Affinage

TRIM39

E3 ubiquitin-protein ligase TRIM39 · UniProt Q9HCM9

Length
518 aa
Mass
59.7 kDa
Annotated
2026-06-10
17 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIM39 is a RING-B box-coiled-coil (RBCC)-B30.2 domain protein and RING-type E3 ubiquitin ligase that governs apoptosis, cell cycle progression, and inflammatory signaling by controlling the stability of diverse substrates (PMID:11006080, PMID:23213260). It acts both as a positive regulator that stabilizes pro-apoptotic and checkpoint factors and as a degradative ligase. TRIM39 stabilizes MOAP-1 by directly inhibiting APC/C(Cdh1)-mediated ubiquitylation, raising mitochondrial MOAP-1 to promote Bax activation, cytochrome c release, and etoposide-induced apoptosis (PMID:19100260, PMID:22529100), and it stabilizes the CDK inhibitor p21 by blocking CRL4-Cdt2 access, thereby enforcing the G1/S and G2 DNA-damage checkpoints (PMID:23213251). Conversely, TRIM39 directly ubiquitylates and degrades p53, restraining its growth-suppressive and apoptotic output (PMID:23213260). It also operates as a SUMO-targeted ubiquitin ligase (STUbL), engaging SUMOylated NFATc3 through its SUMO-interacting motifs to drive its ubiquitin-dependent degradation and limit neuronal apoptosis (PMID:35449213). Through additional substrates it shapes redox and inflammatory responses, degrading PRDX3 (K48-linked, at K73/K149) to elevate ROS and renal fibrosis (PMID:38195664), facilitating p62 ubiquitylation to modulate the KEAP1-NRF2-HO-1 axis in hepatocellular carcinoma (PMID:41422284), and stabilizing Cactin to negatively regulate NFκB signaling (PMID:26363554).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2000 Medium

    Established the molecular identity of TRIM39, defining it as an RBCC-B30.2 (TRIM-family) protein and placing it in the MHC class I region before any enzymatic function was known.

    Evidence cDNA cloning, Northern blot, and chromosomal mapping (RNF23/tfp)

    PMID:11006080

    Open questions at the time
    • No enzymatic activity or substrate assigned at this stage
    • Functional significance of testis-enriched expression not addressed
  2. 2008 High

    Assigned TRIM39 its first functional role, showing it stabilizes the pro-apoptotic factor MOAP-1 to promote mitochondrial apoptosis, framing it as a positive apoptotic regulator.

    Evidence Co-IP, ubiquitination/half-life assays, mitochondrial fractionation, cytochrome c release with recombinant Bax, siRNA in cells

    PMID:19100260

    Open questions at the time
    • Did not identify which ligase TRIM39 antagonizes to stabilize MOAP-1
    • RING ligase activity not directly reconstituted here
  3. 2012 High

    Resolved the mechanism of MOAP-1 stabilization by showing TRIM39 directly inhibits APC/C(Cdh1), linking apoptotic control to cell-cycle machinery.

    Evidence In vitro APC/C ubiquitylation assay, Cdh1 knockdown epistasis, apoptosis assays

    PMID:22529100

    Open questions at the time
    • Structural basis of APC/C inhibition unresolved
    • Whether TRIM39 broadly regulates other APC/C substrates not tested
  4. 2012 High

    Expanded TRIM39 into a checkpoint regulator: it stabilizes p21 by blocking CRL4-Cdt2 binding, enforcing G1/S and G2 arrest after DNA damage.

    Evidence Reciprocal Co-IP, ubiquitination assays, cell cycle and DNA-damage analysis with p21 epistasis

    PMID:23213251

    Open questions at the time
    • Whether TRIM39 catalyzes ubiquitin chains on p21 or acts purely as a competitive shield not fully separated
    • Trigger that engages TRIM39 at p21 upon damage unknown
  5. 2012 High

    Demonstrated a degradative function distinct from its stabilizing roles by showing TRIM39 directly ubiquitylates and degrades p53, establishing it as a bidirectional regulator of cell fate.

    Evidence In vitro ubiquitylation reconstitution, Co-IP, siRNA, growth/apoptosis assays across cell lines

    PMID:23213260

    Open questions at the time
    • How TRIM39 chooses to stabilize versus degrade substrates not explained
    • Physiological context distinguishing p53 versus p21 regulation unclear
  6. 2015 Medium

    Connected TRIM39 to innate immune signaling by identifying Cactin as a stabilized partner that dampens NFκB activation.

    Evidence Yeast two-hybrid, Co-IP, stability assays, NFκB reporter, siRNA

    PMID:26363554

    Open questions at the time
    • Mechanism of Cactin stabilization not dissected
    • Direct ubiquitin chain involvement not established
  7. 2022 High

    Defined TRIM39 as a SUMO-targeted ubiquitin ligase (STUbL), showing SIM-dependent recognition and ubiquitylation of SUMOylated NFATc3 and antagonism by Trim17.

    Evidence In vitro ubiquitination, SIM/SUMO-site mutagenesis, Co-IP, transcriptional and neuronal apoptosis assays

    PMID:35449213

    Open questions at the time
    • Whether STUbL activity extends to other SUMOylated substrates not surveyed
    • In vivo neuronal relevance beyond cell models not established
  8. 2024 Medium

    Linked TRIM39 to redox and fibrotic disease by mapping K48-linked ubiquitylation of PRDX3 at K73/K149 driving ROS and renal fibrosis.

    Evidence Co-IP, ubiquitination assays, K-site mutagenesis, HK-2 cells, UUO mouse model

    PMID:38195664

    Open questions at the time
    • Single-lab finding without independent replication
    • Upstream signals activating TRIM39 in fibrosis unknown
  9. 2025 Medium

    Extended TRIM39 substrate range to p62, coupling its ligase activity to the KEAP1-NRF2-HO-1 axis in hepatocellular carcinoma proliferation.

    Evidence Co-IP, ubiquitination assays, p62 overexpression rescue, in vitro/in vivo proliferation

    PMID:41422284

    Open questions at the time
    • Ubiquitin chain linkage on p62 not specified
    • Single-study mechanism awaiting independent confirmation
  10. 2025 Medium

    Showed TRIM39 can promote SUMOylation of ESR1 to stabilize it and sustain smooth muscle contractile phenotype in aortic dissection, indicating a SUMO-conjugation-promoting activity in addition to STUbL function.

    Evidence Co-IP, SUMO Western blot, TRIM39 overexpression in cell and mouse AD models, substrate prediction

    PMID:40921118

    Open questions at the time
    • Direct catalytic role of TRIM39 in ESR1 SUMOylation versus indirect effect not separated
    • Reconciliation with degradative STUbL activity unclear
  11. 2025 Low

    Proposed a TRIM39-RNF168 axis suppressing autophagy-coupled ferroptosis in triple-negative breast cancer.

    Evidence siRNA knockdown, Western blot, in vitro assays, TNBC xenograft

    PMID:41034232

    Open questions at the time
    • Claimed deubiquitination activity not biochemically reconstituted in abstract
    • Single lab, single study
    • Mechanism by which a RING ligase removes ubiquitin from RNF168 unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TRIM39 selects between stabilizing and degrading substrates, and the upstream signals that direct its ligase versus SUMO-related activities, remain unresolved.
  • No unifying determinant of substrate fate identified
  • Regulation of TRIM39 activity by post-translational modification or partners not mapped
  • No structural model of substrate engagement

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 4 GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 4
Localization
GO:0005739 mitochondrion 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 1
Partners
CACTINCDKN1AESR1MOAP1NFATC3PRDX3SQSTM1TP53

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 TRIM39 directly binds MOAP-1 and stabilizes it by inhibiting its poly-ubiquitination and proteasomal degradation, thereby elevating MOAP-1 levels in mitochondria and promoting cytochrome c release and apoptosis in response to etoposide. Co-immunoprecipitation, ubiquitination assays, half-life measurements, mitochondrial fractionation, cytochrome c release assay with recombinant Bax, siRNA knockdown Experimental cell research High 19100260
2012 TRIM39 (a RING domain E3 ubiquitin ligase) directly inhibits APC/C(Cdh1)-mediated ubiquitylation, thereby preventing proteasomal degradation of MOAP-1; Cdh1 knockdown phenocopies TRIM39 overexpression by stabilizing MOAP-1 and enhancing etoposide-induced Bax activation and apoptosis. In vitro APC/C ubiquitylation assay, siRNA knockdown of Cdh1, immunoprecipitation, cell-based apoptosis assays The Journal of cell biology High 22529100
2012 TRIM39 directly binds and ubiquitylates p53 in vitro and in vivo, promoting p53 degradation; Trim39 loss increases p53 protein levels, causing cell growth retardation in p53-positive cells and enhanced apoptosis. In vitro ubiquitylation assay, co-immunoprecipitation, siRNA knockdown, cell growth and apoptosis assays in multiple cell lines Proceedings of the National Academy of Sciences of the United States of America High 23213260
2012 TRIM39 interacts with p21 and prevents Cdt2 (CRL4-Cdt2 E3 ligase) from binding to p21, thereby blocking p21 ubiquitylation and proteasomal degradation; TRIM39 ablation destabilizes p21, accelerates G1/S transition, abolishes DNA damage-induced p21 accumulation, and abrogates the G2 checkpoint, leading to mitotic entry and apoptosis. Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, cell cycle analysis, DNA damage response assays Proceedings of the National Academy of Sciences of the United States of America High 23213251
2015 TRIM39 interacts with Cactin (identified by yeast two-hybrid screening) and stabilizes Cactin protein; TRIM39 stabilization of Cactin negatively regulates NFκB-mediated signaling, and TRIM39 knockdown activates NFκB signaling. Yeast two-hybrid screening, co-immunoprecipitation, protein stability assays, NFκB reporter assays, siRNA knockdown Cellular and molecular life sciences : CMLS Medium 26363554
2022 Trim39 acts as a SUMO-targeted E3 ubiquitin ligase (STUbL) for NFATc3: it binds and ubiquitinates NFATc3 in vitro and in cells, reducing NFATc3 protein level and transcriptional activity; mutation of SUMOylation sites in NFATc3 or SUMO-interacting motifs (SIMs) in Trim39 reduces their interaction and Trim39-mediated ubiquitination; Trim39 preferentially ubiquitinates SUMOylated forms of NFATc3; Trim17 inhibits this process by reducing Trim39 E3 ligase activity and the NFATc3/Trim39 interaction; silencing Trim39 enhances neuronal apoptosis via increased NFATc3 activity. In vitro ubiquitination assay, co-immunoprecipitation, site-directed mutagenesis of SUMOylation sites and SIMs, siRNA knockdown, transcriptional activity assays, neuronal apoptosis assays Cell death and differentiation High 35449213
2024 TRIM39 directly interacts with PRDX3 and induces its K48-linked poly-ubiquitination and proteasomal degradation at lysines K73 and K149, leading to ROS accumulation, increased inflammatory cytokine generation, and aggravated renal fibrosis. Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K73/K149 sites), siRNA knockdown in HK-2 cells, UUO mouse model Cell death discovery Medium 38195664
2025 TRIM39 interacts with p62 and facilitates its ubiquitination, leading to decreased p62 protein stability; reduced p62 releases KEAP1, which subsequently inhibits the NRF2-HO-1 pathway, promoting hepatocellular carcinoma cell proliferation. Co-immunoprecipitation, ubiquitination assays, overexpression rescue experiments, in vitro and in vivo proliferation assays Scientific reports Medium 41422284
2025 TRIM39 mediates SUMOylation of ESR1 (estrogen receptor alpha), enhancing ESR1 protein stability and strengthening E2-ESR1 signaling; this mechanism is associated with alleviation of aortic dissection progression through maintenance of aortic smooth muscle cell contractile phenotype. Co-immunoprecipitation, TRIM39 overexpression in cell and mouse AD models, Western blot for SUMOylated ESR1, bioinformatics substrate prediction Atherosclerosis Medium 40921118
2025 TRIM39 deubiquitinates RNF168 (upregulates it by preventing its degradation), and the TRIM39-RNF168 axis suppresses autophagy-coupled ferroptosis in triple-negative breast cancer cells; knockdown of TRIM39 or RNF168 activates autophagy-dependent ferroptosis and suppresses TNBC progression in vivo. siRNA knockdown, in vitro and in vivo functional assays, Western blot, TNBC xenograft model NPJ breast cancer Low 41034232
2000 TRIM39 (originally named RNF23/tfp) was cloned and found to encode a RING-B box-coiled coil (RBCC)-B30.2 domain protein; Northern blot showed testis-enriched but ubiquitous expression; the gene was mapped to the class I region of the human MHC. cDNA cloning, Northern blot analysis, chromosomal 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 44 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 26 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
2024 The E3 ubiquitin ligase TRIM39 modulates renal fibrosis induced by unilateral ureteral obstruction through regulating proteasomal degradation of PRDX3. Cell death discovery 13 38195664
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
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-mediated deubiquitination upregulates RNF168 to evade autophagy-ferroptosis in triple-negative breast cancer. NPJ breast cancer 2 41034232
2025 TRIM39 reinforces E2-ESR1 signaling through SUMOylation of ESR1 to hinder the progression of aortic dissection. Atherosclerosis 1 40921118
2025 TRIM39 aggravates hepatocellular carcinoma growth through targeting the p62-KEAP1-NRF2 axis. Scientific reports 0 41422284

Missed literature

Know a paper Affinage missed for TRIM39? Flag it for the maintainers and the community.

No submissions yet.