanism of Pol II pause release by TIF1γ not reconstituted"]},{"year":2011,"claim":"Three advances converged: the PHD-bromodomain was shown to read unmodified H3K4/H3R2 and acetylated H3 to activate TRIM33's E3 ligase activity toward Smad4; TRIM33 was found to form macromolecular complexes with TRIM24/TRIM28 that suppress hepatocellular carcinoma; and TRIM33 was shown to be recruited by TAL1 and PU.1 to specific hematopoietic enhancers.","evidence":"Histone peptide binding/in vitro ubiquitination/mutagenesis (PMID:21726812); MS-confirmed TRIM24/28/33 complex with conditional KO HCC models (PMID:21531907); Co-IP, ChIP, conditional KO HSC transplantation (PMID:21474105); ChIP on PAI-1 promoter with EMT assay (PMID:21597466)","pmids":["21726812","21531907","21474105","21597466"],"confidence":"High","gaps":["Crystal structure of PHD-bromodomain with histone peptide not yet solved","How TRIM24/TRIM28/TRIM33 complexes cooperate mechanistically unclear","E3 activity toward Smad4 shown in vitro but not validated at endogenous chromatin targets"]},{"year":2013,"claim":"Two discoveries established TRIM33's regulation by and of the SUMO pathway: its own sumoylation is required for Smad complex repression, and it participates in the PARP1/ALC1-dependent DNA damage response at laser-induced lesions, broadening its functions beyond TGF-β signaling.","evidence":"Sumoylation site mutagenesis with ChIP on PAI-1 promoter and EMT assay (PMID:23788427); AP-MS, live-cell imaging of TRIM33 recruitment to damage sites, siRNA epistasis with ALC1 (PMID:23926104)","pmids":["23788427","23926104"],"confidence":"High","gaps":["Identity of SUMO E3 ligase acting on TRIM33 itself unknown at this point","Direct substrates of TRIM33 at DNA damage sites not identified","Structural basis of sumoylation-dependent Smad regulation unclear"]},{"year":2014,"claim":"Reconstitution of TRIM33 as a bona fide SUMO E3 ligase for SnoN1—requiring a unique 16-amino-acid SnoN1 peptide—demonstrated dual E3 ligase specificity (ubiquitin and SUMO) and linked it to EMT suppression through a non-Smad mechanism.","evidence":"In vitro sumoylation assay with purified proteins, domain mapping, 3D NMuMG organoid EMT assay (PMID:25059663); conditional KO HSC with Tgfbr1 regulation (PMID:25002492)","pmids":["25059663","25002492"],"confidence":"High","gaps":["Whether TRIM33 SUMOylates substrates beyond SnoN1 not established","Mechanism of Tgfbr1 turnover by TIF1γ not biochemically defined"]},{"year":2015,"claim":"Multiple studies expanded TRIM33's substrate repertoire and genomic functions: it ubiquitinates nuclear β-catenin in a PKCδ/Ser715-dependent manner, is recruited by PU.1 to a single enhancer controlling Bim to prevent leukemia apoptosis, and represses Ifnb1 by blocking CBP/p300 recruitment at a distal control element.","evidence":"In vitro ubiquitination and kinase assays with tumor models (PMID:25639486); ChIP-seq and enhancer deletion in B-ALL (PMID:25919951); ChIP-seq, 3C/4C, KO macrophages with LPS (PMID:26592194); mitotic checkpoint assays with KD (PMID:26282171)","pmids":["25639486","25919951","26592194","26282171"],"confidence":"High","gaps":["How TRIM33 distinguishes its many E3 substrates at different genomic contexts unknown","Mechanism of spindle assembly checkpoint regulation biochemically undefined","Whether β-catenin ubiquitination occurs at specific chromatin loci not tested"]},{"year":2016,"claim":"The demonstration that adenovirus E4-ORF3 hijacks TRIM33 as a substrate for viral SUMO E3 ligase activity, with poly-SUMO3 chain extension, established that TRIM33 is a target of pathogen immune evasion through SUMO modification.","evidence":"In vitro sumoylation reconstitution with purified E4-ORF3 and TIF1γ, SUMO chain elongation, multimerization mutants","pmids":["27247387"],"confidence":"High","gaps":["Functional consequence of E4-ORF3-mediated TRIM33 sumoylation for infection outcome not fully defined","Whether other viruses similarly exploit TRIM33 unknown"]},{"year":2017,"claim":"In vivo studies extended TRIM33's lineage roles to myeloid cell motility (macrophage/microglia colonization), myeloid inflammatory gene regulation, testicular retrotransposon silencing via A-MYB ubiquitination, and BMP-pathway osteoblast differentiation, revealing tissue-wide pleiotropic functions.","evidence":"Zebrafish live imaging and mouse BMDM collagen motility (PMID:28063228 for BMP/osteoblast; PMID:28724755 for motility); ChIP-seq in myeloid cells with conditional KO and LPS challenge (PMID:27974684); ChIP-seq and ubiquitination in testis (PMID:26624618)","pmids":["28724755","27974684","26624618","28063228"],"confidence":"Medium","gaps":["Molecular target mediating cell motility not identified","A-MYB ubiquitination not independently confirmed","How TRIM33 promotes Smad1/5 phosphorylation in BMP signaling is unclear"]},{"year":2018,"claim":"c-Abl tyrosine phosphorylation of TRIM33 at three sites was shown to disrupt Smad3 binding, revealing a mechanism by which EGF synergizes with TGF-β to overcome TRIM33-mediated EMT suppression; concurrently, TRIM33's Smad2-dependent recruitment to Il17a and Il10 loci was shown to govern Th17 inflammatory function.","evidence":"Phosphosite mutagenesis and rescue with EGF/TGF-β EMT assays (PMID:30177833); conditional T-cell KO with ChIP at cytokine loci and autoimmune model (PMID:29930104)","pmids":["30177833","29930104"],"confidence":"High","gaps":["Whether other kinases regulate TRIM33 at different sites unknown","Chromatin remodeling mechanism at Il17a/Il10 not biochemically reconstituted"]},{"year":2019,"claim":"Two studies defined TRIM33's interaction with the FACT complex at distal regulatory elements: in macrophages TRIM33 retains SPT16/FACT and positioned nucleosomes at PU.1-bound enhancers to prevent aberrant transcription, and TRIM33 targets HIV-1 integrase for proteasomal degradation, restricting viral replication.","evidence":"ChIP-seq for SPT16/TRIM33, Co-IP, nucleosome positioning in TRIM33 KO macrophages (PMID:31331374); RNAi screen with HIV integration assays (PMID:30804369)","pmids":["31331374","30804369"],"confidence":"High","gaps":["Whether FACT retention mechanism involves direct TRIM33 ubiquitin ligase activity at enhancers not determined","HIV integrase ubiquitination sites not mapped"]},{"year":2020,"claim":"PIAS1 and TIF1γ were shown to collaborate as SUMO E3 ligases in a trimeric complex with SnoN, and HSPB5 was identified as a direct TRIM33 binding partner that destabilizes it, with TRIM33 loss increasing TGF-β1-driven fibrosis.","evidence":"Trimeric complex Co-IP and in vitro SUMO assay with 3D breast organoid EMT (PMID:32770107); HSPB5 direct binding with conditional KO bleomycin fibrosis model (PMID:32184320)","pmids":["32770107","32184320"],"confidence":"High","gaps":["How PIAS1 and TIF1γ coordinate E3 activity structurally unknown","Whether HSPB5-mediated destabilization is tissue-specific not tested"]},{"year":2021,"claim":"A chemical suppressor screen in zebrafish revealed that TIF1γ's transcription elongation function directly controls coenzyme Q biosynthetic gene expression; CoQ deficiency alters succinate/α-KG ratios, increases histone methylation, and blocks erythropoiesis—linking chromatin-reading and elongation to metabolic output.","evidence":"Chemical genetic screen in tif1γ mutant zebrafish, metabolomics, histone methylation assays, CoQ analog rescue","pmids":["33986176"],"confidence":"High","gaps":["Whether CoQ pathway regulation by TRIM33 is conserved in mammals not fully confirmed","Direct TRIM33 occupancy at CoQ biosynthetic gene loci not shown"]},{"year":2022,"claim":"Multiple substrate-level discoveries demonstrated TRIM33's broad E3 ligase repertoire: it facilitates AR chromatin binding and protects AR from Skp2-mediated degradation in prostate cancer, promotes K63-ubiquitination of Annexin A2 driving NF-κB inflammatory signaling, co-localizes with PML nuclear bodies in ESCs to regulate Lefty1/2, and ubiquitinates TAF15 for nuclear export to suppress IL-6/EMT.","evidence":"Proteomics/ChIP-seq for AR (PMID:35785414); K63-Ub assay and NF-κB Co-IP (PMID:36096861); TurboID/4C-seq for PML-NB co-regulation of Lefty (PMID:36524443); TAF15 ubiquitination and TBP competition (PMID:36261009); TFRC ubiquitination and ferroptosis (PMID:38909931)","pmids":["35785414","36096861","36524443","36261009","38909931"],"confidence":"High","gaps":["How substrate selectivity is achieved among many targets remains a central unresolved question","AR stabilization versus chromatin modification mechanisms appear contradictory across studies","K63-linked Annexin A2 ubiquitination awaits independent confirmation"]},{"year":2023,"claim":"TRIM33 was shown to ubiquitinate E2f4 for degradation, limiting E2f4-Recql chromatin association; replicative stress relieves this control to promote fork recovery—establishing TRIM33 as a replication stress response factor. Separately, TRIM33 itself was identified as a substrate of TRIM21 (K48-Ub at K5) and stabilized by the DUB YOD1.","evidence":"Ubiquitination assays, ChIP-seq, DNA fiber assays for E2f4-Recql (PMID:37612308); TRIM21/TRIM33 Co-IP and K5 site ubiquitination (PMID:37771771); YOD1-TRIM33 Co-IP and stabilization (PMID:37573347)","pmids":["37612308","37771771","37573347"],"confidence":"High","gaps":["Whether TRIM33-E2f4 axis operates in non-transformed cells not confirmed","How TRIM21 and YOD1 activities on TRIM33 are coordinated in physiological contexts unknown"]},{"year":2024,"claim":"The TRIM33 bromodomain was found to uniquely recognize histone lysine lactylation (Kla) via a glutamic acid residue in its binding pocket, expanding the chromatin marks it reads. Concurrently, genome-wide CRISPR screens and conditional KO revealed TRIM33 as essential for dendritic cell lineage commitment upstream of IRF8, operating through CDK9-dependent transcription elongation at Irf8 and PU.1-dependent Bim repression. TRIM33 was also shown to ubiquitinate p53 at K351 promoting glycolysis.","evidence":"AlphaScreen of 28 bromodomains, ITC, NMR, mutagenesis for Kla (PMID:39556662); CRISPR screen and conditional KO for DC (PMID:38608038); ChIP for CDK9/S2P-Pol II at Irf8 (PMID:38822080); p53 K351 ubiquitination assay (PMID:39389957)","pmids":["39556662","38608038","38822080","39389957"],"confidence":"High","gaps":["Functional consequence of Kla reading by TRIM33 in vivo not established","Whether DC lineage role involves TRIM33's SUMO E3 activity not tested","p53 K351 ubiquitination from single lab"]},{"year":2025,"claim":"A contrasting study found that TRIM33 loss reduces H2BK120 ubiquitination and AR transcriptional output without affecting AR protein stability, suggesting TRIM33 supports AR function through chromatin modification rather than protein stabilization.","evidence":"Co-IP, ChIP-seq, H2BK120ub measurement, AR stability assays across prostate cancer lines","pmids":["40646276"],"confidence":"Medium","gaps":["Whether TRIM33 directly ubiquitinates H2BK120 or acts indirectly not determined","Discrepancy with earlier AR stabilization study not resolved","Mechanism linking TRIM33 to the H2B ubiquitination machinery unknown"]},{"year":null,"claim":"Central unresolved questions include: how TRIM33 achieves substrate selectivity among its numerous ubiquitin and SUMO targets; whether its bromodomain Kla-reading activity has distinct physiological outputs from its canonical acetyl-lysine reading; the structural basis of chromatin-activated E3 ligase activity; and how its elongation, E3 ligase, and chromatin-reading functions are coordinated at individual genomic loci.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of full-length TRIM33 or chromatin-engaged TRIM33","Substrate selectivity mechanism unknown","Kla-reading functional consequences in vivo untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,6,10,11,25,28,30,31,32,33,39]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3,21]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,5,8,9,19,35]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[3,6,10,11,25,28,32]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,3,5,7,8,9,18,27,29]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[3,21,39]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,6,13,14,16,40]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,6,10,11,25,28,30,31,32,33]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,14,34,35,36]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2,20,34,40]}],"complexes":["TRIM24-TRIM28-TRIM33","SnoN1-TIF1γ-PIAS1"],"partners":["SMAD2","SMAD4","PU.1","TAL1","SUPT16H","CDK9","ALC1","TRIM24"],"other_free_text":[]},"mechanistic_narrative":"TRIM33 (TIF1γ) is a multifunctional nuclear E3 ubiquitin and SUMO ligase that integrates chromatin reading with transcriptional regulation and signal transduction across hematopoietic, immune, and epithelial lineages. Its PHD finger–bromodomain cassette recognizes histone H3 tails unmethylated at K4/R2 and acetylated at specific lysines—and uniquely among bromodomains binds histone lysine lactylation—coupling chromatin state to its RING-dependent E3 ligase activity, which ubiquitinates Smad4, β-catenin, E2f4, p53, HIV-1 integrase, and other substrates, and SUMOylates SnoN1 cooperatively with PIAS1 to suppress TGF-β-induced EMT [PMID:21726812, PMID:39556662, PMID:25639486, PMID:25059663, PMID:32770107]. TRIM33 competitively binds receptor-phosphorylated Smad2/3 away from Smad4, separating TGF-β signaling into a TRIM33-dependent differentiation arm and a Smad4-dependent antiproliferative arm, while also promoting transcription elongation at lineage-specific genes by recruiting p-TEFb and the FACT complex in partnership with lineage-determining transcription factors PU.1, TAL1/SCL, and the androgen receptor [PMID:16751102, PMID:20603019, PMID:21474105, PMID:35785414]. These elongation and chromatin-remodeling activities underpin TRIM33's essential roles in erythropoiesis, dendritic cell commitment upstream of IRF8, macrophage inflammatory gene regulation, Th17 differentiation, and coenzyme Q biosynthesis, and its loss leads to chromosomal instability, impaired DNA damage response through dysregulated ALC1, and replication stress sensitivity via E2f4-Recql stabilization [PMID:33986176, PMID:38608038, PMID:23926104, PMID:37612308, PMID:26282171]."},"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 controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16751102","citation_count":318,"is_preprint":false},{"pmid":"30261900","id":"PMC_30261900","title":"Circular RNA hsa_circ_0008305 (circPTK2) inhibits TGF-β-induced epithelial-mesenchymal transition and metastasis by controlling TIF1γ in non-small cell lung cancer.","date":"2018","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30261900","citation_count":293,"is_preprint":false},{"pmid":"21531907","id":"PMC_21531907","title":"Transcription cofactors TRIM24, TRIM28, and TRIM33 associate to form regulatory complexes that suppress murine hepatocellular carcinoma.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21531907","citation_count":181,"is_preprint":false},{"pmid":"20603019","id":"PMC_20603019","title":"TIF1gamma controls erythroid cell fate by regulating transcription elongation.","date":"2010","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/20603019","citation_count":178,"is_preprint":false},{"pmid":"25639486","id":"PMC_25639486","title":"Tumour suppressor TRIM33 targets nuclear β-catenin degradation.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25639486","citation_count":148,"is_preprint":false},{"pmid":"10022127","id":"PMC_10022127","title":"TIF1gamma, a novel member of the transcriptional intermediary factor 1 family.","date":"1999","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10022127","citation_count":142,"is_preprint":false},{"pmid":"21726812","id":"PMC_21726812","title":"Recruitment of TIF1γ to chromatin via its PHD finger-bromodomain activates its ubiquitin ligase and transcriptional repressor activities.","date":"2011","source":"Molecular 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TGF-β-induced epithelial-mesenchymal transition in non-small-cell lung cancer.","date":"2015","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/25961934","citation_count":71,"is_preprint":false},{"pmid":"25381221","id":"PMC_25381221","title":"miR-629 Targets TRIM33 to Promote TGFβ/Smad Signaling and Metastatic Phenotypes in ccRCC.","date":"2014","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/25381221","citation_count":69,"is_preprint":false},{"pmid":"25002492","id":"PMC_25002492","title":"Tif1γ regulates the TGF-β1 receptor and promotes physiological aging of hematopoietic stem cells.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25002492","citation_count":63,"is_preprint":false},{"pmid":"21597466","id":"PMC_21597466","title":"Antagonistic regulation of EMT by TIF1γ and Smad4 in mammary epithelial cells.","date":"2011","source":"EMBO 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communications","url":"https://pubmed.ncbi.nlm.nih.gov/26592194","citation_count":57,"is_preprint":false},{"pmid":"33135196","id":"PMC_33135196","title":"Oncocytic intraductal carcinoma of salivary glands: a distinct variant with TRIM33-RET fusions and BRAF V600E mutations.","date":"2021","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/33135196","citation_count":51,"is_preprint":false},{"pmid":"29930104","id":"PMC_29930104","title":"Trim33 mediates the proinflammatory function of Th17 cells.","date":"2018","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29930104","citation_count":51,"is_preprint":false},{"pmid":"34101965","id":"PMC_34101965","title":"TRIM33 protects osteoblasts from oxidative stress-induced apoptosis in osteoporosis by inhibiting FOXO3a ubiquitylation and degradation.","date":"2021","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/34101965","citation_count":45,"is_preprint":false},{"pmid":"27432991","id":"PMC_27432991","title":"Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β-dependent mechanisms.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27432991","citation_count":43,"is_preprint":false},{"pmid":"22294626","id":"PMC_22294626","title":"Anti-TIF1γ antibodies (anti-p155) in adult patients with dermatomyositis: comparison of different diagnostic assays.","date":"2012","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/22294626","citation_count":43,"is_preprint":false},{"pmid":"33986176","id":"PMC_33986176","title":"Cell-specific transcriptional control of mitochondrial metabolism by TIF1γ drives erythropoiesis.","date":"2021","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/33986176","citation_count":40,"is_preprint":false},{"pmid":"25919951","id":"PMC_25919951","title":"The transcriptional cofactor TRIM33 prevents apoptosis in B lymphoblastic leukemia by deactivating a single enhancer.","date":"2015","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/25919951","citation_count":40,"is_preprint":false},{"pmid":"21474105","id":"PMC_21474105","title":"Adult hematopoiesis is regulated by TIF1γ, a repressor of TAL1 and PU.1 transcriptional activity.","date":"2011","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/21474105","citation_count":36,"is_preprint":false},{"pmid":"23159334","id":"PMC_23159334","title":"TiF1-gamma plays an essential role in murine hematopoiesis and regulates transcriptional elongation of erythroid genes.","date":"2012","source":"Developmental 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forming a distinct effector arm of the TGFβ pathway. In human hematopoietic cells, TIF1γ mediates erythroid differentiation response while Smad4 mediates the antiproliferative response downstream of TGFβ.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, siRNA knockdown in human hematopoietic stem/progenitor cells with functional differentiation and proliferation readouts\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP, functional rescue experiments, replicated concept across multiple labs\",\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 architecture. Unlike TIF1α, it does not interact with nuclear receptors or HP1 proteins; unlike TIF1β, it does not interact with the KRAB silencing domain. Deletion of the TIF1 signature sequence (TSS) abrogates its transcriptional repression activity.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, domain-deletion transfection reporter assays in mammalian cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple in vitro binding assays plus mutagenesis, foundational characterization paper\",\n      \"pmids\": [\"10022127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TIF1γ controls erythroid cell fate by promoting transcription elongation: it physically interacts with the blood-specific SCL transcription complex and positive elongation factors p-TEFb and FACT, and recruits them to erythroid genes to counteract RNA Pol II pausing. Loss-of-function of Pol II-associated factors PAF or DSIF rescued erythroid transcription in tif1γ-deficient zebrafish.\",\n      \"method\": \"Genetic epistasis in zebrafish moonshine mutants, co-immunoprecipitation of TIF1γ with SCL complex/p-TEFb/FACT, ChIP in human CD34+ cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic epistasis plus biochemical interactions plus ChIP in primary human cells, replicated in mouse (PMID 23159334)\",\n      \"pmids\": [\"20603019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The PHD finger-bromodomain of TIF1γ/TRIM33 constitutes a multivalent histone-binding module that specifically recognizes histone H3 tails unmethylated at K4 and R2 and acetylated at key lysines. This chromatin binding activates TIF1γ's E3 ubiquitin ligase activity toward Smad4 and its transcriptional repressor activity.\",\n      \"method\": \"Histone peptide binding assays, in vitro ubiquitination assays, PHD-bromodomain mutagenesis, chromatin immunoprecipitation\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of ubiquitin ligase activity with mutagenesis showing histone-binding requirement; mechanistically rigorous single study\",\n      \"pmids\": [\"21726812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRIM24, TRIM28, and TRIM33 physically associate to form at least two macromolecular complexes (TRIM24-TRIM33 and TRIM24-TRIM28-TRIM33), and somatic hepatocyte-specific inactivation of any of these three proteins promotes hepatocellular carcinoma in mice in a cell-autonomous manner.\",\n      \"method\": \"Protein purification and mass spectrometry, conditional knockout mouse models with HCC phenotype assessment\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS-confirmed complex plus multiple conditional KO mouse models with defined tumor phenotype\",\n      \"pmids\": [\"21531907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TIF1γ forms complexes with TAL1 or PU.1 in hematopoietic cells, occupies specific subsets of their DNA binding sites in vivo, and represses their transcriptional activity, regulating adult hematopoietic stem cell function.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, conditional knockout mouse models with HSC transplantation and differentiation assays\",\n      \"journal\": \"Cell Stem Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, and KO mouse with defined cellular phenotypes\",\n      \"pmids\": [\"21474105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM33, acting as an E3 ubiquitin ligase, targets nuclear β-catenin for degradation in a GSK-3β- and β-TrCP-independent manner. Protein kinase Cδ phosphorylates β-catenin at Ser715, which is required for the TRIM33-β-catenin interaction and subsequent ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assays, PKCδ kinase assays, knockdown/overexpression with tumor growth readouts\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro ubiquitination reconstitution, identified phosphorylation requirement, validated in vivo tumor models\",\n      \"pmids\": [\"25639486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRIM33 is recruited to DNA damage sites in a PARP1- and ALC1-dependent manner, and interacts with ALC1 after DNA damage. TRIM33-deficient cells show enhanced sensitivity to DNA damage and prolonged ALC1 retention at damage sites; overexpression of TRIM33 alleviates DNA repair defects caused by ALC1 overexpression.\",\n      \"method\": \"Proteomic analysis (AP-MS), live-cell imaging of TRIM33 recruitment to laser damage sites, siRNA knockdown with DNA damage sensitivity assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS-identified interaction, live imaging of recruitment, functional epistasis with KD and OE\",\n      \"pmids\": [\"23926104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM33 prevents apoptosis in B lymphoblastic leukemia by associating with a single PU.1-bound enhancer upstream of the pro-apoptotic gene Bim; TRIM33 is recruited by PU.1 to this enhancer and antagonizes PU.1 function. Deletion of this enhancer renders TRIM33 dispensable for leukemia cell survival.\",\n      \"method\": \"ChIP-seq, enhancer deletion by genome editing, shRNA knockdown with apoptosis readout\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq genome-wide mapping plus enhancer deletion functional rescue, mechanistically rigorous\",\n      \"pmids\": [\"25919951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM33 switches off Ifnb1 transcription during late-phase macrophage activation by being recruited by PU.1 to a conserved Ifnb1 Control Element (ICE) 15 kb upstream of Ifnb1. At ICE, TRIM33 regulates enhanceosome loading, controls chromatin structure, and represses Ifnb1 transcription by preventing recruitment of CBP/p300.\",\n      \"method\": \"ChIP, ChIP-seq, 3C/4C chromatin interaction assays, TRIM33 KO macrophages with LPS stimulation, ChIP for CBP/p300\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq, chromatin looping, KO with defined molecular mechanism (CBP/p300 exclusion), macrophage-specific\",\n      \"pmids\": [\"26592194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM33 (E3 RING ligase) promotes degradation of HIV-1 integrase via the ubiquitin-proteasome system. TRIM33 knockdown in CD4+ cells increases HIV-1 replication and proviral DNA formation; overexpression has opposite effects.\",\n      \"method\": \"RNAi screen against ubiquitin machinery components, high-content microscopy, TRIM33 KD and OE with HIV infection assays, proviral DNA quantification\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic RNAi screen plus KD/OE functional validation with specific viral integration readout\",\n      \"pmids\": [\"30804369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TIF1γ operates as a SUMO E3 ligase (not only a ubiquitin E3 ligase) that promotes sumoylation of SnoN1 at distinct lysine residues via a 16-amino acid peptide unique to SnoN1 (not SnoN2). TIF1γ-induced SnoN1 sumoylation is required to suppress TGFβ-induced EMT in 3D mammary epithelial organoids.\",\n      \"method\": \"Interaction proteomics, in vitro sumoylation assays, domain mapping, 3D NMuMG organoid EMT assay\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of SUMO E3 ligase activity with domain mapping and functional 3D organoid validation\",\n      \"pmids\": [\"25059663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TIF1γ sumoylation is required for its repressive activity on TGFβ signaling. TIF1γ interacts with Ubc9 (the SUMO-conjugating enzyme) and is sumoylated at four functional sites within its middle domain (the Smad interaction domain). A sumoylation-defective mutant significantly reduces TIF1γ inhibition of Smad complexes and Smad4 binding to the PAI-1 promoter.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of sumoylation sites, ChIP on PAI-1 promoter, EMT assay in mammary epithelial cells\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis plus ChIP plus functional EMT assay\",\n      \"pmids\": [\"23788427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nuclear c-Abl tyrosine kinase phosphorylates TIF1γ/TRIM33 at Tyr-524, Tyr-610, and Tyr-1048, which reduces TIF1γ association with Smad3 and de-suppresses TGFβ signaling. EGF activates c-Abl to increase TIF1γ tyrosine phosphorylation, synergizing with TGFβ to provoke EMT.\",\n      \"method\": \"Phosphorylation site identification, triple tyrosine-to-phenylalanine (3YF) mutant rescue experiments, co-immunoprecipitation of TIF1γ with Smad3, EGF stimulation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis defining specific phosphorylation sites, functional rescue experiments, kinase-substrate relationship established\",\n      \"pmids\": [\"30177833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM33 is required for Th17 cell proinflammatory function: it associates with Smad2 and is recruited to the Il17a and Il10 gene loci in a Smad2-dependent manner, mediating chromatin remodeling during Th17 differentiation to induce IL-17 and suppress IL-10 expression.\",\n      \"method\": \"Conditional T cell-specific TRIM33 KO mice, ChIP at Il17a and Il10 loci, in vitro Th17 differentiation assays, autoimmune disease model\",\n      \"journal\": \"Journal of Experimental Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined phenotype, ChIP showing locus-specific recruitment, Smad2-dependence established\",\n      \"pmids\": [\"29930104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Adenovirus E4-ORF3 protein acts as a SUMO E3 ligase for TIF1γ sumoylation and can extend poly-SUMO3 chains in vitro; E4-ORF3 self-assembly (multimerization) is required for these activities. E4-ORF3 binds TIF1γ through the Coiled-Coil domain and relocalizes it to nuclear track structures in infected cells.\",\n      \"method\": \"In vitro sumoylation reconstitution with purified E4-ORF3 and TIF1γ, SUMO chain elongation assays, E4-ORF3 multimerization mutants, co-immunoprecipitation\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — purified protein in vitro reconstitution demonstrating SUMO E3 ligase activity plus mutagenesis\",\n      \"pmids\": [\"27247387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM33 directly associates with HSPB5 (crystallin alpha B), which diminishes TRIM33 protein level and impairs TRIM33/SMAD4 interaction. TRIM33 acts as a negative regulator of TGFβ1/SMAD signaling in lung fibroblasts and macrophages; its loss increases TGFβ1 secretion and downstream fibrogenic gene expression.\",\n      \"method\": \"Direct binding assay (HSPB5-TRIM33), co-immunoprecipitation, conditional KO mouse with bleomycin-induced fibrosis, primary cell cultures\",\n      \"journal\": \"European Respiratory Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding demonstrated, conditional KO with defined fibrosis phenotype, mechanistic link to SMAD4 interaction\",\n      \"pmids\": [\"32184320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Tif1γ controls TGFβ1 receptor (Tgfbr1) turnover: Tif1γ-deficient HSCs have elevated Tgfbr1 levels and increased TGFβ sensitivity. Two HSC populations discriminated by Tgfbr1 expression level (myeloid-biased Tgfbr1-high vs. balanced Tgfbr1-low) are regulated by Tif1γ.\",\n      \"method\": \"Conditional HSC-specific Tif1γ KO mice, flow cytometry, aging phenotype analysis, Tgfbr1 expression and TGFβ signaling assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined phenotype; Tgfbr1 regulation proposed but mechanism of how Tif1γ controls receptor turnover not fully biochemically defined\",\n      \"pmids\": [\"25002492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM33 facilitates androgen receptor (AR) chromatin binding and directly regulates AR-driven transcription in prostate cancer. TRIM33 also protects AR from Skp2-mediated ubiquitination and proteasomal degradation.\",\n      \"method\": \"Proteomics to identify TRIM33 as AR interactor, Co-IP, ChIP-seq for AR with TRIM33 KD, ubiquitination assays with Skp2\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — proteomics-identified interaction, ChIP-seq, ubiquitination assay defining Skp2 as the E3 ligase blocked by TRIM33\",\n      \"pmids\": [\"35785414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TIF1γ inhibits TGFβ-induced EMT in mammary epithelial cells by competing with Smad4 for binding to Smad2/3, and directly binds and represses the PAI-1 (plasminogen activator inhibitor 1) promoter.\",\n      \"method\": \"siRNA knockdown of TIF1γ or Smad4, microarray analysis of TIF1γ target genes, ChIP on PAI-1 promoter, EMT assays\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating direct promoter occupancy, genetic manipulation with defined EMT phenotype\",\n      \"pmids\": [\"21597466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TIF1γ directly controls coenzyme Q (CoQ) synthesis gene expression through transcription elongation, and CoQ levels regulate mitochondrial respiration. Loss of tif1γ reduces CoQ levels and increases the succinate/α-ketoglutarate ratio, leading to increased histone methylation and impaired erythroid differentiation.\",\n      \"method\": \"Chemical suppressor screen in zebrafish tif1γ mutants, metabolomics (CoQ measurement), histone methylation assays, CoQ analog rescue of bloodless phenotype\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — chemical genetic screen, metabolite rescue, mechanistic link between transcription elongation factor and metabolic output\",\n      \"pmids\": [\"33986176\"],\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. A unique glutamic acid residue within the TRIM33 bromodomain binding pocket confers specificity for Kla over other modifications; mutagenesis of this glutamic acid eliminates Kla binding.\",\n      \"method\": \"AlphaScreen assay of 28 bromodomains, isothermal titration calorimetry, protein-detected NMR, site-directed mutagenesis, molecular modeling\",\n      \"journal\": \"ACS Chemical Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal biophysical methods plus mutagenesis identifying the critical residue for Kla specificity\",\n      \"pmids\": [\"39556662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In macrophages, TRIM33 interacts with FACT subunit SPT16 at PU.1-bound distal regulatory elements. TRIM33 deficiency leads to FACT release, loss of positioned nucleosomes, RNA Pol II recruitment and bidirectional transcription at these elements, and increased gene expression.\",\n      \"method\": \"ChIP-seq for SPT16 and TRIM33, co-immunoprecipitation of TRIM33 with SPT16, ChIP for RNA Pol II and histone marks in TRIM33 KO macrophages, 3C chromatin interaction\",\n      \"journal\": \"Epigenetics & Chromatin\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq, Co-IP, functional consequence of KO on chromatin structure and transcription\",\n      \"pmids\": [\"31331374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In zebrafish, Trim33 deficiency causes primitive macrophages to fail to colonize the CNS to become microglia; both macrophages and neutrophils display reduced basal interstitial motility and fail to respond to inflammatory recruitment signals. Mouse Trim33-deficient bone marrow-derived macrophages show strongly reduced 3D amoeboid mobility in collagen gels.\",\n      \"method\": \"Trim33-deficient zebrafish embryo live imaging, bacterial infection assays, 3D collagen gel motility assay for mouse BMDMs\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — live imaging in zebrafish and mouse BMDM motility assays defining a non-TGFβ function in cell migration\",\n      \"pmids\": [\"28724755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TIF1γ inactivation causes chromosomal defects due to attenuation of the spindle assembly checkpoint and the post-mitotic checkpoint, resulting in loss of contact growth inhibition and increased anchorage-independent growth.\",\n      \"method\": \"TIF1γ siRNA knockdown, mitotic checkpoint assays, chromosomal instability quantification, soft agar and in vivo tumor growth assays\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined mitotic checkpoint phenotype; mechanistic detail on how TIF1γ regulates checkpoints not fully biochemically defined\",\n      \"pmids\": [\"26282171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM33 ubiquitin ligase targets E2f4 for degradation in unperturbed cells, limiting E2f4 genomic binding and interactions with DNA helicase Recql. Replicative stress blunts TRIM33-dependent ubiquitination of E2f4, stimulating transient Recql recruitment to chromatin and facilitating recovery of DNA synthesis.\",\n      \"method\": \"TRIM33 deletion in mouse cells, ubiquitination assays for E2f4, ChIP-seq for E2f4 and Recql, DNA fiber assays for replication fork progression, Myc-overexpression tumor model\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ubiquitination assays, ChIP-seq, DNA fiber analysis, genetic interaction with Myc in tumor model\",\n      \"pmids\": [\"37612308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM33 promotes K63-linked ubiquitination of Annexin A2 (Anxa2) in keratinocytes, which promotes Anxa2 interaction with p50/p65 NF-κB subunits, favors nuclear retention of p50/p65, and drives expression of NF-κB downstream inflammatory genes.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry to identify Anxa2 as TRIM33 substrate, K63-ubiquitination assay, co-immunoprecipitation of Anxa2 with NF-κB subunits, nuclear fractionation\",\n      \"journal\": \"Journal of Dermatological Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS-identified substrate, ubiquitination assay, Co-IP; single lab study\",\n      \"pmids\": [\"36096861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM33 protects osteoblasts from oxidative stress-induced apoptosis by binding CBP and restraining CBP-mediated FOXO3a acetylation, thereby attenuating FOXO3a ubiquitylation and degradation. TRIM33 and FOXO3a co-localize in osteoblast nuclei.\",\n      \"method\": \"Co-immunoprecipitation of TRIM33 with CBP and FOXO3a, immunofluorescence co-localization, FOXO3a acetylation and ubiquitination assays, OVX mouse model\",\n      \"journal\": \"Aging Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with functional assays; mechanism via CBP inhibition is from single lab\",\n      \"pmids\": [\"34101965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM33 promotes K48-linked polyubiquitination and proteasomal degradation of p53 at the K351 site in esophageal squamous cell carcinoma, leading to upregulation of glycolysis target genes GLUT1, HK2, PKM2, and LDHA.\",\n      \"method\": \"Co-immunoprecipitation, in vitro/cell-based ubiquitination assays with K48-linkage specificity, K351 site mutagenesis, glycolysis assays, xenograft model\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — ubiquitination assay with site mutagenesis; single lab study\",\n      \"pmids\": [\"39389957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM33 co-localizes with promyelocytic leukemia nuclear bodies (PML-NBs) specifically in mouse ESCs, and this localization depends on PML. TRIM33 and PML co-regulate Lefty1/2 expression, with PML-NBs directly associating with Lefty1/2 gene loci and required for TRIM33 recruitment to these loci.\",\n      \"method\": \"Co-localization imaging, TurboID proximity-labeling proteomics, PML KO in mESCs, ChIP, 4C-seq\",\n      \"journal\": \"EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — proximity labeling proteomics, KO functional validation, chromatin interaction mapping\",\n      \"pmids\": [\"36524443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIM33 has E3 ubiquitin ligase activity toward A-MYB, regulating its abundance in the testis. ChIP-seq in mouse testis reveals TRIM33 is enriched at RLTR10B LTR elements of MMERVK10C retrotransposons, and Trim33 haploinsufficiency increases expression of genes transcribed from upstream RLTR10B.\",\n      \"method\": \"ChIP-seq in mouse testis, RNA-seq, A-MYB ubiquitination assay\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP-seq plus ubiquitination assay; A-MYB as substrate is novel and from single study\",\n      \"pmids\": [\"26624618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM33 interacts with TFRC (transferrin receptor) and promotes its E3 ligase-dependent ubiquitination and degradation, thereby inducing cellular ferroptosis in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, ferroptosis markers (MDA, Fe2+, mitochondrial superoxide), xenograft model\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and ubiquitination assay with functional ferroptosis readout; single lab\",\n      \"pmids\": [\"38909931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PIAS1 and TIF1γ collaborate as SUMO E3 ligases forming a trimeric complex with SnoN to promote SnoN SUMOylation in an interdependent manner, suppressing EMT in breast organoids.\",\n      \"method\": \"Co-immunoprecipitation of trimeric SnoN-TIF1γ-PIAS1 complex, in vitro SUMOylation assays, loss-of-function studies in 3D breast organoid EMT assay\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — trimeric complex Co-IP, in vitro SUMO assay, functional 3D organoid validation\",\n      \"pmids\": [\"32770107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TIF1γ binds to TBP in competition with TAF15 and impedes TAF15/TBP-mediated IL-6 transactivation. TIF1γ also modifies TAF15 through multi-mono-ubiquitylation and drives nuclear export of TAF15, thereby inhibiting EMT and metastasis of lung adenocarcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation of TIF1γ-TBP and TIF1γ-TAF15 interactions, ubiquitination assay for TAF15, nuclear/cytoplasmic fractionation, IL-6 luciferase reporter, EMT and metastasis assays\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination assay, functional EMT assay; single lab study\",\n      \"pmids\": [\"36261009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM33 is an essential regulator of the entire DC lineage: conditional deletion causes rapid loss of DC progenitors, pDCs, and cDC1s. Trim33-deficient Flt3+ progenitors up-regulate pro-inflammatory and macrophage-specific genes but fail to induce the DC differentiation program, placing TRIM33 upstream of IRF8-driven DC commitment.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen for Flt3L-driven DC differentiation, conditional Trim33 KO mice, RNA-seq of progenitors\",\n      \"journal\": \"Science Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen plus conditional KO in vivo with defined lineage phenotype and transcriptional mechanism\",\n      \"pmids\": [\"38608038\"],\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 Irf8 gene sites (consistent with a transcription elongation function). TRIM33 also directly suppresses PU.1-mediated transcription of Bcl2l11 (Bim) to prevent DC apoptosis.\",\n      \"method\": \"ChIP for CDK9 and S2-phospho-Pol II at Irf8 locus, ChIP for TRIM33 and PU.1 at Bcl2l11, conditional KO mice, differentiation and apoptosis assays\",\n      \"journal\": \"Cellular & Molecular Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP defining transcription elongation mechanism at specific loci, conditional KO functional validation\",\n      \"pmids\": [\"38822080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIM33 is essential for the production of small peritoneal macrophages, monocytes, and bone marrow-derived macrophages. In mature myeloid cells, TRIM33 ChIP-seq reveals binding near inflammatory response genes; TRIM33 loss impairs repression of late LPS activation pathways and causes high LPS sensitivity in vivo.\",\n      \"method\": \"ChIP-seq in immature and mature myeloid cell lines, conditional KO mice with in vivo LPS challenge, macrophage production assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq plus conditional KO with defined immune phenotype; mechanism not fully biochemically reconstituted\",\n      \"pmids\": [\"27974684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM21 E3 ubiquitin ligase forms a complex with TIF1γ in the nucleus and promotes K48-linked ubiquitination of TIF1γ at K5, leading to TIF1γ degradation and consequent increase in nuclear β-catenin presence in glioblastoma.\",\n      \"method\": \"TMT/MS to identify TRIM21 substrates including TIF1γ, Co-IP, K48-ubiquitination assay at K5, luciferase reporter for β-catenin, RING-finger deletion mutant, xenograft model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS, Co-IP, site-specific ubiquitination assay; single lab\",\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 inhibiting ERK/β-catenin pathway activation in head and neck squamous cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation of YOD1 with TRIM33, ubiquitination assay showing YOD1 reduces TRIM33 ubiquitination, KD/OE functional assays with ERK/β-catenin pathway readout\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and ubiquitination assay with functional pathway readout; single lab\",\n      \"pmids\": [\"37573347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM33 loss reduces H2BK120 ubiquitination levels and decreases AR transcriptional output without affecting AR protein stability, suggesting TRIM33 facilitates maximal AR activity through chromatin modification rather than AR stabilization.\",\n      \"method\": \"Co-immunoprecipitation and ChIP-seq across prostate cancer cell lines, H2BK120 ubiquitination measurement, AR stability assays with TRIM33 KD\",\n      \"journal\": \"Communications Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq, chromatin mark measurement, functional transcriptomic output; single study contrasting earlier stabilization claims\",\n      \"pmids\": [\"40646276\"],\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; this interaction triggers phosphorylation of Smad1/5 and promotes BMP-driven differentiation.\",\n      \"method\": \"Co-immunoprecipitation of TRIM33 with Smad1/5, phospho-Smad1/5 assay, TRIM33 overexpression/knockdown with ALP, Runx2, osteocalcin readouts, cell cycle assays\",\n      \"journal\": \"Journal of Cellular Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP plus functional differentiation assay; mechanistic detail on how TRIM33 activates Smad1/5 phosphorylation not fully established\",\n      \"pmids\": [\"28063228\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM33 (TIF1γ) is a multifunctional nuclear E3 ubiquitin/SUMO ligase and chromatin reader that regulates TGFβ/Nodal/BMP signaling by competitively binding receptor-phosphorylated Smad2/3 away from Smad4, ubiquitinating Smad4 only upon recruitment to chromatin via its PHD finger-bromodomain (which recognizes unmodified H3K4/H3R2 and acetylated H3 lysines, and also histone lysine lactylation), promotes transcription elongation at lineage-specific genes through interactions with p-TEFb and FACT, acts as a SUMO E3 ligase for SnoN1 to suppress EMT, targets multiple substrates (nuclear β-catenin, HIV integrase, TFRC, E2f4, p53, A-MYB, AR-protective against Skp2) for ubiquitin-mediated degradation, is recruited to specific genomic regulatory elements by lineage-determining transcription factors (PU.1, TAL1, AR), participates in PARP-dependent DNA damage response by regulating ALC1 activity, and controls mitotic fidelity and replication fork progression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TRIM33 (TIF1γ) is a multifunctional nuclear E3 ubiquitin and SUMO ligase that integrates chromatin reading with transcriptional regulation and signal transduction across hematopoietic, immune, and epithelial lineages. Its PHD finger–bromodomain cassette recognizes histone H3 tails unmethylated at K4/R2 and acetylated at specific lysines—and uniquely among bromodomains binds histone lysine lactylation—coupling chromatin state to its RING-dependent E3 ligase activity, which ubiquitinates Smad4, β-catenin, E2f4, p53, HIV-1 integrase, and other substrates, and SUMOylates SnoN1 cooperatively with PIAS1 to suppress TGF-β-induced EMT [PMID:21726812, PMID:39556662, PMID:25639486, PMID:25059663, PMID:32770107]. TRIM33 competitively binds receptor-phosphorylated Smad2/3 away from Smad4, separating TGF-β signaling into a TRIM33-dependent differentiation arm and a Smad4-dependent antiproliferative arm, while also promoting transcription elongation at lineage-specific genes by recruiting p-TEFb and the FACT complex in partnership with lineage-determining transcription factors PU.1, TAL1/SCL, and the androgen receptor [PMID:16751102, PMID:20603019, PMID:21474105, PMID:35785414]. These elongation and chromatin-remodeling activities underpin TRIM33's essential roles in erythropoiesis, dendritic cell commitment upstream of IRF8, macrophage inflammatory gene regulation, Th17 differentiation, and coenzyme Q biosynthesis, and its loss leads to chromosomal instability, impaired DNA damage response through dysregulated ALC1, and replication stress sensitivity via E2f4-Recql stabilization [PMID:33986176, PMID:38608038, PMID:23926104, PMID:37612308, PMID:26282171].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing TRIM33's domain architecture (RING, B-box, coiled-coil, PHD, bromodomain) and intrinsic transcriptional repression activity distinguished it from paralogs TIF1α and TIF1β and set the framework for all subsequent functional studies.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, and domain-deletion reporter assays in mammalian cells\",\n      \"pmids\": [\"10022127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No endogenous target genes identified\", \"No E3 ligase activity tested\", \"Physiological role unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that TIF1γ competitively binds phospho-Smad2/3 away from Smad4 revealed a bifurcation of TGF-β signaling into distinct effector arms—TIF1γ for differentiation and Smad4 for growth arrest—answering how a single pathway drives divergent cell-fate outcomes.\",\n      \"evidence\": \"Reciprocal Co-IP, GST pulldown, siRNA knockdown in human hematopoietic stem/progenitor cells with erythroid differentiation and proliferation readouts\",\n      \"pmids\": [\"16751102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin-level mechanism of TIF1γ-Smad target gene selection unknown\", \"Whether TIF1γ possesses E3 ligase activity toward Smads not yet tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying TIF1γ as a transcription elongation factor—through physical interaction with p-TEFb and FACT and genetic epistasis with pausing regulators—explained how it activates blood-specific genes beyond simply modulating Smad signaling.\",\n      \"evidence\": \"Genetic epistasis in zebrafish moonshine mutants, Co-IP of TIF1γ with SCL/p-TEFb/FACT, ChIP in human CD34+ cells\",\n      \"pmids\": [\"20603019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether elongation function is general or restricted to erythroid loci\", \"Direct biochemical mechanism of Pol II pause release by TIF1γ not reconstituted\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Three advances converged: the PHD-bromodomain was shown to read unmodified H3K4/H3R2 and acetylated H3 to activate TRIM33's E3 ligase activity toward Smad4; TRIM33 was found to form macromolecular complexes with TRIM24/TRIM28 that suppress hepatocellular carcinoma; and TRIM33 was shown to be recruited by TAL1 and PU.1 to specific hematopoietic enhancers.\",\n      \"evidence\": \"Histone peptide binding/in vitro ubiquitination/mutagenesis (PMID:21726812); MS-confirmed TRIM24/28/33 complex with conditional KO HCC models (PMID:21531907); Co-IP, ChIP, conditional KO HSC transplantation (PMID:21474105); ChIP on PAI-1 promoter with EMT assay (PMID:21597466)\",\n      \"pmids\": [\"21726812\", \"21531907\", \"21474105\", \"21597466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of PHD-bromodomain with histone peptide not yet solved\", \"How TRIM24/TRIM28/TRIM33 complexes cooperate mechanistically unclear\", \"E3 activity toward Smad4 shown in vitro but not validated at endogenous chromatin targets\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two discoveries established TRIM33's regulation by and of the SUMO pathway: its own sumoylation is required for Smad complex repression, and it participates in the PARP1/ALC1-dependent DNA damage response at laser-induced lesions, broadening its functions beyond TGF-β signaling.\",\n      \"evidence\": \"Sumoylation site mutagenesis with ChIP on PAI-1 promoter and EMT assay (PMID:23788427); AP-MS, live-cell imaging of TRIM33 recruitment to damage sites, siRNA epistasis with ALC1 (PMID:23926104)\",\n      \"pmids\": [\"23788427\", \"23926104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of SUMO E3 ligase acting on TRIM33 itself unknown at this point\", \"Direct substrates of TRIM33 at DNA damage sites not identified\", \"Structural basis of sumoylation-dependent Smad regulation unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Reconstitution of TRIM33 as a bona fide SUMO E3 ligase for SnoN1—requiring a unique 16-amino-acid SnoN1 peptide—demonstrated dual E3 ligase specificity (ubiquitin and SUMO) and linked it to EMT suppression through a non-Smad mechanism.\",\n      \"evidence\": \"In vitro sumoylation assay with purified proteins, domain mapping, 3D NMuMG organoid EMT assay (PMID:25059663); conditional KO HSC with Tgfbr1 regulation (PMID:25002492)\",\n      \"pmids\": [\"25059663\", \"25002492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRIM33 SUMOylates substrates beyond SnoN1 not established\", \"Mechanism of Tgfbr1 turnover by TIF1γ not biochemically defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Multiple studies expanded TRIM33's substrate repertoire and genomic functions: it ubiquitinates nuclear β-catenin in a PKCδ/Ser715-dependent manner, is recruited by PU.1 to a single enhancer controlling Bim to prevent leukemia apoptosis, and represses Ifnb1 by blocking CBP/p300 recruitment at a distal control element.\",\n      \"evidence\": \"In vitro ubiquitination and kinase assays with tumor models (PMID:25639486); ChIP-seq and enhancer deletion in B-ALL (PMID:25919951); ChIP-seq, 3C/4C, KO macrophages with LPS (PMID:26592194); mitotic checkpoint assays with KD (PMID:26282171)\",\n      \"pmids\": [\"25639486\", \"25919951\", \"26592194\", \"26282171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRIM33 distinguishes its many E3 substrates at different genomic contexts unknown\", \"Mechanism of spindle assembly checkpoint regulation biochemically undefined\", \"Whether β-catenin ubiquitination occurs at specific chromatin loci not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The demonstration that adenovirus E4-ORF3 hijacks TRIM33 as a substrate for viral SUMO E3 ligase activity, with poly-SUMO3 chain extension, established that TRIM33 is a target of pathogen immune evasion through SUMO modification.\",\n      \"evidence\": \"In vitro sumoylation reconstitution with purified E4-ORF3 and TIF1γ, SUMO chain elongation, multimerization mutants\",\n      \"pmids\": [\"27247387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of E4-ORF3-mediated TRIM33 sumoylation for infection outcome not fully defined\", \"Whether other viruses similarly exploit TRIM33 unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"In vivo studies extended TRIM33's lineage roles to myeloid cell motility (macrophage/microglia colonization), myeloid inflammatory gene regulation, testicular retrotransposon silencing via A-MYB ubiquitination, and BMP-pathway osteoblast differentiation, revealing tissue-wide pleiotropic functions.\",\n      \"evidence\": \"Zebrafish live imaging and mouse BMDM collagen motility (PMID:28063228 for BMP/osteoblast; PMID:28724755 for motility); ChIP-seq in myeloid cells with conditional KO and LPS challenge (PMID:27974684); ChIP-seq and ubiquitination in testis (PMID:26624618)\",\n      \"pmids\": [\"28724755\", \"27974684\", \"26624618\", \"28063228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target mediating cell motility not identified\", \"A-MYB ubiquitination not independently confirmed\", \"How TRIM33 promotes Smad1/5 phosphorylation in BMP signaling is unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"c-Abl tyrosine phosphorylation of TRIM33 at three sites was shown to disrupt Smad3 binding, revealing a mechanism by which EGF synergizes with TGF-β to overcome TRIM33-mediated EMT suppression; concurrently, TRIM33's Smad2-dependent recruitment to Il17a and Il10 loci was shown to govern Th17 inflammatory function.\",\n      \"evidence\": \"Phosphosite mutagenesis and rescue with EGF/TGF-β EMT assays (PMID:30177833); conditional T-cell KO with ChIP at cytokine loci and autoimmune model (PMID:29930104)\",\n      \"pmids\": [\"30177833\", \"29930104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other kinases regulate TRIM33 at different sites unknown\", \"Chromatin remodeling mechanism at Il17a/Il10 not biochemically reconstituted\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two studies defined TRIM33's interaction with the FACT complex at distal regulatory elements: in macrophages TRIM33 retains SPT16/FACT and positioned nucleosomes at PU.1-bound enhancers to prevent aberrant transcription, and TRIM33 targets HIV-1 integrase for proteasomal degradation, restricting viral replication.\",\n      \"evidence\": \"ChIP-seq for SPT16/TRIM33, Co-IP, nucleosome positioning in TRIM33 KO macrophages (PMID:31331374); RNAi screen with HIV integration assays (PMID:30804369)\",\n      \"pmids\": [\"31331374\", \"30804369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FACT retention mechanism involves direct TRIM33 ubiquitin ligase activity at enhancers not determined\", \"HIV integrase ubiquitination sites not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"PIAS1 and TIF1γ were shown to collaborate as SUMO E3 ligases in a trimeric complex with SnoN, and HSPB5 was identified as a direct TRIM33 binding partner that destabilizes it, with TRIM33 loss increasing TGF-β1-driven fibrosis.\",\n      \"evidence\": \"Trimeric complex Co-IP and in vitro SUMO assay with 3D breast organoid EMT (PMID:32770107); HSPB5 direct binding with conditional KO bleomycin fibrosis model (PMID:32184320)\",\n      \"pmids\": [\"32770107\", \"32184320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PIAS1 and TIF1γ coordinate E3 activity structurally unknown\", \"Whether HSPB5-mediated destabilization is tissue-specific not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A chemical suppressor screen in zebrafish revealed that TIF1γ's transcription elongation function directly controls coenzyme Q biosynthetic gene expression; CoQ deficiency alters succinate/α-KG ratios, increases histone methylation, and blocks erythropoiesis—linking chromatin-reading and elongation to metabolic output.\",\n      \"evidence\": \"Chemical genetic screen in tif1γ mutant zebrafish, metabolomics, histone methylation assays, CoQ analog rescue\",\n      \"pmids\": [\"33986176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CoQ pathway regulation by TRIM33 is conserved in mammals not fully confirmed\", \"Direct TRIM33 occupancy at CoQ biosynthetic gene loci not shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Multiple substrate-level discoveries demonstrated TRIM33's broad E3 ligase repertoire: it facilitates AR chromatin binding and protects AR from Skp2-mediated degradation in prostate cancer, promotes K63-ubiquitination of Annexin A2 driving NF-κB inflammatory signaling, co-localizes with PML nuclear bodies in ESCs to regulate Lefty1/2, and ubiquitinates TAF15 for nuclear export to suppress IL-6/EMT.\",\n      \"evidence\": \"Proteomics/ChIP-seq for AR (PMID:35785414); K63-Ub assay and NF-κB Co-IP (PMID:36096861); TurboID/4C-seq for PML-NB co-regulation of Lefty (PMID:36524443); TAF15 ubiquitination and TBP competition (PMID:36261009); TFRC ubiquitination and ferroptosis (PMID:38909931)\",\n      \"pmids\": [\"35785414\", \"36096861\", \"36524443\", \"36261009\", \"38909931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How substrate selectivity is achieved among many targets remains a central unresolved question\", \"AR stabilization versus chromatin modification mechanisms appear contradictory across studies\", \"K63-linked Annexin A2 ubiquitination awaits independent confirmation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"TRIM33 was shown to ubiquitinate E2f4 for degradation, limiting E2f4-Recql chromatin association; replicative stress relieves this control to promote fork recovery—establishing TRIM33 as a replication stress response factor. Separately, TRIM33 itself was identified as a substrate of TRIM21 (K48-Ub at K5) and stabilized by the DUB YOD1.\",\n      \"evidence\": \"Ubiquitination assays, ChIP-seq, DNA fiber assays for E2f4-Recql (PMID:37612308); TRIM21/TRIM33 Co-IP and K5 site ubiquitination (PMID:37771771); YOD1-TRIM33 Co-IP and stabilization (PMID:37573347)\",\n      \"pmids\": [\"37612308\", \"37771771\", \"37573347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRIM33-E2f4 axis operates in non-transformed cells not confirmed\", \"How TRIM21 and YOD1 activities on TRIM33 are coordinated in physiological contexts unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The TRIM33 bromodomain was found to uniquely recognize histone lysine lactylation (Kla) via a glutamic acid residue in its binding pocket, expanding the chromatin marks it reads. Concurrently, genome-wide CRISPR screens and conditional KO revealed TRIM33 as essential for dendritic cell lineage commitment upstream of IRF8, operating through CDK9-dependent transcription elongation at Irf8 and PU.1-dependent Bim repression. TRIM33 was also shown to ubiquitinate p53 at K351 promoting glycolysis.\",\n      \"evidence\": \"AlphaScreen of 28 bromodomains, ITC, NMR, mutagenesis for Kla (PMID:39556662); CRISPR screen and conditional KO for DC (PMID:38608038); ChIP for CDK9/S2P-Pol II at Irf8 (PMID:38822080); p53 K351 ubiquitination assay (PMID:39389957)\",\n      \"pmids\": [\"39556662\", \"38608038\", \"38822080\", \"39389957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Kla reading by TRIM33 in vivo not established\", \"Whether DC lineage role involves TRIM33's SUMO E3 activity not tested\", \"p53 K351 ubiquitination from single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A contrasting study found that TRIM33 loss reduces H2BK120 ubiquitination and AR transcriptional output without affecting AR protein stability, suggesting TRIM33 supports AR function through chromatin modification rather than protein stabilization.\",\n      \"evidence\": \"Co-IP, ChIP-seq, H2BK120ub measurement, AR stability assays across prostate cancer lines\",\n      \"pmids\": [\"40646276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TRIM33 directly ubiquitinates H2BK120 or acts indirectly not determined\", \"Discrepancy with earlier AR stabilization study not resolved\", \"Mechanism linking TRIM33 to the H2B ubiquitination machinery unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Central unresolved questions include: how TRIM33 achieves substrate selectivity among its numerous ubiquitin and SUMO targets; whether its bromodomain Kla-reading activity has distinct physiological outputs from its canonical acetyl-lysine reading; the structural basis of chromatin-activated E3 ligase activity; and how its elongation, E3 ligase, and chromatin-reading functions are coordinated at individual genomic loci.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of full-length TRIM33 or chromatin-engaged TRIM33\", \"Substrate selectivity mechanism unknown\", \"Kla-reading functional consequences in vivo untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 6, 10, 11, 25, 28, 30, 31, 32, 33, 39]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3, 21]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 5, 8, 9, 19, 35]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [3, 6, 10, 11, 25, 28, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 3, 5, 7, 8, 9, 18, 27, 29]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3, 21, 39]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074160\", \"supporting_discovery_ids\": [1, 2, 5, 8, 9, 19, 20, 35]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6, 13, 14, 16, 40]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 6, 10, 11, 25, 28, 30, 31, 32, 33]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 14, 34, 35, 36]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 20, 34, 40]}\n    ],\n    \"complexes\": [\n      \"TRIM24-TRIM28-TRIM33\",\n      \"SnoN1-TIF1γ-PIAS1\"\n    ],\n    \"partners\": [\n      \"SMAD2\",\n      \"SMAD4\",\n      \"PU.1\",\n      \"TAL1\",\n      \"SUPT16H\",\n      \"CDK9\",\n      \"ALC1\",\n      \"TRIM24\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}