{"gene":"TRIM17","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1998,"finding":"TRIM17 (terf/RNF16) was molecularly cloned from rat and human testis libraries and characterized as an RBCC family protein containing an N-terminal RING finger domain, one B-box domain, a middle coiled-coil domain, and a C-terminal domain, with expression almost exclusively in testis.","method":"PCR cloning, Northern blot analysis, sequence analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — molecular cloning and structural characterization in a single study, no functional assays","pmids":["9792805"],"is_preprint":false},{"year":2000,"finding":"Human RNF16 (TRIM17/terf) is chromosomally located at 1q42, as determined by PCR-assisted analysis of human/rodent mono-chromosomal hybrid cell panels and radiation hybrid mapping panels.","method":"Radiation hybrid mapping, chromosomal hybrid panel PCR, fluorescence in situ hybridization","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct chromosomal localization by multiple mapping methods, single study","pmids":["10894938"],"is_preprint":false},{"year":2009,"finding":"TRIM17 (terf) exhibits E3 ubiquitin ligase activity, demonstrated by in vitro ubiquitination assays in the presence of E2 enzyme UbcH6, and undergoes polyubiquitination leading to its own proteasomal degradation. TRIM44 inhibits TRIM17 ubiquitination and stabilizes the protein.","method":"In vitro ubiquitination assay, co-immunoprecipitation, proteasome inhibitor treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro E3 ligase assay plus cellular stabilization experiment, single lab, single paper","pmids":["19358823"],"is_preprint":false},{"year":2010,"finding":"TRIM17 is a RING-domain-dependent E3 ubiquitin ligase necessary and sufficient for neuronal apoptosis upstream of mitochondria. Overexpression of active TRIM17 induced the intrinsic apoptosis pathway in cerebellar granule neurons (CGN); this effect was abolished in Bax-/- neurons and required the RING domain. Knockdown or dominant-negative forms of TRIM17 blocked trophic factor withdrawal-induced apoptosis in CGN and sympathetic neurons. TRIM17 expression is induced at mRNA and protein levels during transcription-dependent neuronal apoptosis, regulated by the PI3K/Akt/GSK3 pathway.","method":"Overexpression/knockdown in primary neurons, dominant-negative mutants, Bax-/- epistasis, apoptosis assays, RING domain mutagenesis","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (gain-of-function, loss-of-function, genetic epistasis with Bax-/-, domain mutagenesis) in a single focused study","pmids":["20559321"],"is_preprint":false},{"year":2011,"finding":"TRIM17 (terf) interacts with ZWINT (ZW10 interacting protein), a kinetochore complex component, via its coiled-coil domain; TRIM17 overexpression causes proteasomal degradation of ZWINT and decreases cell proliferation in MCF7 breast cancer cells.","method":"Yeast two-hybrid screening, co-immunoprecipitation, western blot, stable transfection, siRNA knockdown, cell growth assay","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP, domain mapping, and functional cell proliferation assays, single lab","pmids":["22023800"],"is_preprint":false},{"year":2012,"finding":"TRIM17 ubiquitinates and promotes proteasomal degradation of the anti-apoptotic protein Mcl-1 in neurons, an interaction that depends on prior phosphorylation of Mcl-1 by GSK3. TRIM17 co-immunoprecipitated with Mcl-1; TRIM17 ubiquitinated Mcl-1 in vitro; overexpression of TRIM17 decreased Mcl-1 protein level in a phosphorylation- and proteasome-dependent manner; knockdown of TRIM17 reduced Mcl-1 ubiquitination and degradation. Impairment of Mcl-1 phosphorylation decreased the TRIM17-Mcl-1 physical interaction.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, siRNA knockdown, overexpression, kinase inhibition, site-directed mutagenesis of Mcl-1 phosphorylation sites","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ubiquitination assay plus reciprocal Co-IP plus knockdown plus mutagenesis in one rigorous study","pmids":["22976837"],"is_preprint":false},{"year":2014,"finding":"TRIM17 binds preferentially SUMOylated forms of NFATc3 but does not promote NFATc3 ubiquitination or degradation. Instead, TRIM17 reduces calcium-mediated nuclear localization of NFATc3 by approximately 2-fold and halves NFATc3 transcriptional activity. TRIM17 also inhibits NFATc4 nuclear translocation and activity. NFATc3 induces transcription of the proapoptotic gene Trim17 by binding its promoter together with c-Jun, forming a feedback loop.","method":"Co-immunoprecipitation, luciferase transcriptional reporter assays, nuclear/cytoplasmic fractionation, target gene expression measurement, chromatin immunoprecipitation (promoter binding), overexpression/knockdown","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP of SUMOylated NFATc3, luciferase assays, fractionation, ChIP) in a single focused study","pmids":["25215946"],"is_preprint":false},{"year":2016,"finding":"TRIM17 promotes selective autophagic degradation of midbodies (remnants of cell division machinery) while inhibiting selective autophagy of other targets. Its inhibitory function on bulk autophagy is traced to stabilization of Mcl-1-Beclin-1 complexes; selective loss of Mcl-1 from TRIM17-Beclin-1 complexes at midbodies correlates with TRIM17-promoted midbody removal.","method":"Biochemical fractionation, co-immunoprecipitation, overexpression, fluorescence microscopy, autophagy flux assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical and cell imaging approaches, single lab","pmids":["27562068"],"is_preprint":false},{"year":2018,"finding":"TRIM17 stabilizes BCL2A1 by blocking TRIM28 from binding and ubiquitinating BCL2A1. TRIM17 knock-out reduced BCL2A1 protein levels and restored sensitivity of melanoma cells to BRAF-targeted therapy. GSK3 phosphorylation is involved in inhibiting BCL2A1 degradation. TRIM28 is demonstrated as the E3 ubiquitin ligase for BCL2A1 (endogenous TRIM28 and BCL2A1 interact at the mitochondria), while TRIM17 acts as an inhibitor of TRIM28's E3 activity toward BCL2A1.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, TRIM17 knockout, cycloheximide chase, cell viability/drug sensitivity assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assays, KO and KD, drug sensitivity rescue, multiple orthogonal methods in one study","pmids":["30042493"],"is_preprint":false},{"year":2018,"finding":"TRIM17 decreases TRIM41-mediated degradation of ZSCAN21 (a transcription factor that stimulates SNCA/α-synuclein transcription), thereby indirectly stabilizing ZSCAN21 and increasing α-synuclein expression. Silencing of TRIM17 reduces SNCA expression; overexpression of TRIM17 opposes TRIM41's E3 ligase activity on ZSCAN21.","method":"SiRNA knockdown, overexpression, co-immunoprecipitation, ubiquitination assay, luciferase reporter assay, western blot, mRNA quantification","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays and Co-IP, single lab","pmids":["30485814"],"is_preprint":false},{"year":2023,"finding":"TRIM17 interacts with BAX and promotes K48-linked polyubiquitination and proteasomal degradation of BAX in gastric cancer cells, leading to suppression of BAX-dependent apoptosis. Knockdown of TRIM17 restored BAX levels and sensitized cells to apoptotic stimuli.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), siRNA knockdown, overexpression, apoptosis assays, western blot","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, K48-linkage-specific ubiquitination assay, and functional apoptosis rescue, single lab","pmids":["37697039"],"is_preprint":false},{"year":2023,"finding":"TRIM17 interacts with RBM38 and promotes K48-linked ubiquitination and proteasomal degradation of RBM38, attenuating ROS production and DNA damage to drive cisplatin resistance in NSCLC cells.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linkage), siRNA knockdown, overexpression, ROS and DNA damage assays, in vitro and in vivo drug resistance models","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, K48-linkage ubiquitination assay, functional rescue with RBM38, single lab","pmids":["37219768"],"is_preprint":false},{"year":2025,"finding":"TRIM17 promotes ubiquitination and degradation of FTO (an m6A demethylase), thereby increasing PDK1 mRNA stability via m6A modification and activating the AKT/mTOR signaling pathway in osteosarcoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, m6A modification assay, siRNA knockdown, overexpression, AKT/mTOR pathway activity readouts","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP and ubiquitination assay plus m6A downstream readout, single lab, single paper","pmids":["41145484"],"is_preprint":false},{"year":2025,"finding":"TMEFF2 recruits TRIM17 as an E3 ubiquitin ligase to promote K48-linked ubiquitination and proteasomal degradation of BAX in prostate hyperplasia cells; TMEFF2 interacts with BAX and TRIM17 in a three-component mechanism.","method":"Co-immunoprecipitation, ubiquitination assay, cycloheximide chase assay, siRNA knockdown, overexpression, in vivo BPH model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP, K48-ubiquitination assay, CHX chase, functional apoptosis rescue, single lab, single paper","pmids":["40780616"],"is_preprint":false}],"current_model":"TRIM17 is a RING-domain-dependent E3 ubiquitin ligase that promotes proteasomal degradation of substrates including MCL1 (phospho-dependent, GSK3-primed), BAX, BCL2A1 (indirectly by blocking TRIM28), RBM38, FTO, and ZWINT, thereby regulating neuronal apoptosis, cancer cell survival, autophagy (via Mcl-1-Beclin-1 complexes at midbodies), and α-synuclein expression; it can also act as an inhibitor of other TRIM E3 ligases (TRIM28, TRIM41), stabilizing their substrates rather than targeting them for degradation."},"narrative":{"mechanistic_narrative":"TRIM17 is an RBCC/TRIM-family RING-domain E3 ubiquitin ligase that functions as a switch governing apoptosis, autophagy, and protein stability across neuronal and cancer contexts [PMID:9792805, PMID:20559321]. It possesses intrinsic E3 activity, catalyzing ubiquitination in vitro with the E2 UbcH6 and autoubiquitinating itself for proteasomal turnover [PMID:19358823]. In neurons, TRIM17 is necessary and sufficient for intrinsic apoptosis upstream of mitochondria: its expression is induced during transcription-dependent neuronal death under PI3K/Akt/GSK3 control, and its proapoptotic action requires the RING domain and an intact BAX axis [PMID:20559321]. A central mechanism is the GSK3-primed, phosphorylation-dependent ubiquitination and degradation of the anti-apoptotic factor MCL1 [PMID:22976837]. TRIM17 directly ubiquitinates additional substrates via K48-linked chains to promote their proteasomal degradation, including BAX (suppressing apoptosis in cancer, and recruited by TMEFF2 in a three-component complex) [PMID:37697039, PMID:40780616], the RNA-binding protein RBM38 (driving cisplatin resistance through reduced ROS and DNA damage) [PMID:37219768], the m6A demethylase FTO (activating AKT/mTOR via PDK1 mRNA stabilization) [PMID:41145484], and the kinetochore component ZWINT (restraining cell proliferation) [PMID:22023800]. Beyond direct catalysis, TRIM17 acts as an inhibitor of other TRIM E3 ligases: it blocks TRIM28-mediated ubiquitination of BCL2A1 to stabilize it and confer BRAF-inhibitor resistance in melanoma [PMID:30042493], and it antagonizes TRIM41-mediated degradation of ZSCAN21 to increase SNCA/α-synuclein expression [PMID:30485814]. TRIM17 also binds SUMOylated NFATc3 without degrading it, instead limiting NFAT nuclear translocation and transcriptional activity within a feedback loop in which NFATc3 and c-Jun drive Trim17 transcription [PMID:25215946], and it controls selective autophagic removal of midbodies through dynamic Mcl-1–Beclin-1 complexes [PMID:27562068].","teleology":[{"year":1998,"claim":"Establishing the molecular identity of TRIM17 defined it as an RBCC/TRIM-family protein and provided the structural scaffold (RING, B-box, coiled-coil) later linked to its enzymatic and binding functions.","evidence":"PCR cloning, Northern blot, and sequence analysis from rat and human testis libraries","pmids":["9792805"],"confidence":"Medium","gaps":["No functional or enzymatic assays performed","Testis-restricted expression not reconciled with later somatic/cancer roles"]},{"year":2009,"claim":"Demonstrating intrinsic E3 ligase activity converted TRIM17 from a predicted RING protein into a confirmed ubiquitin ligase and revealed its own regulation by autoubiquitination and TRIM44-mediated stabilization.","evidence":"In vitro ubiquitination with E2 UbcH6, co-IP, and proteasome inhibitor treatment","pmids":["19358823"],"confidence":"Medium","gaps":["No physiological substrate identified at this stage","E2 specificity beyond UbcH6 not explored"]},{"year":2010,"claim":"Placing TRIM17 genetically upstream of mitochondria and BAX established it as a necessary and sufficient driver of intrinsic neuronal apoptosis, defining its cellular role.","evidence":"Gain/loss-of-function and dominant-negative manipulation in primary neurons, Bax-/- epistasis, and RING-domain mutagenesis","pmids":["20559321"],"confidence":"High","gaps":["Direct ubiquitination substrate mediating the proapoptotic effect not yet identified","Mechanism linking GSK3 to TRIM17 induction not resolved"]},{"year":2012,"claim":"Identifying MCL1 as a phospho-dependent substrate provided the direct biochemical link between TRIM17 activity and apoptotic commitment.","evidence":"Reciprocal Co-IP, in vitro ubiquitination, siRNA knockdown, and Mcl-1 phosphosite mutagenesis with GSK3 inhibition in neurons","pmids":["22976837"],"confidence":"High","gaps":["Whether MCL1 fully accounts for the BAX-dependent phenotype not established","Role outside neurons not addressed in this study"]},{"year":2011,"claim":"Mapping the TRIM17-ZWINT interaction to the coiled-coil domain extended TRIM17 substrate scope to kinetochore biology and cell proliferation control.","evidence":"Yeast two-hybrid, co-IP, domain mapping, knockdown, and cell growth assay in MCF7 cells","pmids":["22023800"],"confidence":"Medium","gaps":["In vitro ubiquitination of ZWINT not directly shown","Physiological context for ZWINT degradation unclear"]},{"year":2014,"claim":"Showing that TRIM17 binds SUMOylated NFATc3 without degrading it revealed a non-degradative, localization-controlling mode of action and a transcriptional feedback loop driving its own expression.","evidence":"Co-IP of SUMOylated NFATc3, luciferase reporters, nuclear/cytoplasmic fractionation, and ChIP of the Trim17 promoter","pmids":["25215946"],"confidence":"High","gaps":["Mechanism by which TRIM17 retains NFAT in cytoplasm not defined","Functional consequence of the c-Jun/NFATc3 feedback loop in vivo unclear"]},{"year":2016,"claim":"Linking TRIM17 to selective midbody autophagy and Mcl-1-Beclin-1 complexes showed it can both promote and inhibit autophagy depending on target.","evidence":"Fractionation, co-IP, fluorescence microscopy, and autophagy flux assays","pmids":["27562068"],"confidence":"Medium","gaps":["Molecular basis for target-selective autophagy regulation not resolved","Whether ubiquitin ligase activity is required not established"]},{"year":2018,"claim":"Two studies established TRIM17 as an inhibitor of other TRIM ligases — blocking TRIM28 to stabilize BCL2A1 and opposing TRIM41 to stabilize ZSCAN21 — reframing it as both a degrader and a substrate-protector.","evidence":"Reciprocal Co-IP, ubiquitination assays, knockout/knockdown, cycloheximide chase, luciferase reporters, and drug-sensitivity assays in melanoma and α-synuclein systems","pmids":["30042493","30485814"],"confidence":"High","gaps":["Structural basis for inhibition of partner TRIM ligases unknown","Whether TRIM17 catalytic activity is needed for the inhibitory mode unclear"]},{"year":2023,"claim":"Expansion to BAX, RBM38, and downstream cancer phenotypes generalized TRIM17 as a K48-linked degrader controlling apoptosis and chemoresistance across tumor types.","evidence":"Co-IP, K48-linkage-specific ubiquitination assays, knockdown/overexpression, apoptosis, ROS, and drug-resistance models in gastric cancer and NSCLC","pmids":["37697039","37219768"],"confidence":"Medium","gaps":["Single-lab findings per substrate without independent replication","Relationship between BAX degradation and the earlier BAX-dependent proapoptotic role not reconciled"]},{"year":2025,"claim":"Recent work added FTO as a substrate (linking TRIM17 to m6A/AKT-mTOR signaling) and showed adaptor-directed substrate selection, with TMEFF2 recruiting TRIM17 to degrade BAX.","evidence":"Co-IP, ubiquitination and m6A assays, cycloheximide chase, and pathway/in vivo models in osteosarcoma and benign prostatic hyperplasia","pmids":["41145484","40780616"],"confidence":"Medium","gaps":["Generality of adaptor-mediated substrate recruitment beyond TMEFF2 unknown","Single-study evidence for each substrate"]},{"year":null,"claim":"How TRIM17 selects between its degradative and ligase-inhibitory modes, and what governs substrate choice across tissues, remains unresolved.","evidence":"No single study reconciles the dual mechanisms or defines a unifying substrate-recognition principle","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate or partner-ligase recognition","No unified accounting of tissue-specific substrate repertoire","Determinants switching between degradation and protection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[2,3,5,10,11]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,5,10,11,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,9]}],"localization":[],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,5,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,5,8]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]}],"complexes":[],"partners":["MCL1","BAX","BCL2A1","TRIM28","TRIM41","NFATC3","ZWINT","RBM38"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y577","full_name":"E3 ubiquitin-protein ligase TRIM17","aliases":["RING finger protein 16","RING-type E3 ubiquitin transferase TRIM17","Testis RING finger protein","Tripartite motif-containing protein 17"],"length_aa":477,"mass_kda":54.4,"function":"E3 ubiquitin ligase that plays important roles in the regulation of neuronal apoptosis, selective autophagy or cell proliferation (PubMed:19358823, PubMed:22023800, PubMed:27562068). Stimulates the degradation of kinetochore ZW10 interacting protein ZWINT in a proteasome-dependent manner, leading to negative regulation of cell proliferation (PubMed:22023800). Inhibits autophagic degradation of diverse known targets while contributing to autophagy of midbodies. Autophagy-inhibitory activity involves MCL1, which TRIM17 assembles into complexes with the key autophagy regulator BECN1 (PubMed:27562068). Controls neuronal apoptosis by mediating ubiquitination and degradation of MCL1 to initiate neuronal death. In addition, regulates NFAT transcription factors NFATC3 and NFATC4 activities by preventing their nuclear localization, thus inhibiting their transcriptional activities. Decreases TRIM41-mediated degradation of ZSCAN2 thereby stimulating alpha-synuclein/SNCA transcription in neuronal cells (By similarity). Prevents the E3 ubiquitin-ligase activity of TRIM28 and its interaction with anti-apoptotic BCL2A1, blocking TRIM28 from ubiquitinating BCL2A1 (PubMed:19358823)","subcellular_location":"Cytoplasm; Lysosome","url":"https://www.uniprot.org/uniprotkb/Q9Y577/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM17","classification":"Not Classified","n_dependent_lines":14,"n_total_lines":1208,"dependency_fraction":0.011589403973509934},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRIM17","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":45.2},{"tissue":"testis","ntpm":39.3}],"url":"https://www.proteinatlas.org/search/TRIM17"},"hgnc":{"alias_symbol":["terf","RBCC"],"prev_symbol":["RNF16"]},"alphafold":{"accession":"Q9Y577","domains":[{"cath_id":"3.30.40.10","chopping":"2-48_57-94","consensus_level":"medium","plddt":83.8636,"start":2,"end":94},{"cath_id":"2.60.120.920","chopping":"287-322_332-397_408-476","consensus_level":"high","plddt":86.5259,"start":287,"end":476}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y577","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y577-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y577-F1-predicted_aligned_error_v6.png","plddt_mean":85.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM17","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM17"},"sequence":{"accession":"Q9Y577","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y577.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y577/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y577"}},"corpus_meta":[{"pmid":"16237670","id":"PMC_16237670","title":"TRIM/RBCC, a novel class of 'single protein RING finger' E3 ubiquitin ligases.","date":"2005","source":"BioEssays : news and reviews in molecular, cellular and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16237670","citation_count":608,"is_preprint":false},{"pmid":"10882102","id":"PMC_10882102","title":"The lin-41 RBCC gene acts in the C. elegans heterochronic pathway between the let-7 regulatory RNA and the LIN-29 transcription factor.","date":"2000","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/10882102","citation_count":586,"is_preprint":false},{"pmid":"11704850","id":"PMC_11704850","title":"PML protein isoforms and the RBCC/TRIM motif.","date":"2001","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11704850","citation_count":382,"is_preprint":false},{"pmid":"16434393","id":"PMC_16434393","title":"Subclassification of the RBCC/TRIM superfamily reveals a novel motif necessary for microtubule binding.","date":"2006","source":"The Journal of 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Northern blot analysis, sequence analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — molecular cloning and structural characterization in a single study, no functional assays\",\n      \"pmids\": [\"9792805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human RNF16 (TRIM17/terf) is chromosomally located at 1q42, as determined by PCR-assisted analysis of human/rodent mono-chromosomal hybrid cell panels and radiation hybrid mapping panels.\",\n      \"method\": \"Radiation hybrid mapping, chromosomal hybrid panel PCR, fluorescence in situ hybridization\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct chromosomal localization by multiple mapping methods, single study\",\n      \"pmids\": [\"10894938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TRIM17 (terf) exhibits E3 ubiquitin ligase activity, demonstrated by in vitro ubiquitination assays in the presence of E2 enzyme UbcH6, and undergoes polyubiquitination leading to its own proteasomal degradation. TRIM44 inhibits TRIM17 ubiquitination and stabilizes the protein.\",\n      \"method\": \"In vitro ubiquitination assay, co-immunoprecipitation, proteasome inhibitor treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro E3 ligase assay plus cellular stabilization experiment, single lab, single paper\",\n      \"pmids\": [\"19358823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRIM17 is a RING-domain-dependent E3 ubiquitin ligase necessary and sufficient for neuronal apoptosis upstream of mitochondria. Overexpression of active TRIM17 induced the intrinsic apoptosis pathway in cerebellar granule neurons (CGN); this effect was abolished in Bax-/- neurons and required the RING domain. Knockdown or dominant-negative forms of TRIM17 blocked trophic factor withdrawal-induced apoptosis in CGN and sympathetic neurons. TRIM17 expression is induced at mRNA and protein levels during transcription-dependent neuronal apoptosis, regulated by the PI3K/Akt/GSK3 pathway.\",\n      \"method\": \"Overexpression/knockdown in primary neurons, dominant-negative mutants, Bax-/- epistasis, apoptosis assays, RING domain mutagenesis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (gain-of-function, loss-of-function, genetic epistasis with Bax-/-, domain mutagenesis) in a single focused study\",\n      \"pmids\": [\"20559321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRIM17 (terf) interacts with ZWINT (ZW10 interacting protein), a kinetochore complex component, via its coiled-coil domain; TRIM17 overexpression causes proteasomal degradation of ZWINT and decreases cell proliferation in MCF7 breast cancer cells.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, western blot, stable transfection, siRNA knockdown, cell growth assay\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP, domain mapping, and functional cell proliferation assays, single lab\",\n      \"pmids\": [\"22023800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM17 ubiquitinates and promotes proteasomal degradation of the anti-apoptotic protein Mcl-1 in neurons, an interaction that depends on prior phosphorylation of Mcl-1 by GSK3. TRIM17 co-immunoprecipitated with Mcl-1; TRIM17 ubiquitinated Mcl-1 in vitro; overexpression of TRIM17 decreased Mcl-1 protein level in a phosphorylation- and proteasome-dependent manner; knockdown of TRIM17 reduced Mcl-1 ubiquitination and degradation. Impairment of Mcl-1 phosphorylation decreased the TRIM17-Mcl-1 physical interaction.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, siRNA knockdown, overexpression, kinase inhibition, site-directed mutagenesis of Mcl-1 phosphorylation sites\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ubiquitination assay plus reciprocal Co-IP plus knockdown plus mutagenesis in one rigorous study\",\n      \"pmids\": [\"22976837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIM17 binds preferentially SUMOylated forms of NFATc3 but does not promote NFATc3 ubiquitination or degradation. Instead, TRIM17 reduces calcium-mediated nuclear localization of NFATc3 by approximately 2-fold and halves NFATc3 transcriptional activity. TRIM17 also inhibits NFATc4 nuclear translocation and activity. NFATc3 induces transcription of the proapoptotic gene Trim17 by binding its promoter together with c-Jun, forming a feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, luciferase transcriptional reporter assays, nuclear/cytoplasmic fractionation, target gene expression measurement, chromatin immunoprecipitation (promoter binding), overexpression/knockdown\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP of SUMOylated NFATc3, luciferase assays, fractionation, ChIP) in a single focused study\",\n      \"pmids\": [\"25215946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIM17 promotes selective autophagic degradation of midbodies (remnants of cell division machinery) while inhibiting selective autophagy of other targets. Its inhibitory function on bulk autophagy is traced to stabilization of Mcl-1-Beclin-1 complexes; selective loss of Mcl-1 from TRIM17-Beclin-1 complexes at midbodies correlates with TRIM17-promoted midbody removal.\",\n      \"method\": \"Biochemical fractionation, co-immunoprecipitation, overexpression, fluorescence microscopy, autophagy flux assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical and cell imaging approaches, single lab\",\n      \"pmids\": [\"27562068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM17 stabilizes BCL2A1 by blocking TRIM28 from binding and ubiquitinating BCL2A1. TRIM17 knock-out reduced BCL2A1 protein levels and restored sensitivity of melanoma cells to BRAF-targeted therapy. GSK3 phosphorylation is involved in inhibiting BCL2A1 degradation. TRIM28 is demonstrated as the E3 ubiquitin ligase for BCL2A1 (endogenous TRIM28 and BCL2A1 interact at the mitochondria), while TRIM17 acts as an inhibitor of TRIM28's E3 activity toward BCL2A1.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, TRIM17 knockout, cycloheximide chase, cell viability/drug sensitivity assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assays, KO and KD, drug sensitivity rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"30042493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM17 decreases TRIM41-mediated degradation of ZSCAN21 (a transcription factor that stimulates SNCA/α-synuclein transcription), thereby indirectly stabilizing ZSCAN21 and increasing α-synuclein expression. Silencing of TRIM17 reduces SNCA expression; overexpression of TRIM17 opposes TRIM41's E3 ligase activity on ZSCAN21.\",\n      \"method\": \"SiRNA knockdown, overexpression, co-immunoprecipitation, ubiquitination assay, luciferase reporter assay, western blot, mRNA quantification\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays and Co-IP, single lab\",\n      \"pmids\": [\"30485814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM17 interacts with BAX and promotes K48-linked polyubiquitination and proteasomal degradation of BAX in gastric cancer cells, leading to suppression of BAX-dependent apoptosis. Knockdown of TRIM17 restored BAX levels and sensitized cells to apoptotic stimuli.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), siRNA knockdown, overexpression, apoptosis assays, western blot\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, K48-linkage-specific ubiquitination assay, and functional apoptosis rescue, single lab\",\n      \"pmids\": [\"37697039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM17 interacts with RBM38 and promotes K48-linked ubiquitination and proteasomal degradation of RBM38, attenuating ROS production and DNA damage to drive cisplatin resistance in NSCLC cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linkage), siRNA knockdown, overexpression, ROS and DNA damage assays, in vitro and in vivo drug resistance models\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, K48-linkage ubiquitination assay, functional rescue with RBM38, single lab\",\n      \"pmids\": [\"37219768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM17 promotes ubiquitination and degradation of FTO (an m6A demethylase), thereby increasing PDK1 mRNA stability via m6A modification and activating the AKT/mTOR signaling pathway in osteosarcoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, m6A modification assay, siRNA knockdown, overexpression, AKT/mTOR pathway activity readouts\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP and ubiquitination assay plus m6A downstream readout, single lab, single paper\",\n      \"pmids\": [\"41145484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMEFF2 recruits TRIM17 as an E3 ubiquitin ligase to promote K48-linked ubiquitination and proteasomal degradation of BAX in prostate hyperplasia cells; TMEFF2 interacts with BAX and TRIM17 in a three-component mechanism.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, cycloheximide chase assay, siRNA knockdown, overexpression, in vivo BPH model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP, K48-ubiquitination assay, CHX chase, functional apoptosis rescue, single lab, single paper\",\n      \"pmids\": [\"40780616\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM17 is a RING-domain-dependent E3 ubiquitin ligase that promotes proteasomal degradation of substrates including MCL1 (phospho-dependent, GSK3-primed), BAX, BCL2A1 (indirectly by blocking TRIM28), RBM38, FTO, and ZWINT, thereby regulating neuronal apoptosis, cancer cell survival, autophagy (via Mcl-1-Beclin-1 complexes at midbodies), and α-synuclein expression; it can also act as an inhibitor of other TRIM E3 ligases (TRIM28, TRIM41), stabilizing their substrates rather than targeting them for degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRIM17 is an RBCC/TRIM-family RING-domain E3 ubiquitin ligase that functions as a switch governing apoptosis, autophagy, and protein stability across neuronal and cancer contexts [#0, #3]. It possesses intrinsic E3 activity, catalyzing ubiquitination in vitro with the E2 UbcH6 and autoubiquitinating itself for proteasomal turnover [#2]. In neurons, TRIM17 is necessary and sufficient for intrinsic apoptosis upstream of mitochondria: its expression is induced during transcription-dependent neuronal death under PI3K/Akt/GSK3 control, and its proapoptotic action requires the RING domain and an intact BAX axis [#3]. A central mechanism is the GSK3-primed, phosphorylation-dependent ubiquitination and degradation of the anti-apoptotic factor MCL1 [#5]. TRIM17 directly ubiquitinates additional substrates via K48-linked chains to promote their proteasomal degradation, including BAX (suppressing apoptosis in cancer, and recruited by TMEFF2 in a three-component complex) [#10, #13], the RNA-binding protein RBM38 (driving cisplatin resistance through reduced ROS and DNA damage) [#11], the m6A demethylase FTO (activating AKT/mTOR via PDK1 mRNA stabilization) [#12], and the kinetochore component ZWINT (restraining cell proliferation) [#4]. Beyond direct catalysis, TRIM17 acts as an inhibitor of other TRIM E3 ligases: it blocks TRIM28-mediated ubiquitination of BCL2A1 to stabilize it and confer BRAF-inhibitor resistance in melanoma [#8], and it antagonizes TRIM41-mediated degradation of ZSCAN21 to increase SNCA/\\u03b1-synuclein expression [#9]. TRIM17 also binds SUMOylated NFATc3 without degrading it, instead limiting NFAT nuclear translocation and transcriptional activity within a feedback loop in which NFATc3 and c-Jun drive Trim17 transcription [#6], and it controls selective autophagic removal of midbodies through dynamic Mcl-1\\u2013Beclin-1 complexes [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing the molecular identity of TRIM17 defined it as an RBCC/TRIM-family protein and provided the structural scaffold (RING, B-box, coiled-coil) later linked to its enzymatic and binding functions.\",\n      \"evidence\": \"PCR cloning, Northern blot, and sequence analysis from rat and human testis libraries\",\n      \"pmids\": [\"9792805\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or enzymatic assays performed\", \"Testis-restricted expression not reconciled with later somatic/cancer roles\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating intrinsic E3 ligase activity converted TRIM17 from a predicted RING protein into a confirmed ubiquitin ligase and revealed its own regulation by autoubiquitination and TRIM44-mediated stabilization.\",\n      \"evidence\": \"In vitro ubiquitination with E2 UbcH6, co-IP, and proteasome inhibitor treatment\",\n      \"pmids\": [\"19358823\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No physiological substrate identified at this stage\", \"E2 specificity beyond UbcH6 not explored\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placing TRIM17 genetically upstream of mitochondria and BAX established it as a necessary and sufficient driver of intrinsic neuronal apoptosis, defining its cellular role.\",\n      \"evidence\": \"Gain/loss-of-function and dominant-negative manipulation in primary neurons, Bax-/- epistasis, and RING-domain mutagenesis\",\n      \"pmids\": [\"20559321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitination substrate mediating the proapoptotic effect not yet identified\", \"Mechanism linking GSK3 to TRIM17 induction not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying MCL1 as a phospho-dependent substrate provided the direct biochemical link between TRIM17 activity and apoptotic commitment.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro ubiquitination, siRNA knockdown, and Mcl-1 phosphosite mutagenesis with GSK3 inhibition in neurons\",\n      \"pmids\": [\"22976837\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MCL1 fully accounts for the BAX-dependent phenotype not established\", \"Role outside neurons not addressed in this study\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapping the TRIM17-ZWINT interaction to the coiled-coil domain extended TRIM17 substrate scope to kinetochore biology and cell proliferation control.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, domain mapping, knockdown, and cell growth assay in MCF7 cells\",\n      \"pmids\": [\"22023800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro ubiquitination of ZWINT not directly shown\", \"Physiological context for ZWINT degradation unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing that TRIM17 binds SUMOylated NFATc3 without degrading it revealed a non-degradative, localization-controlling mode of action and a transcriptional feedback loop driving its own expression.\",\n      \"evidence\": \"Co-IP of SUMOylated NFATc3, luciferase reporters, nuclear/cytoplasmic fractionation, and ChIP of the Trim17 promoter\",\n      \"pmids\": [\"25215946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which TRIM17 retains NFAT in cytoplasm not defined\", \"Functional consequence of the c-Jun/NFATc3 feedback loop in vivo unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linking TRIM17 to selective midbody autophagy and Mcl-1-Beclin-1 complexes showed it can both promote and inhibit autophagy depending on target.\",\n      \"evidence\": \"Fractionation, co-IP, fluorescence microscopy, and autophagy flux assays\",\n      \"pmids\": [\"27562068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis for target-selective autophagy regulation not resolved\", \"Whether ubiquitin ligase activity is required not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Two studies established TRIM17 as an inhibitor of other TRIM ligases — blocking TRIM28 to stabilize BCL2A1 and opposing TRIM41 to stabilize ZSCAN21 — reframing it as both a degrader and a substrate-protector.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assays, knockout/knockdown, cycloheximide chase, luciferase reporters, and drug-sensitivity assays in melanoma and \\u03b1-synuclein systems\",\n      \"pmids\": [\"30042493\", \"30485814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for inhibition of partner TRIM ligases unknown\", \"Whether TRIM17 catalytic activity is needed for the inhibitory mode unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expansion to BAX, RBM38, and downstream cancer phenotypes generalized TRIM17 as a K48-linked degrader controlling apoptosis and chemoresistance across tumor types.\",\n      \"evidence\": \"Co-IP, K48-linkage-specific ubiquitination assays, knockdown/overexpression, apoptosis, ROS, and drug-resistance models in gastric cancer and NSCLC\",\n      \"pmids\": [\"37697039\", \"37219768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings per substrate without independent replication\", \"Relationship between BAX degradation and the earlier BAX-dependent proapoptotic role not reconciled\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Recent work added FTO as a substrate (linking TRIM17 to m6A/AKT-mTOR signaling) and showed adaptor-directed substrate selection, with TMEFF2 recruiting TRIM17 to degrade BAX.\",\n      \"evidence\": \"Co-IP, ubiquitination and m6A assays, cycloheximide chase, and pathway/in vivo models in osteosarcoma and benign prostatic hyperplasia\",\n      \"pmids\": [\"41145484\", \"40780616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of adaptor-mediated substrate recruitment beyond TMEFF2 unknown\", \"Single-study evidence for each substrate\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRIM17 selects between its degradative and ligase-inhibitory modes, and what governs substrate choice across tissues, remains unresolved.\",\n      \"evidence\": \"No single study reconciles the dual mechanisms or defines a unifying substrate-recognition principle\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate or partner-ligase recognition\", \"No unified accounting of tissue-specific substrate repertoire\", \"Determinants switching between degradation and protection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [2, 3, 5, 10, 11]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 5, 10, 11, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 5, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 5, 8]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MCL1\", \"BAX\", \"BCL2A1\", \"TRIM28\", \"TRIM41\", \"NFATc3\", \"ZWINT\", \"RBM38\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}