Affinage

TRIM17

E3 ubiquitin-protein ligase TRIM17 · UniProt Q9Y577

Length
477 aa
Mass
54.4 kDa
Annotated
2026-04-28
51 papers in source corpus 14 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIM17 is a RING-domain E3 ubiquitin ligase that functions as a dual regulator of protein stability — directly ubiquitinating substrates for proteasomal degradation and inhibiting partner E3 ligases to stabilize specific targets. TRIM17 promotes K48-linked ubiquitination and degradation of the anti-apoptotic protein Mcl-1 in a GSK3 phosphorylation-dependent manner, triggering Bax-dependent neuronal apoptosis, and also targets ZWINT, RBM38, BAX, and FTO for proteasomal degradation in various cellular contexts (PMID:22976837, PMID:22023800, PMID:37219768, PMID:37697039, PMID:41145484). Paradoxically, TRIM17 stabilizes BCL2A1 and ZSCAN21 by physically blocking the E3 ligases TRIM28 and TRIM41, respectively, from ubiquitinating these substrates, thereby modulating melanoma drug resistance and α-synuclein transcription (PMID:30042493, PMID:30485814). TRIM17 also regulates selective autophagy of midbodies through modulation of Mcl-1–Beclin-1 complexes, and its expression is transcriptionally induced by NFATc3/c-Jun in a feedback loop and regulated upstream by the PI3K/Akt/GSK3 pathway during developmental neuronal apoptosis (PMID:27562068, PMID:25215946, PMID:20559321).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1998 Medium

    Identification of TRIM17 as a novel RBCC/TRIM family member with RING, B-box, and coiled-coil domains established the gene's structural framework and revealed near-exclusive testis expression, posing the question of its enzymatic and biological function.

    Evidence PCR cloning, cDNA library screening, Northern blot in mouse tissues

    PMID:9792805

    Open questions at the time
    • No enzymatic activity demonstrated
    • Function unknown beyond domain architecture
    • Expression in other tissues not explored at protein level
  2. 2009 Medium

    Demonstration that TRIM17 possesses intrinsic E3 ubiquitin ligase activity with UbcH6 as its cognate E2, and that TRIM44 stabilizes TRIM17 by blocking its auto-ubiquitination, established TRIM17 as a bona fide ubiquitin ligase subject to regulation by a partner TRIM protein.

    Evidence In vitro ubiquitination assay, proteasome inhibitor chase, Co-IP of TRIM17–TRIM44

    PMID:19358823

    Open questions at the time
    • No physiological substrate identified
    • Functional consequence of TRIM44-mediated stabilization not tested in vivo
  3. 2010 High

    Showing that TRIM17 RING domain activity is necessary and sufficient for Bax-dependent neuronal apoptosis, and that TRIM17 is induced by PI3K/Akt/GSK3 pathway inhibition in cerebellar granule neurons, answered the central question of TRIM17's biological role and placed it in a defined signaling axis during developmental cell death.

    Evidence OE/KD in primary CGN and sympathetic neurons, dominant-negative RING mutants, Bax−/− epistasis, pharmacological pathway inhibition, in vivo immunostaining

    PMID:20559321

    Open questions at the time
    • Direct ubiquitination substrate mediating apoptosis not yet identified
    • Transcriptional regulation mechanism not resolved
  4. 2011 Medium

    Identification of ZWINT as a TRIM17 substrate degraded via the coiled-coil domain interaction linked TRIM17 to kinetochore biology and cell proliferation control beyond its neuronal apoptosis role.

    Evidence Yeast two-hybrid, Co-IP, coiled-coil deletion mapping, siRNA KD, proliferation assay

    PMID:22023800

    Open questions at the time
    • Ubiquitin chain linkage type on ZWINT not determined
    • In vivo relevance to cell cycle not shown
  5. 2012 High

    Identification of Mcl-1 as the direct pro-apoptotic substrate of TRIM17, requiring GSK3-dependent phosphorylation for recognition and K48-linked ubiquitination, resolved how TRIM17 E3 activity connects to the Bax-dependent apoptotic pathway in neurons.

    Evidence Endogenous Co-IP, in vitro ubiquitination, phospho-site mutagenesis blocking interaction, KD reducing Mcl-1 ubiquitination

    PMID:22976837

    Open questions at the time
    • Whether TRIM17 is the sole E3 for Mcl-1 degradation in neurons not resolved
    • Structural basis of phospho-dependent recognition unknown
  6. 2014 High

    Discovery that NFATc3/c-Jun directly transcribes TRIM17 while TRIM17 reciprocally inhibits NFATc3 nuclear translocation established a negative feedback loop governing TRIM17 expression during neuronal apoptosis.

    Evidence ChIP on Trim17 promoter, luciferase reporters, nuclear/cytoplasmic fractionation, OE/KD in CGN

    PMID:25215946

    Open questions at the time
    • Mechanism by which TRIM17 retains SUMOylated NFATc3 in cytoplasm unknown
    • Whether TRIM17 ubiquitinates NFATc3 indirectly not excluded
  7. 2016 Medium

    Demonstrating that TRIM17 promotes selective autophagic degradation of midbodies while inhibiting bulk autophagy through Mcl-1–Beclin-1 complex stabilization revealed a non-apoptotic function and explained how TRIM17 coordinates apoptotic and autophagic pathways via a shared Mcl-1 node.

    Evidence Co-IP, autophagy flux assays, midbody imaging, OE/KD in mammalian cells

    PMID:27562068

    Open questions at the time
    • Mechanism of selective Mcl-1 loss at midbodies unclear
    • Whether TRIM17 directly ubiquitinates autophagy components not tested
  8. 2018 High

    Two studies revealed that TRIM17 can stabilize proteins by inhibiting partner E3 ligases: it blocks TRIM28-mediated ubiquitination of BCL2A1 (relevant to melanoma drug resistance) and TRIM41-mediated ubiquitination of ZSCAN21 (controlling α-synuclein transcription), fundamentally expanding TRIM17's mechanism from substrate-directed E3 to E3 ligase antagonist.

    Evidence Endogenous Co-IP, KO/KD with ubiquitination readouts, subcellular fractionation, melanoma drug sensitivity assays (BCL2A1); Co-IP, ubiquitination assays, SNCA mRNA measurement, MPTP mouse model (ZSCAN21)

    PMID:30042493 PMID:30485814

    Open questions at the time
    • Structural basis of TRIM17-mediated E3 inhibition not determined
    • Whether TRIM17 catalytic activity is required for the inhibitory function not resolved
    • Relevance of ZSCAN21–SNCA axis to Parkinson's disease pathology not confirmed in human tissue
  9. 2023 Medium

    Identification of BAX and RBM38 as direct K48-linked ubiquitination substrates of TRIM17 in gastric cancer and lung cancer cells, respectively, showed that TRIM17 can function as an anti-apoptotic and chemoresistance factor in cancer contexts — inverting its neuronal pro-apoptotic role.

    Evidence K48-linkage-specific ubiquitination assays, Co-IP, OE/KD with apoptosis and drug resistance readouts in cancer cell lines

    PMID:37219768 PMID:37697039

    Open questions at the time
    • Context-dependent switch between pro- and anti-apoptotic roles mechanistically unexplained
    • BAX ubiquitination by TRIM17 reported from single labs — independent confirmation lacking
  10. 2025 Medium

    Demonstration that TRIM17 ubiquitinates FTO to regulate m6A-dependent mRNA stability and AKT/mTOR signaling in osteosarcoma, and that TMEFF2 recruits TRIM17 to BAX in a ternary complex in prostate tissue, expanded the substrate repertoire and revealed adaptor-mediated substrate recruitment as a regulatory mechanism.

    Evidence Co-IP, ubiquitination assays, m6A profiling, AKT/mTOR readouts (FTO); Co-IP of ternary complex, CHX chase, rat BPH model (BAX/TMEFF2)

    PMID:40780616 PMID:41145484

    Open questions at the time
    • Generality of adaptor-mediated recruitment to other substrates unknown
    • FTO as TRIM17 substrate awaits independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • What determines whether TRIM17 acts as a substrate-directed E3 ligase versus an E3 ligase antagonist in different cellular contexts remains unresolved, as does the structural basis for substrate versus partner E3 recognition.
  • No structural model of TRIM17 or its complexes available
  • Context-dependent functional switch mechanism undefined
  • Physiological role in testis (highest expression tissue) completely uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0098772 molecular function regulator activity 2
Localization
GO:0005739 mitochondrion 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-5357801 Programmed Cell Death 3 R-HSA-162582 Signal Transduction 2 R-HSA-9612973 Autophagy 1
Partners
BAXFTOMCL1TRIM28TRIM41TRIM44ZSCAN21ZWINT

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 TRIM17 is a novel E3 ubiquitin ligase whose RING domain confers E3 activity that is both necessary and sufficient for initiating neuronal apoptosis via the intrinsic (Bax-dependent) pathway; its pro-apoptotic effect is abolished in Bax-/- neurons and by dominant-negative RING mutants. Overexpression/knockdown in primary cerebellar granule neurons (CGN) and sympathetic neurons, dominant-negative RING mutants, Bax-/- genetic rescue Cell death and differentiation High 20559321
2012 TRIM17 directly ubiquitinates Mcl-1 (anti-apoptotic Bcl-2 family member) in a phosphorylation (GSK3)-dependent manner: GSK3-mediated phosphorylation of Mcl-1 is required for its physical interaction with TRIM17, after which TRIM17 promotes K48-linked ubiquitination and proteasomal degradation of Mcl-1 to initiate neuronal apoptosis. Co-immunoprecipitation of endogenous proteins, in vitro ubiquitination assay, Trim17 knockdown reducing Mcl-1 ubiquitination/degradation, kinase inhibition and phospho-site point mutations blocking Trim17-Mcl-1 interaction Cell death and differentiation High 22976837
2011 TRIM17 (Terf) interacts with kinetochore protein ZWINT via its coiled-coil domain and promotes proteasomal degradation of ZWINT, negatively regulating cell proliferation. Yeast two-hybrid screening, immunoprecipitation/western blot, coiled-coil deletion mutants, overexpression causing ZWINT downregulation, siRNA knockdown, stable transfection cell growth assay Journal of biochemistry Medium 22023800
2009 TRIM17 (Terf) exhibits E3 ubiquitin ligase activity in vitro using UbcH6 as E2 enzyme; it auto-polyubiquitinates and is itself degraded by the proteasome. TRIM44 interacts with TRIM17 and inhibits its auto-ubiquitination, thereby stabilizing TRIM17 protein levels. In vitro ubiquitination assay with UbcH6, proteasome inhibitor stabilization in cells, co-immunoprecipitation of TRIM17 and TRIM44 Biochemical and biophysical research communications Medium 19358823
2018 TRIM17 stabilizes BCL2A1 by physically blocking TRIM28 (an E3 ubiquitin ligase for BCL2A1) from binding and ubiquitinating BCL2A1; TRIM28 and BCL2A1 interact at the mitochondria, and TRIM28 knockdown decreases BCL2A1 ubiquitination. Knockout of TRIM17 reduces BCL2A1 protein levels and sensitizes melanoma cells to BRAF-targeted therapy. Co-immunoprecipitation of endogenous proteins, TRIM17 knockout, TRIM28 knockdown, ubiquitination assays, subcellular fractionation (mitochondria), cell viability assays Cell death and differentiation High 30042493
2014 TRIM17 binds preferentially SUMOylated forms of NFATc3 (and NFATc4) but does not ubiquitinate/degrade them; instead, TRIM17 reduces calcium-mediated nuclear translocation of NFATc3/c4 by approximately 2-fold, thereby inhibiting their transcriptional activity. Conversely, NFATc3 (together with c-Jun) directly binds the Trim17 gene promoter and induces Trim17 transcription, establishing a feedback loop. Co-immunoprecipitation, luciferase transcriptional reporter assays, nuclear/cytoplasmic fractionation, target gene expression measurement, ChIP (NFATc3 binding to Trim17 promoter), overexpression/knockdown in cerebellar granule neurons Cell death and differentiation High 25215946
2016 TRIM17 promotes selective autophagic removal of midbodies while inhibiting bulk autophagy through stabilization of Mcl-1–Beclin-1 complexes; selective loss of Mcl-1 from TRIM17-Beclin-1 complexes at midbodies correlates with TRIM17's ability to promote midbody degradation. Biochemical co-immunoprecipitation, autophagy flux assays, midbody localization imaging, overexpression/knockdown in mammalian cells Journal of cell science Medium 27562068
2018 TRIM17 decreases TRIM41-mediated ubiquitination and degradation of the transcription factor ZSCAN21, thereby stabilizing ZSCAN21 and increasing SNCA (α-synuclein) transcription. TRIM41 is an E3 ubiquitin ligase for ZSCAN21, and TRIM17 antagonizes this activity. Co-immunoprecipitation, ubiquitination assays, TRIM17/TRIM41/ZSCAN21 knockdown with measurement of ZSCAN21 protein and SNCA mRNA levels, mouse MPTP model Cell reports High 30485814
2019 TRIM17 expression is controlled by the PI3K/Akt/GSK3 signaling pathway in cerebellar granule neurons; inhibition of this pathway upregulates Trim17 mRNA and protein, and Trim17 protein is expressed in vivo in apoptotic neurons during postnatal cerebellar development. Pharmacological inhibition of PI3K/Akt/GSK3, immunostaining of apoptotic neurons in vivo, RT-PCR/western blot Cell death and differentiation Medium 20559321
2023 TRIM17 interacts with BAX and promotes its K48-linked ubiquitination and proteasomal degradation in gastric cancer cells, leading to suppression of BAX-dependent apoptosis and enhanced cancer cell survival. Co-immunoprecipitation, ubiquitination assays (K48-linkage specific), overexpression/knockdown in AGS and HGC-27 gastric cancer cell lines, apoptosis assays Cell death and differentiation Medium 37697039
2023 TRIM17 interacts with RBM38 and promotes its K48-linked ubiquitination and proteasomal degradation, thereby attenuating ROS production and DNA damage to drive cisplatin resistance in non-small cell lung cancer cells. Co-immunoprecipitation, K48-linkage ubiquitination assay, TRIM17 knockdown/overexpression, ROS and DNA damage measurements, in vitro and in vivo cisplatin sensitivity assays Cellular oncology Medium 37219768
2025 TMEFF2 recruits TRIM17 as the E3 ubiquitin ligase to promote K48-linked ubiquitination and proteasomal degradation of BAX, thereby driving benign prostatic hyperplasia progression; TMEFF2 interacts with BAX and TRIM17 in a ternary complex. Co-immunoprecipitation, ubiquitination assay (K48-linkage), cycloheximide chase assay, knockdown/overexpression in prostate cell lines and rat BPH model Cellular signalling Medium 40780616
2025 TRIM17 ubiquitinates and promotes proteasomal degradation of FTO (an m6A RNA demethylase), which increases N6-methyladenosine modification and stability of PDK1 mRNA, activating the AKT/mTOR signaling pathway to drive osteosarcoma malignancy. Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, m6A profiling, AKT/mTOR pathway analysis in osteosarcoma cells Cell death & disease Medium 41145484
1998 TRIM17 (Terf/RNF16) was molecularly cloned and characterized as a novel RBCC/TRIM protein containing an N-terminal RING finger domain, one B-box, and a middle coiled-coil domain; Northern blot showed near-exclusive expression in testis. PCR with degenerate primers, cDNA library screening, Northern blot analysis, domain analysis Biochemical and biophysical research communications Medium 9792805
2011 PPARγ activation (by DEHP or the PPARγ agonist troglitazone) induces Trim17 protein expression in Neuro-2a neuroblastoma cells, which is associated with caspase-3 cleavage and apoptosis; this induction is blocked by the PPARγ antagonist GW9662. Chemical activation/inhibition of PPARγ, western blot for Trim17 and cleaved caspase-3, cell viability assays Toxicology letters Low 21856391

Source papers

Stage 0 corpus · 51 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 TRIM/RBCC, a novel class of 'single protein RING finger' E3 ubiquitin ligases. BioEssays : news and reviews in molecular, cellular and developmental biology 603 16237670
2000 The lin-41 RBCC gene acts in the C. elegans heterochronic pathway between the let-7 regulatory RNA and the LIN-29 transcription factor. Molecular cell 584 10882102
2001 PML protein isoforms and the RBCC/TRIM motif. Oncogene 381 11704850
2006 Subclassification of the RBCC/TRIM superfamily reveals a novel motif necessary for microtubule binding. The Journal of biological chemistry 270 16434393
2002 An RBCC protein implicated in maintenance of steady-state neuregulin receptor levels. Proceedings of the National Academy of Sciences of the United States of America 105 11867753
2007 The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin ligase involved in ERAD. Molecular biology of the cell 96 17314412
2006 Solution structure of the RBCC/TRIM B-box1 domain of human MID1: B-box with a RING. Journal of molecular biology 92 16529770
2003 BTBD1 and BTBD2 colocalize to cytoplasmic bodies with the RBCC/tripartite motif protein, TRIM5delta. Experimental cell research 89 12878161
2012 Trim17-mediated ubiquitination and degradation of Mcl-1 initiate apoptosis in neurons. Cell death and differentiation 77 22976837
2002 Hetero-oligomerization among the TIF family of RBCC/TRIM domain-containing nuclear cofactors: a potential mechanism for regulating the switch between coactivation and corepression. Journal of molecular biology 74 12096914
2011 Activation of Trim17 by PPARγ is involved in di(2-ethylhexyl) phthalate (DEHP)-induced apoptosis on Neuro-2a cells. Toxicology letters 52 21856391
1998 Molecular cloning and characterization of a novel protein kinase C-interacting protein with structural motifs related to RBCC family proteins. Biochemical and biophysical research communications 51 9514928
2004 TRIM45, a novel human RBCC/TRIM protein, inhibits transcriptional activities of ElK-1 and AP-1. Biochemical and biophysical research communications 50 15351693
2018 TRIM17 and TRIM28 antagonistically regulate the ubiquitination and anti-apoptotic activity of BCL2A1. Cell death and differentiation 49 30042493
2011 Terf/TRIM17 stimulates degradation of kinetochore protein ZWINT and regulates cell proliferation. Journal of biochemistry 49 22023800
2009 TRIM44 interacts with and stabilizes terf, a TRIM ubiquitin E3 ligase. Biochemical and biophysical research communications 48 19358823
2001 Molecular cloning and characterization of neural activity-related RING finger protein (NARF): a new member of the RBCC family is a candidate for the partner of myosin V. Journal of neurochemistry 47 11432975
2008 Characterization of TRIM31, upregulated in gastric adenocarcinoma, as a novel RBCC protein. Journal of cellular biochemistry 46 18773414
2010 Trim17, a novel E3 ubiquitin-ligase, initiates neuronal apoptosis. Cell death and differentiation 43 20559321
2005 bloodthirsty, an RBCC/TRIM gene required for erythropoiesis in zebrafish. Developmental biology 42 15890331
2016 TRIM17 contributes to autophagy of midbodies while actively sparing other targets from degradation. Journal of cell science 35 27562068
2018 The E3 Ubiquitin Ligases TRIM17 and TRIM41 Modulate α-Synuclein Expression by Regulating ZSCAN21. Cell reports 34 30485814
2011 The cellular level of TRIM31, an RBCC protein overexpressed in gastric cancer, is regulated by multiple mechanisms including the ubiquitin-proteasome system. Cell biology international 31 21231912
2023 The E3 ubiquitin ligase TRIM17 promotes gastric cancer survival and progression via controlling BAX stability and antagonizing apoptosis. Cell death and differentiation 28 37697039
2014 Control of neuronal apoptosis by reciprocal regulation of NFATc3 and Trim17. Cell death and differentiation 28 25215946
2003 HLS5, a novel RBCC (ring finger, B box, coiled-coil) family member isolated from a hemopoietic lineage switch, is a candidate tumor suppressor. The Journal of biological chemistry 28 14662771
1998 Molecular cloning of a novel RING finger-B box-coiled coil (RBCC) protein, terf, expressed in the testis. Biochemical and biophysical research communications 27 9792805
1998 Transcriptional activity of RBCK1 protein (RBCC protein interacting with PKC 1): requirement of RING-finger and B-Box motifs and regulation by protein kinases. Biochemical and biophysical research communications 26 9642138
2007 The structurally disordered KRAB repression domain is incorporated into a protease resistant core upon binding to KAP-1-RBCC domain. Journal of molecular biology 25 17512541
2016 Characterisation of assembly and ubiquitylation by the RBCC motif of Trim5α. Scientific reports 23 27230667
2005 Structural organization and Zn2+-dependent subdomain interactions involving autoantigenic epitopes in the Ring-B-box-coiled-coil (RBCC) region of Ro52. The Journal of biological chemistry 22 15964842
2013 Abba is an essential TRIM/RBCC protein to maintain the integrity of sarcomeric cytoarchitecture. Journal of cell science 19 23729735
2012 MuRFs: specialized members of the TRIM/RBCC family with roles in the regulation of the trophic state of muscle and its metabolism. Advances in experimental medicine and biology 17 23631004
2023 TRIM17-mediated ubiquitination and degradation of RBM38 promotes cisplatin resistance in non-small cell lung cancer. Cellular oncology (Dordrecht, Netherlands) 15 37219768
2022 MiR-1246 is responsible for lung cancer cells-derived exosomes-mediated promoting effects on lung cancer stemness via targeting TRIM17. Environmental toxicology 15 35894553
1992 TerF, the sixth identified replication arrest site in Escherichia coli, is located within the rcsC gene. Journal of bacteriology 15 1447156
2021 To Ubiquitinate or Not to Ubiquitinate: TRIM17 in Cell Life and Death. Cells 14 34069831
2011 Association of the testis-specific TRIM/RBCC protein RNF33/TRIM60 with the cytoplasmic motor proteins KIF3A and KIF3B. Molecular and cellular biochemistry 13 21909995
1998 Molecular cloning and characterization of RBCK2, a splicing variant of a RBCC family protein, RBCK1. FEBS letters 13 9755849
2001 Expression of MUL, a gene encoding a novel RBCC family ring-finger protein, in human and mouse embryogenesis. Mechanisms of development 12 11578880
2001 A novel member of the RBCC family, Trif, expressed specifically in the spermatids of mouse testis. Mechanisms of development 11 11578878
2024 Cryo-EM structure of PML RBCC dimer reveals CC-mediated octopus-like nuclear body assembly mechanism. Cell discovery 3 39587079
2023 The neuro-protective role of telomerase via TERT/TERF-2 in the acute phase of spinal cord injury. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 2 37165116
2022 Multimodal approach to characterize the tetrameric form of human PML-RBCC domain and ATO-mediated conformational changes. International journal of biological macromolecules 2 36356867
2009 Accumulation of polyubiquitinated proteins by overexpression of RBCC protein interacting with protein kinase C2, a splice variant of ubiquitin ligase RBCC protein interacting with protein kinase C1. The FEBS journal 2 19796170
2000 Chromosome mapping of RNF16 and rnf16, human, mouse and rat genes coding for testis RING finger protein (terf), a member of the RING finger family. Cytogenetics and cell genetics 2 10894938
2025 Conditional Binding of Arsenic Trioxide (ATO) to Cysteine-Rich Zinc Finger Motifs within RBCC Domain of PML Protein. Chemical research in toxicology 1 40219955
2023 Mutations at proximal cysteine residues in PML impair ATO binding by destabilizing the RBCC domain. The FEBS journal 1 38129745
1996 Inhibitory effect of phenyl N-terf-butyl nitrone on Kupffer cell phagocytosis. Redox report : communications in free radical research 1 27406416
2025 TMEFF2 promotes hyperplastic prostate progression by degrading BAX via TRIM17. Cellular signalling 0 40780616
2025 TRIM17 promotes the progression of osteosarcoma by regulating PDK1 m6A modification-mediated AKT/mTOR pathway activation through ubiquitination of FTO. Cell death & disease 0 41145484