Affinage

TRIM39

E3 ubiquitin-protein ligase TRIM39 · UniProt Q9HCM9

Length
518 aa
Mass
59.7 kDa
Annotated
2026-04-28
17 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIM39 is a RING-domain E3 ubiquitin ligase that controls apoptosis, cell cycle progression, and inflammatory signaling by selectively ubiquitylating or stabilizing multiple substrates. It directly ubiquitylates and promotes proteasomal degradation of p53, NFATc3 (functioning as a SUMO-targeted ubiquitin ligase/STUbL), PRDX3 (K48-linked ubiquitination at K73/K149), and p62 (K48-linked), while stabilizing MOAP-1 by blocking APC/C(Cdh1)-mediated ubiquitylation and stabilizing p21 by preventing CRL4(Cdt2) access (PMID:22529100, PMID:23213260, PMID:23213251, PMID:35449213, PMID:38195664, PMID:41422284). Through these activities, TRIM39 promotes Bax-dependent apoptosis via MOAP-1, enforces G1/S and DNA damage-induced G2 checkpoints via p21, modulates NF-κB signaling through Cactin stabilization, and influences oxidative stress responses through PRDX3 degradation and p62-dependent NRF2 pathway suppression (PMID:19100260, PMID:23213251, PMID:26363554, PMID:38195664, PMID:41422284).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2000 Medium

    Identification of TRIM39 as an RBCC/B30.2-domain protein encoded in the MHC class I region established the gene's domain architecture and predicted E3 ligase function, but left substrates and biological roles unknown.

    Evidence Molecular cloning, Northern blot, and genomic mapping from human testis cDNA

    PMID:11006080

    Open questions at the time
    • No substrates or enzymatic activity demonstrated
    • Expression beyond testis not systematically characterized
  2. 2008 High

    The first functional role was established when TRIM39 was shown to bind and stabilize the Bax-activating protein MOAP-1 by inhibiting its poly-ubiquitination, linking TRIM39 to mitochondrial apoptosis.

    Evidence Co-immunoprecipitation, ubiquitination assays, mitochondrial fractionation, and cytochrome c release assay in mammalian cells

    PMID:19100260

    Open questions at the time
    • The E3 ligase responsible for MOAP-1 ubiquitylation that TRIM39 counteracts was not identified
    • Whether TRIM39's RING domain catalytic activity was required was untested
  3. 2012 High

    Three major substrates were defined in rapid succession: TRIM39 inhibits APC/C(Cdh1)-mediated MOAP-1 ubiquitylation, directly ubiquitylates p53 for proteasomal degradation independently of MDM2, and stabilizes p21 by blocking CRL4(Cdt2) access—establishing TRIM39 as a multifunctional node connecting apoptosis and cell cycle control.

    Evidence In vitro reconstituted ubiquitylation assays, epistasis experiments (Cdh1 knockdown), competitive binding assays (TRIM39 blocks Cdt2–p21 interaction), cell cycle analysis by flow cytometry across multiple cell lines

    PMID:22529100 PMID:23213251 PMID:23213260

    Open questions at the time
    • How TRIM39 simultaneously stabilizes some substrates (MOAP-1, p21) while degrading others (p53) was mechanistically unexplained
    • Structural basis for substrate selectivity unknown
    • In vivo validation in animal models was lacking
  4. 2015 Medium

    TRIM39 was connected to innate immune signaling when it was found to stabilize Cactin and negatively regulate NF-κB, broadening its functional scope beyond cell cycle and apoptosis.

    Evidence Yeast two-hybrid screen, co-immunoprecipitation, NF-κB reporter assay upon TRIM39 knockdown

    PMID:26363554

    Open questions at the time
    • Mechanism by which TRIM39 stabilizes Cactin (direct deubiquitylation vs. shielding) not resolved
    • Whether Cactin is a direct ubiquitylation substrate or a binding partner was unclear
  5. 2022 High

    TRIM39 was demonstrated to function as a SUMO-targeted ubiquitin ligase (STUbL) for NFATc3 in neurons, revealing that substrate SUMOylation is a prerequisite for TRIM39-mediated ubiquitylation and providing a selectivity mechanism.

    Evidence In vitro ubiquitylation with SUMOylated vs. unmodified NFATc3, mutagenesis of SUMO-interacting motifs in TRIM39 and SUMOylation sites in NFATc3, neuronal apoptosis readout

    PMID:35449213

    Open questions at the time
    • Whether STUbL activity applies to other TRIM39 substrates beyond NFATc3 is untested
    • The relative contribution of SIM-dependent vs. SIM-independent ubiquitylation in physiological contexts is undefined
  6. 2024 High

    Site-specific K48-linked ubiquitylation of PRDX3 at K73 and K149 by TRIM39 was mapped, linking TRIM39 to mitochondrial redox control and renal fibrosis through ROS accumulation and inflammatory cytokine generation.

    Evidence Co-immunoprecipitation, K48 chain-specific ubiquitination assay, K73R/K149R mutagenesis, UUO mouse model and HK-2 cells

    PMID:38195664

    Open questions at the time
    • Whether TRIM39 localizes to mitochondria to access PRDX3 or acts on cytosolic pools is unclear
    • Upstream signals regulating TRIM39 activity in renal injury not identified
  7. 2025 Medium

    TRIM39 was shown to K48-ubiquitylate p62/SQSTM1, releasing KEAP1 to suppress the NRF2-HO-1 antioxidant axis, and separately reported to deubiquitylate RNF168 to confer ferroptosis resistance—expanding its substrate range but raising questions about dual E3/DUB activity.

    Evidence Co-IP and ubiquitination assays with p62 plus xenograft rescue; knockdown/deubiquitination assays with RNF168 in TNBC cells and xenograft models

    PMID:41034232 PMID:41422284

    Open questions at the time
    • Reported deubiquitinase activity toward RNF168 is mechanistically unexpected for a RING E3 ligase and requires biochemical reconstitution with purified components
    • p62 ubiquitylation sites not mapped
    • Whether p62 degradation and RNF168 stabilization occur in the same cellular context is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for TRIM39's substrate selectivity across its diverse targets, whether its reported deubiquitinase activity is direct or indirect, and the physiological signals that switch TRIM39 between stabilizing and degradative modes.
  • No crystal or cryo-EM structure of TRIM39 or its substrate complexes
  • No systematic identification of TRIM39 regulators or post-translational modifications controlling its activity
  • In vivo knockout phenotype in mammals not reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016874 ligase activity 4
Localization
GO:0005634 nucleus 3 GO:0005739 mitochondrion 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-1640170 Cell Cycle 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-168256 Immune System 1
Partners
CACTINCDH1CDKN1AMOAP1NFATC3PRDX3SQSTM1TP53

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 TRIM39 directly binds MOAP-1 (a Bax-activating protein) and inhibits its poly-ubiquitination, thereby stabilizing MOAP-1 and promoting apoptosis. TRIM39 elevates MOAP-1 levels in mitochondria and promotes cytochrome c release from isolated mitochondria stimulated by recombinant Bax. Co-immunoprecipitation, ubiquitination assays, mitochondrial fractionation, cytochrome c release assay, siRNA knockdown Experimental cell research High 19100260
2012 TRIM39 directly inhibits APC/C(Cdh1)-mediated ubiquitylation of MOAP-1, identifying TRIM39 as a novel APC/C regulator. Cdh1 knockdown similarly stabilizes MOAP-1 and enhances etoposide-induced Bax activation and apoptosis. In vitro ubiquitylation assay, siRNA knockdown of Cdh1 and Trim39, co-immunoprecipitation, cell death assays The Journal of cell biology High 22529100
2012 TRIM39 directly binds and ubiquitylates p53 in vitro and in vivo, leading to p53 proteasomal degradation. Depletion of TRIM39 increases p53 protein levels and retards cell growth, identifying TRIM39 as an E3 ligase for p53 distinct from MDM2. In vitro ubiquitylation assay, co-immunoprecipitation, siRNA knockdown, cell growth and apoptosis assays Proceedings of the National Academy of Sciences of the United States of America High 23213260
2012 TRIM39 stabilizes p21 by binding p21 and preventing CRL4(Cdt2) E3 ligase from accessing p21 (blocking Cdt2 binding), thereby inhibiting ubiquitylation and proteasomal degradation of p21. This mechanism controls G1/S transition and DNA damage-induced G2 checkpoint. Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, cell cycle analysis (flow cytometry), competitive binding assay (TRIM39 blocks Cdt2-p21 interaction) Proceedings of the National Academy of Sciences of the United States of America High 23213251
2015 TRIM39 stabilizes Cactin protein (identified by yeast two-hybrid screening), and Cactin is upregulated after TNFα stimulation. TRIM39 knockdown activates NFκB signaling, indicating TRIM39 negatively regulates NFκB in collaboration with Cactin. Yeast two-hybrid screening, co-immunoprecipitation, siRNA knockdown, NFκB reporter assay, Western blot Cellular and molecular life sciences : CMLS Medium 26363554
2022 TRIM39 acts as a SUMO-targeted E3 ubiquitin ligase (STUbL) for the transcription factor NFATc3 in neurons. TRIM39 binds and ubiquitinates NFATc3 in vitro and in cells, reducing NFATc3 protein level and transcriptional activity. TRIM39 preferentially ubiquitinates SUMOylated NFATc3; mutation of SUMO-interacting motifs in TRIM39 or SUMOylation sites in NFATc3 reduces their interaction and ubiquitination. TRIM17 inhibits TRIM39-mediated NFATc3 ubiquitination by reducing TRIM39's E3 ligase activity and the NFATc3/TRIM39 interaction. In vitro ubiquitylation assay with SUMOylated vs. unmodified substrates, co-immunoprecipitation, mutagenesis of SIMs and SUMOylation sites, neuronal knockdown with apoptosis readout Cell death and differentiation High 35449213
2024 TRIM39 directly interacts with PRDX3 and induces its K48-linked poly-ubiquitination at K73 and K149, leading to proteasomal degradation of PRDX3, ROS accumulation, and inflammatory cytokine generation that aggravates renal fibrosis. Co-immunoprecipitation, ubiquitination assay (K48 chain-specific), site-directed mutagenesis (K73R, K149R), siRNA knockdown in UUO mouse model and HK-2 cells Cell death discovery High 38195664
2025 TRIM39 interacts with p62 and facilitates its K48-linked ubiquitination, leading to decreased p62 stability. Reduced p62 releases KEAP1, which subsequently inhibits the NRF2-HO-1 pathway, promoting hepatocellular carcinoma growth. Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown in vitro and in vivo xenograft models, rescue by p62 overexpression Scientific reports Medium 41422284
2025 TRIM39 mediates SUMOylation of ESR1 (estrogen receptor alpha), enhancing ESR1 protein stability and strengthening E2-ESR1 signaling, thereby alleviating aortic dissection progression. Co-immunoprecipitation, bioinformatics prediction (UBIBROWSER, GPS-SUMO), overexpression in AD mouse and cell models, Western blot for ESR1 stability Atherosclerosis Low 40921118
2025 TRIM39 deubiquitinates RNF168, upregulating RNF168 protein levels in TNBC cells, which suppresses autophagy-coupled ferroptosis and confers ferroptosis resistance. Knockdown experiments, ubiquitination/deubiquitination assays, in vivo xenograft model NPJ breast cancer Medium 41034232
2000 TRIM39 (originally named testis-abundant finger protein/tfp) was cloned and characterized as an RBCC-B30.2 (RING-B-box-coiled coil) domain protein encoded in the MHC class I region, highly expressed in testis. Molecular cloning, Northern blot, genomic mapping Biochemical and biophysical research communications Medium 11006080

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Fish TRIM39 regulates cell cycle progression and exerts its antiviral function against iridovirus and nodavirus. Fish & shellfish immunology 54 26784918
2015 TRIM39 negatively regulates the NFκB-mediated signaling pathway through stabilization of Cactin. Cellular and molecular life sciences : CMLS 54 26363554
2012 The Trim39 ubiquitin ligase inhibits APC/CCdh1-mediated degradation of the Bax activator MOAP-1. The Journal of cell biology 54 22529100
2008 TRIM39 is a MOAP-1-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process. Experimental cell research 48 19100260
2012 TRIM39 regulates cell cycle progression and DNA damage responses via stabilizing p21. Proceedings of the National Academy of Sciences of the United States of America 43 23213251
2012 Ubiquitylation of p53 by the APC/C inhibitor Trim39. Proceedings of the National Academy of Sciences of the United States of America 40 23213260
2010 TRIM39 and RNF39 are associated with Behçet's disease independently of HLA-B∗51 and -A∗26. Biochemical and biophysical research communications 32 20875797
2020 Nasopharyngeal carcinoma MHC region deep sequencing identifies HLA and novel non-HLA TRIM31 and TRIM39 loci. Communications biology 24 33311639
2000 Molecular cloning of testis-abundant finger Protein/Ring finger protein 23 (RNF23), a novel RING-B box-coiled coil-B30.2 protein on the class I region of the human MHC. Biochemical and biophysical research communications 22 11006080
2022 Trim39 regulates neuronal apoptosis by acting as a SUMO-targeted E3 ubiquitin-ligase for the transcription factor NFATc3. Cell death and differentiation 12 35449213
2024 The E3 ubiquitin ligase TRIM39 modulates renal fibrosis induced by unilateral ureteral obstruction through regulating proteasomal degradation of PRDX3. Cell death discovery 11 38195664
2022 Sequence Variant in the TRIM39-RPP21 Gene Readthrough is Shared Across a Cohort of Arabian Foals Diagnosed with Juvenile Idiopathic Epilepsy. Journal of genetic mutation disorders 5 35465405
2022 Nile tilapia TRIM39 recruits I3K413 and I3KL45 as adaptors and is involved in the NF-κB pathway. Journal of fish biology 4 35514248
2019 TRIM39-RPP21 Variants (∆19InsCCC) Are Not Associated with Juvenile Idiopathic Epilepsy in Egyptian Arabian Horses. Genes 4 31623255
2025 TRIM39 reinforces E2-ESR1 signaling through SUMOylation of ESR1 to hinder the progression of aortic dissection. Atherosclerosis 1 40921118
2025 TRIM39-mediated deubiquitination upregulates RNF168 to evade autophagy-ferroptosis in triple-negative breast cancer. NPJ breast cancer 1 41034232
2025 TRIM39 aggravates hepatocellular carcinoma growth through targeting the p62-KEAP1-NRF2 axis. Scientific reports 0 41422284