Affinage

TRIM17

E3 ubiquitin-protein ligase TRIM17 · UniProt Q9Y577

Length
477 aa
Mass
54.4 kDa
Annotated
2026-06-10
51 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

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

    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

    PMID:9792805

    Open questions at the time
    • No functional or enzymatic assays performed
    • Testis-restricted expression not reconciled with later somatic/cancer roles
  2. 2009 Medium

    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

    PMID:19358823

    Open questions at the time
    • No physiological substrate identified at this stage
    • E2 specificity beyond UbcH6 not explored
  3. 2010 High

    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

    PMID:20559321

    Open questions at the time
    • Direct ubiquitination substrate mediating the proapoptotic effect not yet identified
    • Mechanism linking GSK3 to TRIM17 induction not resolved
  4. 2012 High

    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

    PMID:22976837

    Open questions at the time
    • Whether MCL1 fully accounts for the BAX-dependent phenotype not established
    • Role outside neurons not addressed in this study
  5. 2011 Medium

    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

    PMID:22023800

    Open questions at the time
    • In vitro ubiquitination of ZWINT not directly shown
    • Physiological context for ZWINT degradation unclear
  6. 2014 High

    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

    PMID:25215946

    Open questions at the time
    • Mechanism by which TRIM17 retains NFAT in cytoplasm not defined
    • Functional consequence of the c-Jun/NFATc3 feedback loop in vivo unclear
  7. 2016 Medium

    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

    PMID:27562068

    Open questions at the time
    • Molecular basis for target-selective autophagy regulation not resolved
    • Whether ubiquitin ligase activity is required not established
  8. 2018 High

    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

    PMID:30042493 PMID:30485814

    Open questions at the time
    • Structural basis for inhibition of partner TRIM ligases unknown
    • Whether TRIM17 catalytic activity is needed for the inhibitory mode unclear
  9. 2023 Medium

    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

    PMID:37219768 PMID:37697039

    Open questions at the time
    • Single-lab findings per substrate without independent replication
    • Relationship between BAX degradation and the earlier BAX-dependent proapoptotic role not reconciled
  10. 2025 Medium

    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

    PMID:40780616 PMID:41145484

    Open questions at the time
    • Generality of adaptor-mediated substrate recruitment beyond TMEFF2 unknown
    • Single-study evidence for each substrate

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TRIM17 selects between its degradative and ligase-inhibitory modes, and what governs substrate choice across tissues, remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 5 GO:0140096 catalytic activity, acting on a protein 5 GO:0098772 molecular function regulator activity 2
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9612973 Autophagy 1
Partners
BAXBCL2A1MCL1NFATC3RBM38TRIM28TRIM41ZWINT

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. PCR cloning, Northern blot analysis, sequence analysis Biochemical and biophysical research communications Medium 9792805
2000 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. Radiation hybrid mapping, chromosomal hybrid panel PCR, fluorescence in situ hybridization Cytogenetics and cell genetics Medium 10894938
2009 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. In vitro ubiquitination assay, co-immunoprecipitation, proteasome inhibitor treatment Biochemical and biophysical research communications Medium 19358823
2010 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. Overexpression/knockdown in primary neurons, dominant-negative mutants, Bax-/- epistasis, apoptosis assays, RING domain mutagenesis Cell death and differentiation High 20559321
2011 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. Yeast two-hybrid screening, co-immunoprecipitation, western blot, stable transfection, siRNA knockdown, cell growth assay Journal of biochemistry Medium 22023800
2012 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. Co-immunoprecipitation, in vitro ubiquitination assay, siRNA knockdown, overexpression, kinase inhibition, site-directed mutagenesis of Mcl-1 phosphorylation sites Cell death and differentiation High 22976837
2014 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. Co-immunoprecipitation, luciferase transcriptional reporter assays, nuclear/cytoplasmic fractionation, target gene expression measurement, chromatin immunoprecipitation (promoter binding), overexpression/knockdown Cell death and differentiation High 25215946
2016 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. Biochemical fractionation, co-immunoprecipitation, overexpression, fluorescence microscopy, autophagy flux assays Journal of cell science Medium 27562068
2018 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. Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, TRIM17 knockout, cycloheximide chase, cell viability/drug sensitivity assays Cell death and differentiation High 30042493
2018 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. SiRNA knockdown, overexpression, co-immunoprecipitation, ubiquitination assay, luciferase reporter assay, western blot, mRNA quantification Cell reports Medium 30485814
2023 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. Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), siRNA knockdown, overexpression, apoptosis assays, western blot Cell death and differentiation Medium 37697039
2023 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. Co-immunoprecipitation, ubiquitination assay (K48-linkage), siRNA knockdown, overexpression, ROS and DNA damage assays, in vitro and in vivo drug resistance models Cellular oncology Medium 37219768
2025 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. Co-immunoprecipitation, ubiquitination assay, m6A modification assay, siRNA knockdown, overexpression, AKT/mTOR pathway activity readouts Cell death & disease Medium 41145484
2025 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. Co-immunoprecipitation, ubiquitination assay, cycloheximide chase assay, siRNA knockdown, overexpression, in vivo BPH model Cellular signalling Medium 40780616

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 608 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 586 10882102
2001 PML protein isoforms and the RBCC/TRIM motif. Oncogene 382 11704850
2006 Subclassification of the RBCC/TRIM superfamily reveals a novel motif necessary for microtubule binding. The Journal of biological chemistry 273 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 95 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 78 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 54 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
2018 TRIM17 and TRIM28 antagonistically regulate the ubiquitination and anti-apoptotic activity of BCL2A1. Cell death and differentiation 50 30042493
2011 Terf/TRIM17 stimulates degradation of kinetochore protein ZWINT and regulates cell proliferation. Journal of biochemistry 50 22023800
2004 TRIM45, a novel human RBCC/TRIM protein, inhibits transcriptional activities of ElK-1 and AP-1. Biochemical and biophysical research communications 50 15351693
2009 TRIM44 interacts with and stabilizes terf, a TRIM ubiquitin E3 ligase. Biochemical and biophysical research communications 49 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
2018 The E3 Ubiquitin Ligases TRIM17 and TRIM41 Modulate α-Synuclein Expression by Regulating ZSCAN21. Cell reports 35 30485814
2016 TRIM17 contributes to autophagy of midbodies while actively sparing other targets from degradation. Journal of cell science 35 27562068
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 30 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
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 26 17512541
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
2016 Characterisation of assembly and ubiquitylation by the RBCC motif of Trim5α. Scientific reports 24 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
2022 MiR-1246 is responsible for lung cancer cells-derived exosomes-mediated promoting effects on lung cancer stemness via targeting TRIM17. Environmental toxicology 18 35894553
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) 16 37219768
2021 To Ubiquitinate or Not to Ubiquitinate: TRIM17 in Cell Life and Death. Cells 16 34069831
1992 TerF, the sixth identified replication arrest site in Escherichia coli, is located within the rcsC gene. Journal of bacteriology 15 1447156
2011 Association of the testis-specific TRIM/RBCC protein RNF33/TRIM60 with the cytoplasmic motor proteins KIF3A and KIF3B. Molecular and cellular biochemistry 14 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 4 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 3 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

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