{"gene":"TRIM37","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2014,"finding":"TRIM37 functions as an E3 ubiquitin ligase that mono-ubiquitinates histone H2A, a chromatin modification associated with transcriptional repression. TRIM37 associates with PRC2 (not PRC1 like RNF2), and together with PRC1 co-occupies target gene promoters to silence them. RNAi-mediated knockdown of TRIM37 results in loss of ubiquitinated H2A, dissociation of PRC1 and PRC2 from target promoters, and transcriptional reactivation.","method":"ChIP-chip, RNAi knockdown, co-immunoprecipitation, in vivo xenograft","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, genome-wide ChIP, loss-of-function with defined molecular phenotype, multiple orthogonal methods in single high-impact study","pmids":["25470042"],"is_preprint":false},{"year":2005,"finding":"TRIM37 acts as a RING domain-dependent E3 ubiquitin ligase; full-length TRIM37 and its TRIM domain undergo polyubiquitination in cell-free conditions, and disruption of the RING domain (Cys35Ser;Cys36Ser) or a disease-associated missense mutation (Leu76Pro) abolishes this activity. Ectopically expressed TRIM37 forms ubiquitin-, proteasome subunit-, and chaperone-positive aggresomes, and disease mutants are markedly less prone to aggregation.","method":"Cell-free ubiquitination assay, co-expression with ubiquitin, active-site mutagenesis, immunofluorescence","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with active-site mutagenesis, multiple mutants tested","pmids":["15885686"],"is_preprint":false},{"year":2002,"finding":"TRIM37 protein localizes to peroxisomes; peroxisomal import depends on PEX1 and PEX5 but not PEX7. The major Finnish disease-associated mutant protein fails to localize to peroxisomes, while the minor Finnish mutant retains peroxisomal targeting, classifying Mulibrey nanism as a peroxisomal disorder.","method":"Transient transfection, double immunofluorescence with peroxisomal markers, analysis in PEX1/PEX5/PEX7 mutant fibroblasts, antibody localization","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiment with functional consequence across multiple genetic backgrounds","pmids":["11938494"],"is_preprint":false},{"year":2017,"finding":"TRIM37 localizes to peroxisomal membranes and ubiquitylates PEX5 at K464 by interacting with the C-terminal 51 amino acids (CT51) of PEX5; this ubiquitylation stabilizes PEX5 and is required for peroxisomal matrix protein import. TRIM37 depletion or PEX5 K464A/ΔCT51 mutations promote proteasomal degradation of PEX5, impair cargo binding, and induce apoptosis and oxidative stress sensitivity.","method":"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K464A), siRNA knockdown, cell fractionation, functional import assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1/2 — biochemical reconstitution of ubiquitination with mutagenesis, functional import assay, multiple orthogonal methods","pmids":["28724525"],"is_preprint":false},{"year":2018,"finding":"TRIM37 interacts with MTOR and RRAGB, enhances the MTOR-RRAGB interaction, and promotes lysosomal localization of MTOR, thereby activating amino acid-stimulated MTORC1 signaling. TRIM37 loss reduces TFEB phosphorylation, causing its nuclear translocation and transcriptional activation of autophagy and lysosome biogenesis genes.","method":"Co-immunoprecipitation, subcellular fractionation, TFEB localization assay, MTORC1 activity readouts (phospho-substrates), siRNA knockdown","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP, functional pathway readouts; single lab study","pmids":["29940807"],"is_preprint":false},{"year":2018,"finding":"TRIM37 monoubiquitinates NEMO at K309 in the nucleus in response to genotoxic stress. ATM kinase, activated by DNA damage, phosphorylates TRIM37 in the cytoplasm, triggering its nuclear translocation where it forms a complex with NEMO and TRAF6 via a TRAF6-binding motif (TBM), leading to nuclear export of NEMO and IKK/NF-κB activation.","method":"Co-immunoprecipitation, ubiquitination assay, subcellular fractionation, site-directed mutagenesis, cell-penetrating TAT-TBM peptide inhibition, in vivo xenograft","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1/2 — biochemical identification of ubiquitination site, mutagenesis, mechanistic peptide inhibitor with in vivo validation, multiple orthogonal methods","pmids":["30254148"],"is_preprint":false},{"year":2018,"finding":"TRIM37 promotes K63-linked polyubiquitination of TRAF2, sustaining NF-κB pathway activation in NSCLC. Mutation of the RING finger domain of TRIM37 abolishes TRAF2 K63 polyubiquitination and NF-κB activation.","method":"Co-immunoprecipitation, ubiquitination assay, RING domain mutagenesis, NF-κB reporter assay, siRNA knockdown and overexpression","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with mutagenesis confirmation, functional pathway readout; single lab","pmids":["30043491"],"is_preprint":false},{"year":2020,"finding":"TRIM37 levels determine mitotic vulnerability to PLK4 inhibition. High TRIM37 inhibits acentrosomal spindle assembly by degrading the centrosomal component CEP192. TRIM37 also prevents PLK4 from self-assembling into centrosome-independent condensates that serve as ectopic microtubule-organizing centers (MTOCs). TRIM37 amplification (17q23) in breast cancer and neuroblastoma renders these cancers highly sensitive to PLK4 inhibition.","method":"TRIM37 knockdown/overexpression, live-cell imaging, centrosome depletion assay (PLK4 inhibitor centrinone), epistasis with TRIM37 loss, CEP192 degradation assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional assays, epistasis analysis, replicated across two concurrent Nature papers","pmids":["32908304"],"is_preprint":false},{"year":2020,"finding":"TRIM37 overexpression acts as a negative regulator of centrosomal pericentriolar material (PCM). In 17q23-amplified cells lacking centrosomes (after PLK4 inhibition), elevated TRIM37 blocks formation of PCM foci required for acentrosomal spindle assembly, causing mitotic catastrophe. TRIM37 overexpression also delays centrosome maturation and separation at mitotic entry, increasing mitotic error frequency.","method":"PLK4 inhibitor treatment, live-cell imaging, PCM focus formation assay, TRIM37 siRNA and overexpression, centrosome maturation timing analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple functional assays with direct imaging evidence, replicated concurrent with PMID 32908304","pmids":["32908313"],"is_preprint":false},{"year":2021,"finding":"TRIM37 prevents formation of centriolar protein assemblies (Cenpas) by regulating the stability and solubility of Centrobin; TRIM37 depletion leads to Centrobin accumulation in elongated entities. Cenpas can act as ectopic MTOCs and their formation upon TRIM37 depletion requires PLK4 and two parallel pathways relying on Centrobin and PLK1, respectively. Patient-derived Mulibrey nanism cells harbor these assemblies.","method":"Correlative light electron microscopy, siRNA knockdown, Centrobin ubiquitination assay, PLK4 inhibition epistasis, live imaging, patient-derived cell analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1/2 — correlative EM, biochemical ubiquitination, genetic epistasis with multiple pathways, patient cell validation","pmids":["33491649"],"is_preprint":false},{"year":2021,"finding":"TRIM37 prevents assembly of centrobin-scaffolded structured condensates that bud off centrosomes and organize ectopic spindle poles. In ~25% of TRIM37-deficient cells an ectopic spindle pole forms, recruiting centrosomal proteins and acquiring microtubule nucleation capacity. Centrobin interacts with and is ubiquitinated by TRIM37; removing centrobin suppresses ectopic spindle pole formation and multipolar segregation in TRIM37-deficient cells.","method":"Live-cell imaging, ubiquitination assay, Co-IP (Centrobin-TRIM37), centrobin knockout epistasis, multipolar mitosis quantification","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1/2 — biochemical ubiquitination with epistasis, live imaging, multiple orthogonal methods","pmids":["33983387"],"is_preprint":false},{"year":2020,"finding":"TRIM37-directed histone H2A monoubiquitination enforces changes in DNA repair that rendered TP53-mutant TNBC cells resistant to chemotherapy. Chemotherapeutic drugs trigger a positive feedback loop via ATM/E2F1/STAT signaling that amplifies the TRIM37 network.","method":"H2A ubiquitination assay, knockdown/overexpression, in vivo metastasis model, antisense oligonucleotide nanoparticle delivery, ATM/E2F1/STAT pathway analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — functional assays with defined molecular mechanism; single lab with in vivo validation","pmids":["32855208"],"is_preprint":false},{"year":2020,"finding":"ASB16-AS1 lncRNA promotes TRIM37 phosphorylation by cooperating with ATM serine/threonine kinase, inducing TRIM37 nuclear translocation and NF-κB pathway activation in gastric cancer cells.","method":"Co-immunoprecipitation, RNA immunoprecipitation, pulldown, luciferase reporter, NF-κB pathway analysis, phosphorylation assay","journal":"Gastric cancer","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP and biochemical assays identifying ATM as TRIM37 kinase; single lab","pmids":["32572790"],"is_preprint":false},{"year":2022,"finding":"PBK (PDZ-binding kinase) directly interacts with TRIM37 and promotes its phosphorylation and nuclear translocation, subsequently activating the NF-κB pathway and conferring PARP inhibitor resistance in ovarian cancer.","method":"Co-immunoprecipitation, phosphorylation assay, nuclear translocation imaging, NF-κB reporter, in vitro and in vivo drug resistance assays","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP with functional consequence; single lab","pmids":["35859118"],"is_preprint":false},{"year":2020,"finding":"TRIM37 physically interacts with SMAD7 and promotes ubiquitination-mediated degradation of SMAD7, thereby facilitating TGF-β signaling and HBV-associated hepatic fibrosis. NF-κB activation mediated by ROS is necessary for transcriptional induction of TRIM37 during HBV infection.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, mouse fibrosis model, NF-κB inhibition","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP and ubiquitination assay with in vivo model; single lab","pmids":["32916597"],"is_preprint":false},{"year":2021,"finding":"TRIM37 promotes K63-linked ubiquitination of TRAF6, negatively regulating inflammatory responses induced by virus (H1N1) infection. Direct interaction between TRIM37 and TRAF6 was demonstrated by immunoprecipitation, and TRIM37 knockout in mice inhibited immune responses and reduced proinflammatory cytokines in macrophages.","method":"Immunoprecipitation, ubiquitination assay (K63-specific), TRIM37 knockout mice, ELISA, flow cytometry","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with in vivo KO validation; single lab","pmids":["33839419"],"is_preprint":false},{"year":2021,"finding":"During PM (particulate matter)-induced autophagy in lung epithelial cells, TRIM37 is degraded via autophagy, which protects TRAF6 from proteasomal degradation, promoting NF-κB-dependent chemokine production and neutrophil recruitment. TRIM37 thus normally promotes TRAF6 ubiquitin-mediated proteasomal degradation.","method":"Autophagy inhibition, siRNA knockdown of TRIM37 and TRAF6, mouse lung metastasis model, NF-κB reporter","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2/3 — functional assays with in vivo model; single lab","pmids":["34524943"],"is_preprint":false},{"year":2023,"finding":"TRIM37 directly interacts with TRAF6, induces K63-linked ubiquitination of TRAF6, leading to IKKβ phosphorylation. TRIM37 also enhances translocation of IKKγ (NEMO) from nucleus to cytoplasm, stabilizing the cytoplasmic IKK complex and prolonging inflammatory NF-κB signaling during hepatic ischemia/reperfusion injury.","method":"Immunoprecipitation, ubiquitination assay, Western blot of subcellular fractions, immunofluorescence, IKK inhibitor rescue in vivo","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical interaction and ubiquitination with in vivo functional rescue; single lab","pmids":["37158850"],"is_preprint":false},{"year":2021,"finding":"TRIM37 orchestrates renal cell carcinoma progression via TGF-β1 signaling activation mediated by ubiquitinating histone H2A modifications, promoting EMT and malignant progression.","method":"H2A ubiquitination assay, Co-IP, gain/loss-of-function models, in vivo xenograft, TGF-β1 pathway analysis","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2/3 — ubiquitination and Co-IP with in vivo model; single lab","pmids":["34130705"],"is_preprint":false},{"year":2020,"finding":"TRIM37 modulates ubiquitination and degradation of PTEN via its E3 ligase activity, negatively regulating the AKT-GSK-3β-β-catenin signaling pathway in pancreatic cancer cells, thereby sustaining aberrant activation and stemness.","method":"Co-immunoprecipitation, ubiquitination assay, protein stability assay, immunofluorescence, in vivo xenograft","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP and ubiquitination with in vivo validation; single lab","pmids":["33194618"],"is_preprint":false},{"year":2022,"finding":"TRIM37 interacts with P53 and induces its K48-linked ubiquitination and proteasomal degradation, thereby promoting aerobic glycolysis and tumor progression in hepatocellular carcinoma. Genetic knockdown of P53 reverses TRIM37's pro-tumorigenic effects.","method":"Co-immunoprecipitation, ubiquitination assay (K48-specific), siRNA epistasis, in vivo xenograft","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP with ubiquitination assay and epistasis; single lab","pmids":["36252649"],"is_preprint":false},{"year":2016,"finding":"Trim37 knockout mice recapitulate several features of Mulibrey nanism including infertility (germ cell aplasia), non-compaction cardiomyopathy, hepatomegaly, fatty liver, elevated fasting blood glucose, and tumor formation, establishing TRIM37 loss-of-function as causal for this multi-organ disorder.","method":"Congenic knockout mouse model, histopathology, hormone assays, metabolic measurements, CT skeletal analysis","journal":"Biology open","confidence":"High","confidence_rationale":"Tier 2 — in vivo knockout model with multiple defined phenotypic readouts recapitulating human disease","pmids":["27044324"],"is_preprint":false},{"year":2021,"finding":"TRIM37 is highly expressed during mitosis in chondrocytes; during M phase, TRIM37 co-localizes with tubulin. TRIM37 knockdown inhibits chondrocyte proliferation with cell cycle anomalies and increased autophagy, while overexpression enhances proliferation. miR-223 directly targets and negatively regulates TRIM37 expression.","method":"Western blotting, confocal microscopy, imaging flow cytometry, siRNA knockdown, overexpression, cell cycle analysis","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2/3 — direct localization during cell cycle phases with functional consequence; single lab","pmids":["32353567"],"is_preprint":false}],"current_model":"TRIM37 is a RING domain-dependent E3 ubiquitin ligase that localizes to peroxisomes, centrosomes, and the nucleus, and exerts its functions through multiple substrates: it mono-ubiquitinates histone H2A (silencing tumor suppressors in association with PRC2), ubiquitylates PEX5 (stabilizing it for peroxisomal matrix protein import), ubiquitinates Centrobin (preventing formation of ectopic centrosomal condensates and extra spindle poles to ensure mitotic fidelity), monoubiquitinates NEMO/IKKγ at K309 to activate NF-κB in response to ATM-mediated genotoxic stress, promotes K63-linked ubiquitination of TRAF2 and TRAF6 for NF-κB signaling, and targets PTEN, SMAD7, and p53 for proteasomal degradation; furthermore, TRIM37 enhances MTORC1 activity by promoting lysosomal localization of MTOR, and its amplification at 17q23 sensitizes cancer cells to PLK4 inhibition by blocking acentrosomal spindle assembly through CEP192 degradation."},"narrative":{"teleology":[{"year":2002,"claim":"Establishing where TRIM37 resides answered the basic question of its organellar context: TRIM37 localizes to peroxisomes via PEX5-dependent import, classifying Mulibrey nanism as a peroxisomal disorder.","evidence":"Double immunofluorescence with peroxisomal markers in wild-type and PEX-mutant fibroblasts","pmids":["11938494"],"confidence":"High","gaps":["Peroxisomal membrane vs. matrix topology was not resolved","No enzymatic activity had yet been demonstrated"]},{"year":2005,"claim":"Demonstrating that TRIM37 possesses intrinsic E3 ubiquitin ligase activity dependent on its RING domain established the enzymatic basis for all subsequent substrate studies.","evidence":"Cell-free ubiquitination assay with RING domain mutagenesis and disease-associated missense mutations","pmids":["15885686"],"confidence":"High","gaps":["No physiological substrate was identified","Ubiquitin chain type was not determined"]},{"year":2014,"claim":"Identification of histone H2A as a TRIM37 substrate revealed an unexpected chromatin-silencing function: TRIM37 mono-ubiquitinates H2A and cooperates with PRC2 and PRC1 to repress tumor-suppressor promoters.","evidence":"ChIP-chip, RNAi knockdown, co-immunoprecipitation, and in vivo xenograft in breast cancer cells","pmids":["25470042"],"confidence":"High","gaps":["Whether H2A ubiquitination is direct or requires additional cofactors in vivo was not fully resolved","Structural basis of TRIM37-PRC2 interaction unknown"]},{"year":2016,"claim":"A Trim37 knockout mouse recapitulated Mulibrey nanism features — cardiomyopathy, infertility, hepatomegaly, and tumor predisposition — providing definitive in vivo genetic proof of causality.","evidence":"Congenic knockout mouse model with histopathology and metabolic characterization","pmids":["27044324"],"confidence":"High","gaps":["Which specific substrates underlie each organ-level phenotype remains undetermined","Tissue-specific conditional knockouts were not generated"]},{"year":2017,"claim":"Discovery that TRIM37 ubiquitylates PEX5 at K464 to stabilize it for peroxisomal matrix protein import connected the peroxisomal localization to a defined biochemical function and explained oxidative stress sensitivity in TRIM37-deficient cells.","evidence":"Co-immunoprecipitation, site-directed mutagenesis of PEX5 K464, ubiquitination assay, and functional peroxisomal import assay","pmids":["28724525"],"confidence":"High","gaps":["The ubiquitin chain type on PEX5 was not specified","Relationship between PEX5 ubiquitylation defect and specific Mulibrey nanism organ pathology is unclear"]},{"year":2018,"claim":"Three studies expanded TRIM37's signaling roles: it activates NF-κB by monoubiquitinating NEMO at K309 downstream of ATM-mediated genotoxic stress, promotes K63-linked ubiquitination of TRAF2 for NF-κB signaling, and enhances MTORC1 activity by promoting lysosomal localization of MTOR.","evidence":"Ubiquitination assays with site-directed mutagenesis (NEMO K309), RING domain mutagenesis (TRAF2), co-immunoprecipitation with MTOR/RRAGB, subcellular fractionation, and NF-κB/MTORC1 pathway readouts","pmids":["30254148","30043491","29940807"],"confidence":"High","gaps":["Whether NEMO monoubiquitination and TRAF2/TRAF6 K63-ubiquitination represent parallel or sequential steps in the same pathway was not clarified","MTORC1 regulation was shown only in one cancer system"]},{"year":2020,"claim":"Two concurrent studies revealed TRIM37's centrosomal function: elevated TRIM37 degrades CEP192, blocks pericentriolar material foci formation, and prevents acentrosomal spindle assembly — making 17q23-amplified cancers exquisitely sensitive to PLK4 inhibition.","evidence":"TRIM37 knockdown/overexpression with PLK4 inhibitor centrinone, live-cell imaging, CEP192 degradation assays, epistasis analysis in breast cancer and neuroblastoma lines","pmids":["32908304","32908313"],"confidence":"High","gaps":["Direct ubiquitination of CEP192 by TRIM37 was not reconstituted in vitro","Whether TRIM37 normally restrains centrosome number in non-amplified cells at physiological expression levels is unclear"]},{"year":2020,"claim":"Multiple substrate identifications broadened TRIM37's oncogenic repertoire: it ubiquitinates PTEN for degradation (sustaining AKT signaling), promotes SMAD7 degradation (facilitating TGF-β signaling), and enforces H2A-ubiquitination-dependent chemoresistance in TNBC.","evidence":"Co-immunoprecipitation and ubiquitination assays for PTEN and SMAD7; H2A ubiquitination with antisense oligonucleotide nanoparticle delivery in vivo","pmids":["33194618","32916597","32855208"],"confidence":"Medium","gaps":["Each substrate was characterized by a single lab; independent replication is lacking","Chain-type specificity for PTEN ubiquitination was not fully defined"]},{"year":2021,"claim":"The centrosomal substrate was identified as Centrobin: TRIM37 ubiquitinates Centrobin to prevent formation of centriolar protein assemblies (Cenpas) that act as ectopic MTOCs; Mulibrey nanism patient cells harbor these assemblies.","evidence":"Correlative light-electron microscopy, Centrobin ubiquitination assay, genetic epistasis with PLK4 and PLK1, patient-derived cell analysis","pmids":["33491649","33983387"],"confidence":"High","gaps":["The ubiquitin chain type on Centrobin and the precise degradation vs. regulatory fate was not determined","Whether Cenpa formation contributes to Mulibrey nanism clinical features beyond cell division defects is unknown"]},{"year":2022,"claim":"TRIM37 was shown to target p53 for K48-linked ubiquitination and proteasomal degradation, connecting TRIM37 overexpression to metabolic reprogramming (aerobic glycolysis) in hepatocellular carcinoma.","evidence":"Co-immunoprecipitation, K48-specific ubiquitination assay, siRNA epistasis, in vivo xenograft","pmids":["36252649"],"confidence":"Medium","gaps":["Single lab finding; independent confirmation needed","Whether p53 is a direct in vitro substrate has not been shown with purified components"]},{"year":null,"claim":"How TRIM37 selects among its diverse substrates in different subcellular compartments, and which specific substrate losses drive individual organ pathologies in Mulibrey nanism, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of TRIM37 exists","Substrate selectivity determinants are unknown","Tissue-specific conditional knockout studies have not been performed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,5,6,9,10,14,15,19,20]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[1,5,6]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,11,18]}],"localization":[{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[7,8,9,10,22]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,12,13]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[7,8,9,10,22]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,15,17,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,6,15,17]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,11,18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,3,14,20]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,3]}],"complexes":[],"partners":["PEX5","NEMO","TRAF6","TRAF2","CENTROBIN","CEP192","MTOR","RRAGB"],"other_free_text":[]},"mechanistic_narrative":"TRIM37 is a RING domain-dependent E3 ubiquitin ligase that operates at the intersection of centrosome homeostasis, peroxisomal protein import, chromatin silencing, and NF-κB signaling. At centrosomes, TRIM37 ubiquitinates Centrobin and degrades CEP192, thereby preventing formation of ectopic centriolar protein assemblies and surplus microtubule-organizing centers; its amplification at 17q23 in cancer sensitizes cells to PLK4 inhibition by blocking acentrosomal spindle assembly [PMID:32908304, PMID:33983387, PMID:33491649]. TRIM37 localizes to peroxisomes where it ubiquitylates PEX5 at K464 to stabilize it for matrix protein import [PMID:28724525], mono-ubiquitinates histone H2A in concert with PRC2 to silence tumor-suppressor gene promoters [PMID:25470042], and activates NF-κB by monoubiquitinating NEMO at K309 and catalyzing K63-linked ubiquitination of TRAF2/TRAF6 [PMID:30254148, PMID:30043491, PMID:33839419]. Loss-of-function mutations in TRIM37 cause Mulibrey nanism, a multi-organ disorder recapitulated in knockout mice featuring cardiomyopathy, infertility, and tumor predisposition [PMID:27044324]."},"prefetch_data":{"uniprot":{"accession":"O94972","full_name":"E3 ubiquitin-protein ligase TRIM37","aliases":["Mulibrey nanism protein","RING-type E3 ubiquitin transferase TRIM37","Tripartite motif-containing protein 37"],"length_aa":964,"mass_kda":107.9,"function":"E3 ubiquitin-protein ligase required to prevent centriole reduplication (PubMed:15885686, PubMed:23769972). Probably acts by ubiquitinating positive regulators of centriole reduplication (PubMed:23769972). Mediates monoubiquitination of 'Lys-119' of histone H2A (H2AK119Ub), a specific tag for epigenetic transcriptional repression: associates with some Polycomb group (PcG) multiprotein PRC2-like complex and mediates repression of target genes (PubMed:25470042). Also acts as a positive regulator of peroxisome import by mediating monoubiquitination of PEX5 at 'Lys-472': monoubiquitination promotes PEX5 stabilitation by preventing its polyubiquitination and degradation by the proteasome (PubMed:28724525). Has anti-HIV activity (PubMed:24317724)","subcellular_location":"Chromosome; Cytoplasm, perinuclear region; Peroxisome membrane","url":"https://www.uniprot.org/uniprotkb/O94972/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM37","classification":"Not Classified","n_dependent_lines":397,"n_total_lines":1208,"dependency_fraction":0.32864238410596025},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRIM37","total_profiled":1310},"omim":[{"mim_id":"621115","title":"RIB43A DOMAIN WITH COILED-COILS PROTEIN 2; RIBC2","url":"https://www.omim.org/entry/621115"},{"mim_id":"605073","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 37; TRIM37","url":"https://www.omim.org/entry/605073"},{"mim_id":"253250","title":"MULIBREY NANISM; MUL","url":"https://www.omim.org/entry/253250"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":58.2}],"url":"https://www.proteinatlas.org/search/TRIM37"},"hgnc":{"alias_symbol":["KIAA0898","POB1","TEF3"],"prev_symbol":["MUL"]},"alphafold":{"accession":"O94972","domains":[{"cath_id":"3.30.40.10","chopping":"2-85","consensus_level":"medium","plddt":86.3238,"start":2,"end":85},{"cath_id":"-","chopping":"132-260","consensus_level":"medium","plddt":94.6473,"start":132,"end":260},{"cath_id":"2.60.210.10","chopping":"278-428","consensus_level":"high","plddt":95.405,"start":278,"end":428}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94972","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94972-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94972-F1-predicted_aligned_error_v6.png","plddt_mean":63.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM37","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM37"},"sequence":{"accession":"O94972","fasta_url":"https://rest.uniprot.org/uniprotkb/O94972.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94972/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94972"}},"corpus_meta":[{"pmid":"7105409","id":"PMC_7105409","title":"A simple, rapid method for the determination of glucose, lactate, pyruvate, alanine, 3-hydroxybutyrate and acetoacetate on a single 20-mul blood sample.","date":"1982","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7105409","citation_count":297,"is_preprint":false},{"pmid":"25470042","id":"PMC_25470042","title":"TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein.","date":"2014","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/25470042","citation_count":149,"is_preprint":false},{"pmid":"32908304","id":"PMC_32908304","title":"TRIM37 controls cancer-specific vulnerability to PLK4 inhibition.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32908304","citation_count":118,"is_preprint":false},{"pmid":"6089104","id":"PMC_6089104","title":"Nucleotide sequence of the maize transposable element Mul.","date":"1984","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/6089104","citation_count":97,"is_preprint":false},{"pmid":"32908313","id":"PMC_32908313","title":"Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32908313","citation_count":93,"is_preprint":false},{"pmid":"1448101","id":"PMC_1448101","title":"Evidence that POB1, a Saccharomyces cerevisiae protein that binds to DNA polymerase alpha, acts in DNA metabolism in vivo.","date":"1992","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/1448101","citation_count":87,"is_preprint":false},{"pmid":"23315315","id":"PMC_23315315","title":"Is frequent CD4+ T-lymphocyte count monitoring necessary for persons with counts >=300 cells/μL and HIV-1 suppression?","date":"2013","source":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America","url":"https://pubmed.ncbi.nlm.nih.gov/23315315","citation_count":81,"is_preprint":false},{"pmid":"10557078","id":"PMC_10557078","title":"Epsin binds to the EH domain of POB1 and regulates receptor-mediated endocytosis.","date":"1999","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10557078","citation_count":76,"is_preprint":false},{"pmid":"12898700","id":"PMC_12898700","title":"Expression and regulation of L-cystine transporter, system xc-, in the newly developed rat retinal Müller cell line (TR-MUL).","date":"2003","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/12898700","citation_count":72,"is_preprint":false},{"pmid":"15885686","id":"PMC_15885686","title":"TRIM37 defective in mulibrey nanism is a novel RING finger ubiquitin E3 ligase.","date":"2005","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/15885686","citation_count":66,"is_preprint":false},{"pmid":"28724525","id":"PMC_28724525","title":"TRIM37, a novel E3 ligase for PEX5-mediated peroxisomal matrix protein import.","date":"2017","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28724525","citation_count":65,"is_preprint":false},{"pmid":"28419377","id":"PMC_28419377","title":"Gene-Tree Reconciliation with MUL-Trees to Resolve Polyploidy Events.","date":"2017","source":"Systematic biology","url":"https://pubmed.ncbi.nlm.nih.gov/28419377","citation_count":65,"is_preprint":false},{"pmid":"20932259","id":"PMC_20932259","title":"TRPM6 and TRPM7: A Mul-TRP-PLIK-cation of channel functions.","date":"2011","source":"Current pharmaceutical biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/20932259","citation_count":64,"is_preprint":false},{"pmid":"26208456","id":"PMC_26208456","title":"Over-expression of TRIM37 promotes cell migration and metastasis in hepatocellular carcinoma by activating Wnt/β-catenin signaling.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26208456","citation_count":62,"is_preprint":false},{"pmid":"11938494","id":"PMC_11938494","title":"The TRIM37 gene encodes a peroxisomal RING-B-box-coiled-coil protein: classification of mulibrey nanism as a new peroxisomal disorder.","date":"2002","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11938494","citation_count":57,"is_preprint":false},{"pmid":"31409898","id":"PMC_31409898","title":"LSD1 suppresses invasion, migration and metastasis of luminal breast cancer cells via activation of GATA3 and repression of TRIM37 expression.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/31409898","citation_count":56,"is_preprint":false},{"pmid":"10764745","id":"PMC_10764745","title":"Regulation of complex formation of POB1/epsin/adaptor protein complex 2 by mitotic phosphorylation.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10764745","citation_count":53,"is_preprint":false},{"pmid":"32572790","id":"PMC_32572790","title":"ASB16-AS1 up-regulated and phosphorylated TRIM37 to activate NF-κB pathway and promote proliferation, stemness, and cisplatin resistance of gastric cancer.","date":"2020","source":"Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association","url":"https://pubmed.ncbi.nlm.nih.gov/32572790","citation_count":53,"is_preprint":false},{"pmid":"22423133","id":"PMC_22423133","title":"HIV-infected ugandan adults taking antiretroviral therapy with CD4 counts >200 cells/μL who discontinue cotrimoxazole prophylaxis have increased risk of malaria and diarrhea.","date":"2012","source":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America","url":"https://pubmed.ncbi.nlm.nih.gov/22423133","citation_count":52,"is_preprint":false},{"pmid":"30586926","id":"PMC_30586926","title":"TRIMming down to TRIM37: Relevance to Inflammation, Cardiovascular Disorders, and Cancer in MULIBREY Nanism.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30586926","citation_count":51,"is_preprint":false},{"pmid":"18474607","id":"PMC_18474607","title":"Hsf-1 and POB1 induce drug sensitivity and apoptosis by inhibiting Ralbp1.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18474607","citation_count":51,"is_preprint":false},{"pmid":"21311808","id":"PMC_21311808","title":"A μL-scale micromachined microbial fuel cell having high power density.","date":"2011","source":"Lab on a chip","url":"https://pubmed.ncbi.nlm.nih.gov/21311808","citation_count":48,"is_preprint":false},{"pmid":"30020446","id":"PMC_30020446","title":"Impact of Routine Cryptococcal Antigen Screening and Targeted Preemptive Fluconazole Therapy in Antiretroviral-naive Human Immunodeficiency Virus-infected Adults With CD4 Cell Counts <100/μL: A Systematic Review and Meta-analysis.","date":"2019","source":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America","url":"https://pubmed.ncbi.nlm.nih.gov/30020446","citation_count":47,"is_preprint":false},{"pmid":"28063815","id":"PMC_28063815","title":"Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per μL: secondary outcome results from a randomised controlled trial.","date":"2017","source":"The lancet. HIV","url":"https://pubmed.ncbi.nlm.nih.gov/28063815","citation_count":46,"is_preprint":false},{"pmid":"29324313","id":"PMC_29324313","title":"Knockdown of TRIM37 suppresses the proliferation, migration and invasion of glioma cells through the inactivation of PI3K/Akt signaling pathway.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/29324313","citation_count":45,"is_preprint":false},{"pmid":"27213624","id":"PMC_27213624","title":"Characterization and Functional Analysis of 4-Coumarate:CoA Ligase Genes in Mul-berry.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27213624","citation_count":45,"is_preprint":false},{"pmid":"30043491","id":"PMC_30043491","title":"Tripartite motif-containing 37 (TRIM37) promotes the aggressiveness of non-small-cell lung cancer cells by activating the NF-κB pathway.","date":"2018","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30043491","citation_count":44,"is_preprint":false},{"pmid":"12771942","id":"PMC_12771942","title":"REPS2/POB1 is downregulated during human prostate cancer progression and inhibits growth factor signalling in prostate cancer cells.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12771942","citation_count":44,"is_preprint":false},{"pmid":"15707977","id":"PMC_15707977","title":"POB1 over-expression inhibits RLIP76-mediated transport of glutathione-conjugates, drugs and promotes apoptosis.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15707977","citation_count":43,"is_preprint":false},{"pmid":"19710424","id":"PMC_19710424","title":"Pob1 participates in the Cdc42 regulation of fission yeast actin cytoskeleton.","date":"2009","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/19710424","citation_count":42,"is_preprint":false},{"pmid":"26020949","id":"PMC_26020949","title":"Risk of Severe Non AIDS Events Is Increased among Patients Unable to Increase their CD4+ T-Cell Counts >200+/μl Despite Effective HAART.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26020949","citation_count":41,"is_preprint":false},{"pmid":"30257365","id":"PMC_30257365","title":"Mulberrin (Mul) reduces spinal cord injury (SCI)-induced apoptosis, inflammation and oxidative stress in rats via miroRNA-337 by targeting Nrf-2.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30257365","citation_count":40,"is_preprint":false},{"pmid":"29683843","id":"PMC_29683843","title":"Benefits and harms of lung cancer screening in HIV-infected individuals with CD4+ cell count at least 500 cells/μl.","date":"2018","source":"AIDS (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29683843","citation_count":39,"is_preprint":false},{"pmid":"28056034","id":"PMC_28056034","title":"BTB-BACK Domain Protein POB1 Suppresses Immune Cell Death by Targeting Ubiquitin E3 ligase PUB17 for Degradation.","date":"2017","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28056034","citation_count":37,"is_preprint":false},{"pmid":"29940807","id":"PMC_29940807","title":"TRIM37 deficiency induces autophagy through deregulating the MTORC1-TFEB axis.","date":"2018","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/29940807","citation_count":37,"is_preprint":false},{"pmid":"28098873","id":"PMC_28098873","title":"TRIM37 promotes epithelial‑mesenchymal transition in colorectal cancer.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/28098873","citation_count":37,"is_preprint":false},{"pmid":"30254148","id":"PMC_30254148","title":"An ATM/TRIM37/NEMO Axis Counteracts Genotoxicity by Activating Nuclear-to-Cytoplasmic NF-κB Signaling.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/30254148","citation_count":36,"is_preprint":false},{"pmid":"12149250","id":"PMC_12149250","title":"Interaction of POB1, a downstream molecule of small G protein Ral, with PAG2, a paxillin-binding protein, is involved in cell migration.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12149250","citation_count":34,"is_preprint":false},{"pmid":"26395261","id":"PMC_26395261","title":"TRIM37 promoted the growth and migration of the pancreatic cancer cells.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26395261","citation_count":33,"is_preprint":false},{"pmid":"33728810","id":"PMC_33728810","title":"Circular RNA circRNA_101996 promoted cervical cancer development by regulating miR-1236-3p/TRIM37 axis.","date":"2021","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33728810","citation_count":32,"is_preprint":false},{"pmid":"25711330","id":"PMC_25711330","title":"Pulmonary function in an international sample of HIV-positive, treatment-naïve adults with CD4 counts > 500 cells/μL: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.","date":"2015","source":"HIV medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25711330","citation_count":32,"is_preprint":false},{"pmid":"21756956","id":"PMC_21756956","title":"Regulation of glutamate metabolism by hydrocortisone and branched chain keto acids in cultured rat retinal Müller cells (TR-MUL).","date":"2011","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/21756956","citation_count":31,"is_preprint":false},{"pmid":"20942650","id":"PMC_20942650","title":"A randomized factorial trial comparing 4 treatment regimens in treatment-naive HIV-infected persons with AIDS and/or a CD4 cell count <200 cells/μL in South Africa.","date":"2010","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/20942650","citation_count":31,"is_preprint":false},{"pmid":"15108285","id":"PMC_15108285","title":"Novel mutations in the TRIM37 gene in Mulibrey Nanism.","date":"2004","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/15108285","citation_count":30,"is_preprint":false},{"pmid":"9549894","id":"PMC_9549894","title":"Cytotoxic principles of a Bangladeshi crude drug, akond mul (roots of Calotropis gigantea L.).","date":"1998","source":"Chemical & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/9549894","citation_count":30,"is_preprint":false},{"pmid":"22823983","id":"PMC_22823983","title":"Estimating malaria parasite density: assumed white blood cell count of 10,000/μl of blood is appropriate measure in Central Ghana.","date":"2012","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/22823983","citation_count":30,"is_preprint":false},{"pmid":"29498256","id":"PMC_29498256","title":"BIABooster: Online DNA Concentration and Size Profiling with a Limit of Detection of 10 fg/μL and Application to High-Sensitivity Characterization of Circulating Cell-Free DNA.","date":"2018","source":"Analytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29498256","citation_count":30,"is_preprint":false},{"pmid":"29477054","id":"PMC_29477054","title":"TRIM37 inhibits PDGF-BB-induced proliferation and migration of airway smooth muscle cells.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/29477054","citation_count":29,"is_preprint":false},{"pmid":"34130705","id":"PMC_34130705","title":"TRIM37 orchestrates renal cell carcinoma progression via histone H2A ubiquitination-dependent manner.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/34130705","citation_count":28,"is_preprint":false},{"pmid":"16306379","id":"PMC_16306379","title":"Insulin resistance syndrome in subjects with mutated RING finger protein TRIM37.","date":"2005","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/16306379","citation_count":28,"is_preprint":false},{"pmid":"25022596","id":"PMC_25022596","title":"Successful antiretroviral therapy delivery and retention in care among asymptomatic individuals with high CD4+ T-cell counts above 350 cells/μl in rural Uganda.","date":"2014","source":"AIDS (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25022596","citation_count":28,"is_preprint":false},{"pmid":"20852403","id":"PMC_20852403","title":"Despite CD4 cell count rebound the higher initial costs of medical care for HIV-infected patients persist 5 years after presentation with CD4 cell counts less than 350 μl.","date":"2010","source":"AIDS (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/20852403","citation_count":28,"is_preprint":false},{"pmid":"32855208","id":"PMC_32855208","title":"Oncogenic TRIM37 Links Chemoresistance and Metastatic Fate in Triple-Negative Breast Cancer.","date":"2020","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32855208","citation_count":27,"is_preprint":false},{"pmid":"21401840","id":"PMC_21401840","title":"Pob1 ensures cylindrical cell shape by coupling two distinct rho signaling events during secretory vesicle targeting.","date":"2011","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/21401840","citation_count":26,"is_preprint":false},{"pmid":"22268850","id":"PMC_22268850","title":"Vertically grown multiwalled carbon nanotube anode and nickel silicide integrated high performance microsized (1.25 μL) microbial fuel cell.","date":"2012","source":"Nano letters","url":"https://pubmed.ncbi.nlm.nih.gov/22268850","citation_count":26,"is_preprint":false},{"pmid":"22955429","id":"PMC_22955429","title":"The effect of a \"universal antiretroviral therapy\" recommendation on HIV RNA levels among HIV-infected patients entering care with a CD4 count greater than 500/μL in a public health setting.","date":"2012","source":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America","url":"https://pubmed.ncbi.nlm.nih.gov/22955429","citation_count":26,"is_preprint":false},{"pmid":"32916597","id":"PMC_32916597","title":"ROS/NF-κB Signaling Pathway-Mediated Transcriptional Activation of TRIM37 Promotes HBV-Associated Hepatic Fibrosis.","date":"2020","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/32916597","citation_count":25,"is_preprint":false},{"pmid":"33491649","id":"PMC_33491649","title":"TRIM37 prevents formation of centriolar protein assemblies by regulating Centrobin.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/33491649","citation_count":24,"is_preprint":false},{"pmid":"35859118","id":"PMC_35859118","title":"PBK drives PARP inhibitor resistance through the TRIM37/NFκB axis in ovarian cancer.","date":"2022","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35859118","citation_count":24,"is_preprint":false},{"pmid":"25966339","id":"PMC_25966339","title":"Efficacy and Safety of Antiretroviral Therapy Initiated One Week after Tuberculosis Therapy in Patients with CD4 Counts < 200 Cells/μL: TB-HAART Study, a Randomized Clinical Trial.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25966339","citation_count":24,"is_preprint":false},{"pmid":"34524943","id":"PMC_34524943","title":"Increased alveolar epithelial TRAF6 via autophagy-dependent TRIM37 degradation mediates particulate matter-induced lung metastasis.","date":"2021","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/34524943","citation_count":23,"is_preprint":false},{"pmid":"17100991","id":"PMC_17100991","title":"Wilms' tumor and novel TRIM37 mutations in an Australian patient with mulibrey nanism.","date":"2006","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17100991","citation_count":22,"is_preprint":false},{"pmid":"33194618","id":"PMC_33194618","title":"TRIM37 Mediates Chemoresistance and Maintenance of Stemness in Pancreatic Cancer Cells via Ubiquitination of PTEN and Activation of the AKT-GSK-3β-β-Catenin Signaling Pathway.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33194618","citation_count":22,"is_preprint":false},{"pmid":"30573971","id":"PMC_30573971","title":"TRIM37 promotes cell invasion and metastasis by regulating SIP1-mediated epithelial-mesenchymal transition in gastric cancer.","date":"2018","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30573971","citation_count":21,"is_preprint":false},{"pmid":"33387087","id":"PMC_33387087","title":"TRIM37 overexpression is associated with chemoresistance in hepatocellular carcinoma via activating the AKT signaling pathway.","date":"2021","source":"International journal of clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33387087","citation_count":21,"is_preprint":false},{"pmid":"22441247","id":"PMC_22441247","title":"Response to antiretroviral therapy: improved survival associated with CD4 above 500 cells/μl.","date":"2012","source":"AIDS (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/22441247","citation_count":21,"is_preprint":false},{"pmid":"29163677","id":"PMC_29163677","title":"TRIM37 promotes tumor cell proliferation and drug resistance in pediatric osteosarcoma.","date":"2017","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29163677","citation_count":20,"is_preprint":false},{"pmid":"37279162","id":"PMC_37279162","title":"Discovery of the First Potent, Selective, and In Vivo Efficacious Polo-like Kinase 4 Proteolysis Targeting Chimera Degrader for the Treatment of TRIM37-Amplified Breast Cancer.","date":"2023","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37279162","citation_count":20,"is_preprint":false},{"pmid":"26108273","id":"PMC_26108273","title":"Risk factors for loss to follow-up prior to ART initiation among patients enrolling in HIV care with CD4+ cell count ≥200 cells/μL in the multi-country MTCT-Plus Initiative.","date":"2015","source":"BMC health services research","url":"https://pubmed.ncbi.nlm.nih.gov/26108273","citation_count":20,"is_preprint":false},{"pmid":"18353508","id":"PMC_18353508","title":"Dehydroascorbic acid uptake and intracellular ascorbic acid accumulation in cultured Müller glial cells (TR-MUL).","date":"2008","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/18353508","citation_count":20,"is_preprint":false},{"pmid":"27044324","id":"PMC_27044324","title":"Trim37-deficient mice recapitulate several features of the multi-organ disorder Mulibrey nanism.","date":"2016","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/27044324","citation_count":20,"is_preprint":false},{"pmid":"26190571","id":"PMC_26190571","title":"High throughput cryopreservation of cells by rapid freezing of sub-μl drops using inkjet printing--cryoprinting.","date":"2015","source":"Lab on a chip","url":"https://pubmed.ncbi.nlm.nih.gov/26190571","citation_count":20,"is_preprint":false},{"pmid":"12754710","id":"PMC_12754710","title":"A novel splice site mutation in the TRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity.","date":"2003","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/12754710","citation_count":19,"is_preprint":false},{"pmid":"28081740","id":"PMC_28081740","title":"Knockdown of Tripartite Motif-Containing Protein 37 (TRIM37) Inhibits the Proliferation and Tumorigenesis in Colorectal Cancer Cells.","date":"2017","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/28081740","citation_count":19,"is_preprint":false},{"pmid":"18154663","id":"PMC_18154663","title":"Binding to DPF-motif by the POB1 EH domain is responsible for POB1-Eps15 interaction.","date":"2007","source":"BMC biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18154663","citation_count":19,"is_preprint":false},{"pmid":"20659176","id":"PMC_20659176","title":"Nevirapine-associated hepatotoxicity was not predicted by CD4 count ≥250 cells/μL among women in Zambia, Thailand and Kenya.","date":"2010","source":"HIV medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20659176","citation_count":19,"is_preprint":false},{"pmid":"33451755","id":"PMC_33451755","title":"LncRNA NEAT1 acts as a key regulator of cell apoptosis and inflammatory response by the miR-944/TRIM37 axis in acute lung injury.","date":"2020","source":"Journal of pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33451755","citation_count":18,"is_preprint":false},{"pmid":"33981362","id":"PMC_33981362","title":"Long non-coding RNA TMPO-AS1 facilitates chemoresistance and invasion in breast cancer by modulating the miR-1179/TRIM37 axis.","date":"2021","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/33981362","citation_count":18,"is_preprint":false},{"pmid":"24833016","id":"PMC_24833016","title":"Is primary mycobacterium avium complex prophylaxis necessary in patients with CD4 <50 cells/μL who are virologically suppressed on cART?","date":"2014","source":"AIDS patient care and STDs","url":"https://pubmed.ncbi.nlm.nih.gov/24833016","citation_count":18,"is_preprint":false},{"pmid":"33983387","id":"PMC_33983387","title":"TRIM37 prevents formation of condensate-organized ectopic spindle poles to ensure mitotic fidelity.","date":"2021","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/33983387","citation_count":18,"is_preprint":false},{"pmid":"30510432","id":"PMC_30510432","title":"TRIM37 targets AKT in the growth of lung cancer cells.","date":"2018","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30510432","citation_count":18,"is_preprint":false},{"pmid":"21342809","id":"PMC_21342809","title":"Shear-mediated platelet adhesion analysis in less than 100 μl of blood: toward a POC platelet diagnostic.","date":"2011","source":"IEEE transactions on bio-medical engineering","url":"https://pubmed.ncbi.nlm.nih.gov/21342809","citation_count":18,"is_preprint":false},{"pmid":"32353567","id":"PMC_32353567","title":"TRIM37 is highly expressed during mitosis in CHON-002 chondrocytes cell line and is regulated by miR-223.","date":"2020","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/32353567","citation_count":17,"is_preprint":false},{"pmid":"35576702","id":"PMC_35576702","title":"Design, synthesis, and biological evaluation of novel pyrazolo [3,4-d]pyrimidine derivatives as potent PLK4 inhibitors for the treatment of TRIM37-amplified breast cancer.","date":"2022","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35576702","citation_count":17,"is_preprint":false},{"pmid":"16514549","id":"PMC_16514549","title":"Tissue expression of the mulibrey nanism-associated Trim37 protein in embryonic and adult mouse tissues.","date":"2006","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16514549","citation_count":17,"is_preprint":false},{"pmid":"33839419","id":"PMC_33839419","title":"TRIM37 negatively regulates inflammatory responses induced by virus infection via controlling TRAF6 ubiquitination.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/33839419","citation_count":17,"is_preprint":false},{"pmid":"24721983","id":"PMC_24721983","title":"Assumed white blood cell count of 8,000 cells/μL overestimates malaria parasite density in the Brazilian Amazon.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24721983","citation_count":16,"is_preprint":false},{"pmid":"18840614","id":"PMC_18840614","title":"Transcription enhancer factor 3 (TEF3) mediates the expression of Down syndrome candidate region 1 isoform 1 (DSCR1-1L) in endothelial cells.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18840614","citation_count":16,"is_preprint":false},{"pmid":"34716956","id":"PMC_34716956","title":"miR-942-5p prevents sepsis-induced acute lung injury via targeting TRIM37.","date":"2021","source":"International journal of experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/34716956","citation_count":16,"is_preprint":false},{"pmid":"26849213","id":"PMC_26849213","title":"Vaccination with the Surface Proteins MUL_2232 and MUL_3720 of Mycobacterium ulcerans Induces Antibodies but Fails to Provide Protection against Buruli Ulcer.","date":"2016","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/26849213","citation_count":16,"is_preprint":false},{"pmid":"32014633","id":"PMC_32014633","title":"Mul-tiomics analysis of cadmium stress on the ovarian function of the wolf spider Pardosa pseudoannulata.","date":"2020","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/32014633","citation_count":16,"is_preprint":false},{"pmid":"36252649","id":"PMC_36252649","title":"Aerobic glycolysis and tumor progression of hepatocellular carcinoma are mediated by ubiquitin of P53 K48-linked regulated by TRIM37.","date":"2022","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/36252649","citation_count":15,"is_preprint":false},{"pmid":"19329943","id":"PMC_19329943","title":"Gynecological tumors in Mulibrey nanism and role for RING finger protein TRIM37 in the pathogenesis of ovarian fibrothecomas.","date":"2009","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/19329943","citation_count":15,"is_preprint":false},{"pmid":"32532212","id":"PMC_32532212","title":"The prevalence of cryptococcal antigen (CrAg) and benefits of pre-emptive antifungal treatment among HIV-infected persons with CD4+ T-cell counts < 200 cells/μL: evidence based on a meta-analysis.","date":"2020","source":"BMC infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/32532212","citation_count":14,"is_preprint":false},{"pmid":"25668636","id":"PMC_25668636","title":"Identification of the Mycobacterium ulcerans protein MUL_3720 as a promising target for the development of a diagnostic test for Buruli ulcer.","date":"2015","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/25668636","citation_count":14,"is_preprint":false},{"pmid":"28874694","id":"PMC_28874694","title":"Focusing analytes from 50 μL into 500 pL: On-chip focusing from large sample volumes using isotachophoresis.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28874694","citation_count":14,"is_preprint":false},{"pmid":"34762593","id":"PMC_34762593","title":"Mul-SNO: A Novel Prediction Tool for S-Nitrosylation Sites Based on Deep Learning Methods.","date":"2022","source":"IEEE journal of biomedical and health informatics","url":"https://pubmed.ncbi.nlm.nih.gov/34762593","citation_count":14,"is_preprint":false},{"pmid":"16310976","id":"PMC_16310976","title":"Characterisation of the mulibrey nanism-associated TRIM37 gene: transcription initiation, promoter region and alternative splicing.","date":"2005","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/16310976","citation_count":13,"is_preprint":false},{"pmid":"34672905","id":"PMC_34672905","title":"TRIM37: a critical orchestrator of centrosome function.","date":"2021","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/34672905","citation_count":13,"is_preprint":false},{"pmid":"37158850","id":"PMC_37158850","title":"TRIM37 exacerbates hepatic ischemia/reperfusion injury by facilitating IKKγ translocation.","date":"2023","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/37158850","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51085,"output_tokens":5664,"usd":0.119108},"stage2":{"model":"claude-opus-4-6","input_tokens":9280,"output_tokens":3059,"usd":0.184312},"total_usd":0.30342,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIM37 functions as an E3 ubiquitin ligase that mono-ubiquitinates histone H2A, a chromatin modification associated with transcriptional repression. TRIM37 associates with PRC2 (not PRC1 like RNF2), and together with PRC1 co-occupies target gene promoters to silence them. RNAi-mediated knockdown of TRIM37 results in loss of ubiquitinated H2A, dissociation of PRC1 and PRC2 from target promoters, and transcriptional reactivation.\",\n      \"method\": \"ChIP-chip, RNAi knockdown, co-immunoprecipitation, in vivo xenograft\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, genome-wide ChIP, loss-of-function with defined molecular phenotype, multiple orthogonal methods in single high-impact study\",\n      \"pmids\": [\"25470042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRIM37 acts as a RING domain-dependent E3 ubiquitin ligase; full-length TRIM37 and its TRIM domain undergo polyubiquitination in cell-free conditions, and disruption of the RING domain (Cys35Ser;Cys36Ser) or a disease-associated missense mutation (Leu76Pro) abolishes this activity. Ectopically expressed TRIM37 forms ubiquitin-, proteasome subunit-, and chaperone-positive aggresomes, and disease mutants are markedly less prone to aggregation.\",\n      \"method\": \"Cell-free ubiquitination assay, co-expression with ubiquitin, active-site mutagenesis, immunofluorescence\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with active-site mutagenesis, multiple mutants tested\",\n      \"pmids\": [\"15885686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TRIM37 protein localizes to peroxisomes; peroxisomal import depends on PEX1 and PEX5 but not PEX7. The major Finnish disease-associated mutant protein fails to localize to peroxisomes, while the minor Finnish mutant retains peroxisomal targeting, classifying Mulibrey nanism as a peroxisomal disorder.\",\n      \"method\": \"Transient transfection, double immunofluorescence with peroxisomal markers, analysis in PEX1/PEX5/PEX7 mutant fibroblasts, antibody localization\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional consequence across multiple genetic backgrounds\",\n      \"pmids\": [\"11938494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIM37 localizes to peroxisomal membranes and ubiquitylates PEX5 at K464 by interacting with the C-terminal 51 amino acids (CT51) of PEX5; this ubiquitylation stabilizes PEX5 and is required for peroxisomal matrix protein import. TRIM37 depletion or PEX5 K464A/ΔCT51 mutations promote proteasomal degradation of PEX5, impair cargo binding, and induce apoptosis and oxidative stress sensitivity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K464A), siRNA knockdown, cell fractionation, functional import assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — biochemical reconstitution of ubiquitination with mutagenesis, functional import assay, multiple orthogonal methods\",\n      \"pmids\": [\"28724525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM37 interacts with MTOR and RRAGB, enhances the MTOR-RRAGB interaction, and promotes lysosomal localization of MTOR, thereby activating amino acid-stimulated MTORC1 signaling. TRIM37 loss reduces TFEB phosphorylation, causing its nuclear translocation and transcriptional activation of autophagy and lysosome biogenesis genes.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, TFEB localization assay, MTORC1 activity readouts (phospho-substrates), siRNA knockdown\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, functional pathway readouts; single lab study\",\n      \"pmids\": [\"29940807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM37 monoubiquitinates NEMO at K309 in the nucleus in response to genotoxic stress. ATM kinase, activated by DNA damage, phosphorylates TRIM37 in the cytoplasm, triggering its nuclear translocation where it forms a complex with NEMO and TRAF6 via a TRAF6-binding motif (TBM), leading to nuclear export of NEMO and IKK/NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, subcellular fractionation, site-directed mutagenesis, cell-penetrating TAT-TBM peptide inhibition, in vivo xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — biochemical identification of ubiquitination site, mutagenesis, mechanistic peptide inhibitor with in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"30254148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM37 promotes K63-linked polyubiquitination of TRAF2, sustaining NF-κB pathway activation in NSCLC. Mutation of the RING finger domain of TRIM37 abolishes TRAF2 K63 polyubiquitination and NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, RING domain mutagenesis, NF-κB reporter assay, siRNA knockdown and overexpression\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with mutagenesis confirmation, functional pathway readout; single lab\",\n      \"pmids\": [\"30043491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM37 levels determine mitotic vulnerability to PLK4 inhibition. High TRIM37 inhibits acentrosomal spindle assembly by degrading the centrosomal component CEP192. TRIM37 also prevents PLK4 from self-assembling into centrosome-independent condensates that serve as ectopic microtubule-organizing centers (MTOCs). TRIM37 amplification (17q23) in breast cancer and neuroblastoma renders these cancers highly sensitive to PLK4 inhibition.\",\n      \"method\": \"TRIM37 knockdown/overexpression, live-cell imaging, centrosome depletion assay (PLK4 inhibitor centrinone), epistasis with TRIM37 loss, CEP192 degradation assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays, epistasis analysis, replicated across two concurrent Nature papers\",\n      \"pmids\": [\"32908304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM37 overexpression acts as a negative regulator of centrosomal pericentriolar material (PCM). In 17q23-amplified cells lacking centrosomes (after PLK4 inhibition), elevated TRIM37 blocks formation of PCM foci required for acentrosomal spindle assembly, causing mitotic catastrophe. TRIM37 overexpression also delays centrosome maturation and separation at mitotic entry, increasing mitotic error frequency.\",\n      \"method\": \"PLK4 inhibitor treatment, live-cell imaging, PCM focus formation assay, TRIM37 siRNA and overexpression, centrosome maturation timing analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with direct imaging evidence, replicated concurrent with PMID 32908304\",\n      \"pmids\": [\"32908313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM37 prevents formation of centriolar protein assemblies (Cenpas) by regulating the stability and solubility of Centrobin; TRIM37 depletion leads to Centrobin accumulation in elongated entities. Cenpas can act as ectopic MTOCs and their formation upon TRIM37 depletion requires PLK4 and two parallel pathways relying on Centrobin and PLK1, respectively. Patient-derived Mulibrey nanism cells harbor these assemblies.\",\n      \"method\": \"Correlative light electron microscopy, siRNA knockdown, Centrobin ubiquitination assay, PLK4 inhibition epistasis, live imaging, patient-derived cell analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — correlative EM, biochemical ubiquitination, genetic epistasis with multiple pathways, patient cell validation\",\n      \"pmids\": [\"33491649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM37 prevents assembly of centrobin-scaffolded structured condensates that bud off centrosomes and organize ectopic spindle poles. In ~25% of TRIM37-deficient cells an ectopic spindle pole forms, recruiting centrosomal proteins and acquiring microtubule nucleation capacity. Centrobin interacts with and is ubiquitinated by TRIM37; removing centrobin suppresses ectopic spindle pole formation and multipolar segregation in TRIM37-deficient cells.\",\n      \"method\": \"Live-cell imaging, ubiquitination assay, Co-IP (Centrobin-TRIM37), centrobin knockout epistasis, multipolar mitosis quantification\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — biochemical ubiquitination with epistasis, live imaging, multiple orthogonal methods\",\n      \"pmids\": [\"33983387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM37-directed histone H2A monoubiquitination enforces changes in DNA repair that rendered TP53-mutant TNBC cells resistant to chemotherapy. Chemotherapeutic drugs trigger a positive feedback loop via ATM/E2F1/STAT signaling that amplifies the TRIM37 network.\",\n      \"method\": \"H2A ubiquitination assay, knockdown/overexpression, in vivo metastasis model, antisense oligonucleotide nanoparticle delivery, ATM/E2F1/STAT pathway analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assays with defined molecular mechanism; single lab with in vivo validation\",\n      \"pmids\": [\"32855208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ASB16-AS1 lncRNA promotes TRIM37 phosphorylation by cooperating with ATM serine/threonine kinase, inducing TRIM37 nuclear translocation and NF-κB pathway activation in gastric cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, pulldown, luciferase reporter, NF-κB pathway analysis, phosphorylation assay\",\n      \"journal\": \"Gastric cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP and biochemical assays identifying ATM as TRIM37 kinase; single lab\",\n      \"pmids\": [\"32572790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PBK (PDZ-binding kinase) directly interacts with TRIM37 and promotes its phosphorylation and nuclear translocation, subsequently activating the NF-κB pathway and conferring PARP inhibitor resistance in ovarian cancer.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay, nuclear translocation imaging, NF-κB reporter, in vitro and in vivo drug resistance assays\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP with functional consequence; single lab\",\n      \"pmids\": [\"35859118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM37 physically interacts with SMAD7 and promotes ubiquitination-mediated degradation of SMAD7, thereby facilitating TGF-β signaling and HBV-associated hepatic fibrosis. NF-κB activation mediated by ROS is necessary for transcriptional induction of TRIM37 during HBV infection.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, mouse fibrosis model, NF-κB inhibition\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP and ubiquitination assay with in vivo model; single lab\",\n      \"pmids\": [\"32916597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM37 promotes K63-linked ubiquitination of TRAF6, negatively regulating inflammatory responses induced by virus (H1N1) infection. Direct interaction between TRIM37 and TRAF6 was demonstrated by immunoprecipitation, and TRIM37 knockout in mice inhibited immune responses and reduced proinflammatory cytokines in macrophages.\",\n      \"method\": \"Immunoprecipitation, ubiquitination assay (K63-specific), TRIM37 knockout mice, ELISA, flow cytometry\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with in vivo KO validation; single lab\",\n      \"pmids\": [\"33839419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"During PM (particulate matter)-induced autophagy in lung epithelial cells, TRIM37 is degraded via autophagy, which protects TRAF6 from proteasomal degradation, promoting NF-κB-dependent chemokine production and neutrophil recruitment. TRIM37 thus normally promotes TRAF6 ubiquitin-mediated proteasomal degradation.\",\n      \"method\": \"Autophagy inhibition, siRNA knockdown of TRIM37 and TRAF6, mouse lung metastasis model, NF-κB reporter\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — functional assays with in vivo model; single lab\",\n      \"pmids\": [\"34524943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM37 directly interacts with TRAF6, induces K63-linked ubiquitination of TRAF6, leading to IKKβ phosphorylation. TRIM37 also enhances translocation of IKKγ (NEMO) from nucleus to cytoplasm, stabilizing the cytoplasmic IKK complex and prolonging inflammatory NF-κB signaling during hepatic ischemia/reperfusion injury.\",\n      \"method\": \"Immunoprecipitation, ubiquitination assay, Western blot of subcellular fractions, immunofluorescence, IKK inhibitor rescue in vivo\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical interaction and ubiquitination with in vivo functional rescue; single lab\",\n      \"pmids\": [\"37158850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM37 orchestrates renal cell carcinoma progression via TGF-β1 signaling activation mediated by ubiquitinating histone H2A modifications, promoting EMT and malignant progression.\",\n      \"method\": \"H2A ubiquitination assay, Co-IP, gain/loss-of-function models, in vivo xenograft, TGF-β1 pathway analysis\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — ubiquitination and Co-IP with in vivo model; single lab\",\n      \"pmids\": [\"34130705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM37 modulates ubiquitination and degradation of PTEN via its E3 ligase activity, negatively regulating the AKT-GSK-3β-β-catenin signaling pathway in pancreatic cancer cells, thereby sustaining aberrant activation and stemness.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein stability assay, immunofluorescence, in vivo xenograft\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP and ubiquitination with in vivo validation; single lab\",\n      \"pmids\": [\"33194618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM37 interacts with P53 and induces its K48-linked ubiquitination and proteasomal degradation, thereby promoting aerobic glycolysis and tumor progression in hepatocellular carcinoma. Genetic knockdown of P53 reverses TRIM37's pro-tumorigenic effects.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-specific), siRNA epistasis, in vivo xenograft\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP with ubiquitination assay and epistasis; single lab\",\n      \"pmids\": [\"36252649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Trim37 knockout mice recapitulate several features of Mulibrey nanism including infertility (germ cell aplasia), non-compaction cardiomyopathy, hepatomegaly, fatty liver, elevated fasting blood glucose, and tumor formation, establishing TRIM37 loss-of-function as causal for this multi-organ disorder.\",\n      \"method\": \"Congenic knockout mouse model, histopathology, hormone assays, metabolic measurements, CT skeletal analysis\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knockout model with multiple defined phenotypic readouts recapitulating human disease\",\n      \"pmids\": [\"27044324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM37 is highly expressed during mitosis in chondrocytes; during M phase, TRIM37 co-localizes with tubulin. TRIM37 knockdown inhibits chondrocyte proliferation with cell cycle anomalies and increased autophagy, while overexpression enhances proliferation. miR-223 directly targets and negatively regulates TRIM37 expression.\",\n      \"method\": \"Western blotting, confocal microscopy, imaging flow cytometry, siRNA knockdown, overexpression, cell cycle analysis\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — direct localization during cell cycle phases with functional consequence; single lab\",\n      \"pmids\": [\"32353567\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM37 is a RING domain-dependent E3 ubiquitin ligase that localizes to peroxisomes, centrosomes, and the nucleus, and exerts its functions through multiple substrates: it mono-ubiquitinates histone H2A (silencing tumor suppressors in association with PRC2), ubiquitylates PEX5 (stabilizing it for peroxisomal matrix protein import), ubiquitinates Centrobin (preventing formation of ectopic centrosomal condensates and extra spindle poles to ensure mitotic fidelity), monoubiquitinates NEMO/IKKγ at K309 to activate NF-κB in response to ATM-mediated genotoxic stress, promotes K63-linked ubiquitination of TRAF2 and TRAF6 for NF-κB signaling, and targets PTEN, SMAD7, and p53 for proteasomal degradation; furthermore, TRIM37 enhances MTORC1 activity by promoting lysosomal localization of MTOR, and its amplification at 17q23 sensitizes cancer cells to PLK4 inhibition by blocking acentrosomal spindle assembly through CEP192 degradation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TRIM37 is a RING domain-dependent E3 ubiquitin ligase that operates at the intersection of centrosome homeostasis, peroxisomal protein import, chromatin silencing, and NF-κB signaling. At centrosomes, TRIM37 ubiquitinates Centrobin and degrades CEP192, thereby preventing formation of ectopic centriolar protein assemblies and surplus microtubule-organizing centers; its amplification at 17q23 in cancer sensitizes cells to PLK4 inhibition by blocking acentrosomal spindle assembly [PMID:32908304, PMID:33983387, PMID:33491649]. TRIM37 localizes to peroxisomes where it ubiquitylates PEX5 at K464 to stabilize it for matrix protein import [PMID:28724525], mono-ubiquitinates histone H2A in concert with PRC2 to silence tumor-suppressor gene promoters [PMID:25470042], and activates NF-κB by monoubiquitinating NEMO at K309 and catalyzing K63-linked ubiquitination of TRAF2/TRAF6 [PMID:30254148, PMID:30043491, PMID:33839419]. Loss-of-function mutations in TRIM37 cause Mulibrey nanism, a multi-organ disorder recapitulated in knockout mice featuring cardiomyopathy, infertility, and tumor predisposition [PMID:27044324].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing where TRIM37 resides answered the basic question of its organellar context: TRIM37 localizes to peroxisomes via PEX5-dependent import, classifying Mulibrey nanism as a peroxisomal disorder.\",\n      \"evidence\": \"Double immunofluorescence with peroxisomal markers in wild-type and PEX-mutant fibroblasts\",\n      \"pmids\": [\"11938494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Peroxisomal membrane vs. matrix topology was not resolved\", \"No enzymatic activity had yet been demonstrated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that TRIM37 possesses intrinsic E3 ubiquitin ligase activity dependent on its RING domain established the enzymatic basis for all subsequent substrate studies.\",\n      \"evidence\": \"Cell-free ubiquitination assay with RING domain mutagenesis and disease-associated missense mutations\",\n      \"pmids\": [\"15885686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No physiological substrate was identified\", \"Ubiquitin chain type was not determined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of histone H2A as a TRIM37 substrate revealed an unexpected chromatin-silencing function: TRIM37 mono-ubiquitinates H2A and cooperates with PRC2 and PRC1 to repress tumor-suppressor promoters.\",\n      \"evidence\": \"ChIP-chip, RNAi knockdown, co-immunoprecipitation, and in vivo xenograft in breast cancer cells\",\n      \"pmids\": [\"25470042\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether H2A ubiquitination is direct or requires additional cofactors in vivo was not fully resolved\", \"Structural basis of TRIM37-PRC2 interaction unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A Trim37 knockout mouse recapitulated Mulibrey nanism features — cardiomyopathy, infertility, hepatomegaly, and tumor predisposition — providing definitive in vivo genetic proof of causality.\",\n      \"evidence\": \"Congenic knockout mouse model with histopathology and metabolic characterization\",\n      \"pmids\": [\"27044324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific substrates underlie each organ-level phenotype remains undetermined\", \"Tissue-specific conditional knockouts were not generated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that TRIM37 ubiquitylates PEX5 at K464 to stabilize it for peroxisomal matrix protein import connected the peroxisomal localization to a defined biochemical function and explained oxidative stress sensitivity in TRIM37-deficient cells.\",\n      \"evidence\": \"Co-immunoprecipitation, site-directed mutagenesis of PEX5 K464, ubiquitination assay, and functional peroxisomal import assay\",\n      \"pmids\": [\"28724525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The ubiquitin chain type on PEX5 was not specified\", \"Relationship between PEX5 ubiquitylation defect and specific Mulibrey nanism organ pathology is unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Three studies expanded TRIM37's signaling roles: it activates NF-κB by monoubiquitinating NEMO at K309 downstream of ATM-mediated genotoxic stress, promotes K63-linked ubiquitination of TRAF2 for NF-κB signaling, and enhances MTORC1 activity by promoting lysosomal localization of MTOR.\",\n      \"evidence\": \"Ubiquitination assays with site-directed mutagenesis (NEMO K309), RING domain mutagenesis (TRAF2), co-immunoprecipitation with MTOR/RRAGB, subcellular fractionation, and NF-κB/MTORC1 pathway readouts\",\n      \"pmids\": [\"30254148\", \"30043491\", \"29940807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NEMO monoubiquitination and TRAF2/TRAF6 K63-ubiquitination represent parallel or sequential steps in the same pathway was not clarified\", \"MTORC1 regulation was shown only in one cancer system\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Two concurrent studies revealed TRIM37's centrosomal function: elevated TRIM37 degrades CEP192, blocks pericentriolar material foci formation, and prevents acentrosomal spindle assembly — making 17q23-amplified cancers exquisitely sensitive to PLK4 inhibition.\",\n      \"evidence\": \"TRIM37 knockdown/overexpression with PLK4 inhibitor centrinone, live-cell imaging, CEP192 degradation assays, epistasis analysis in breast cancer and neuroblastoma lines\",\n      \"pmids\": [\"32908304\", \"32908313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitination of CEP192 by TRIM37 was not reconstituted in vitro\", \"Whether TRIM37 normally restrains centrosome number in non-amplified cells at physiological expression levels is unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Multiple substrate identifications broadened TRIM37's oncogenic repertoire: it ubiquitinates PTEN for degradation (sustaining AKT signaling), promotes SMAD7 degradation (facilitating TGF-β signaling), and enforces H2A-ubiquitination-dependent chemoresistance in TNBC.\",\n      \"evidence\": \"Co-immunoprecipitation and ubiquitination assays for PTEN and SMAD7; H2A ubiquitination with antisense oligonucleotide nanoparticle delivery in vivo\",\n      \"pmids\": [\"33194618\", \"32916597\", \"32855208\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each substrate was characterized by a single lab; independent replication is lacking\", \"Chain-type specificity for PTEN ubiquitination was not fully defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The centrosomal substrate was identified as Centrobin: TRIM37 ubiquitinates Centrobin to prevent formation of centriolar protein assemblies (Cenpas) that act as ectopic MTOCs; Mulibrey nanism patient cells harbor these assemblies.\",\n      \"evidence\": \"Correlative light-electron microscopy, Centrobin ubiquitination assay, genetic epistasis with PLK4 and PLK1, patient-derived cell analysis\",\n      \"pmids\": [\"33491649\", \"33983387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The ubiquitin chain type on Centrobin and the precise degradation vs. regulatory fate was not determined\", \"Whether Cenpa formation contributes to Mulibrey nanism clinical features beyond cell division defects is unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"TRIM37 was shown to target p53 for K48-linked ubiquitination and proteasomal degradation, connecting TRIM37 overexpression to metabolic reprogramming (aerobic glycolysis) in hepatocellular carcinoma.\",\n      \"evidence\": \"Co-immunoprecipitation, K48-specific ubiquitination assay, siRNA epistasis, in vivo xenograft\",\n      \"pmids\": [\"36252649\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab finding; independent confirmation needed\", \"Whether p53 is a direct in vitro substrate has not been shown with purified components\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRIM37 selects among its diverse substrates in different subcellular compartments, and which specific substrate losses drive individual organ pathologies in Mulibrey nanism, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of TRIM37 exists\", \"Substrate selectivity determinants are unknown\", \"Tissue-specific conditional knockout studies have not been performed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 5, 6, 9, 10, 14, 15, 19, 20]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [1, 5, 6]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 11, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [7, 8, 9, 10, 22]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 12, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7, 8, 9, 10, 22]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 15, 17, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 6, 15, 17]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 11, 18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 3, 14, 20]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PEX5\",\n      \"NEMO\",\n      \"TRAF6\",\n      \"TRAF2\",\n      \"Centrobin\",\n      \"CEP192\",\n      \"MTOR\",\n      \"RRAGB\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}