Affinage

TRIM15

E3 ubiquitin-protein ligase TRIM15 · UniProt Q9C019

Length
465 aa
Mass
52.1 kDa
Annotated
2026-06-10
18 papers in source corpus 14 papers cited in narrative 14 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

TRIM15 is a RING-domain E3 ubiquitin ligase that functions as a multi-substrate node coupling cell adhesion to proliferative and inflammatory signaling, predominantly acting through non-canonical and degradative polyubiquitination of diverse targets (PMID:34497368, PMID:25015296, PMID:41461634). At the structural level, TRIM15 localizes to focal adhesions: it oligomerizes and binds the LD2 motif of paxillin through its coiled-coil domain, behaving as a stable, restricted-mobility adhesome component whose depletion impairs focal adhesion disassembly and cell migration (PMID:25015296). Its catalytic output is strikingly linkage-diverse — it assembles K63-linked chains on ERK1/2 to promote MEK-dependent ERK activation (opposed by the deubiquitinase CYLD) (PMID:34497368) and on AKT at its PH domain to drive AKT signaling (PMID:40026037), builds non-degradative K6-linked chains on VDAC3 to stabilize it and suppress autophagy/mitophagy (PMID:41617671), generates K48-linked chains on YAP at K254 to displace angiomotin and enhance YAP nuclear translocation (PMID:40138455), and directs proteasomal degradation of Keap1 (activating Nrf2) (PMID:35534896), APOA1 (PMID:34311082), and the transcription factor YY2 (PMID:41237333). Beyond enzymatic substrates, TRIM15 disrupts Axin1 polymerization via its coiled-coil domain to block β-catenin destruction-complex assembly and activate Wnt signaling (PMID:41461634), and inhibits TNF-α-induced NF-κB signaling by promoting turnover of K63-ubiquitin chains on TAK1 through its PRY/SPRY domain (PMID:34871740). Across these axes TRIM15 is embedded in feed-forward loops — induced by AKT/FOXO1, HIF-1α, and Wnt signaling — that reinforce its pro-proliferative roles in multiple cancers and in chondrocyte senescence, where conditional Trim15 deletion impairs skeletal growth and tumor formation in vivo (PMID:36670097, PMID:40138455, PMID:40026037, PMID:41461634).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2014 High

    Established TRIM15's subcellular home and its first functional role by showing it is a stable focal adhesion component that controls adhesion turnover and migration, defining the structural platform on which its later signaling activities operate.

    Evidence Fluorescence/live imaging, FRAP, domain mapping of coiled-coil to paxillin LD2 and of B-box2/PRY for localization, adhesome interaction screen, and knockdown migration assays in two independent studies

    PMID:25015296 PMID:25450970

    Open questions at the time
    • Whether focal-adhesion localization requires its E3 ligase activity was not addressed
    • No ubiquitination substrate at adhesions identified in these studies
    • Mechanism linking adhesion residence to downstream signaling unresolved
  2. 2021 High

    Defined TRIM15 as a catalytically active E3 ligase using non-degradative K63 chains on ERK1/2 to enhance MEK-dependent activation, the first demonstration that TRIM15 ubiquitination can be activating rather than degradative.

    Evidence Co-IP, in vitro ubiquitination, acceptor-lysine mutagenesis, ERK-MEK interaction assays, and TRIM15/CYLD epistasis

    PMID:34497368

    Open questions at the time
    • Did not address whether ERK ubiquitination occurs at focal adhesions
    • Structural basis of the mutually exclusive TRIM15/CYLD interaction not resolved
  3. 2021 Medium

    Showed TRIM15 also performs classical degradative ubiquitination (APOA1) and acts as a negative regulator of NF-κB via TAK1 K63-chain turnover, revealing that the same enzyme operates in both degradative and chain-editing modes through distinct domains.

    Evidence Mass spectrometry, reciprocal Co-IP, domain mapping (RING for catalysis, PRY/SPRY for substrate/TAK1 binding), ubiquitination assays, NF-κB reporters in multiple cell lines

    PMID:34311082 PMID:34871740

    Open questions at the time
    • Single-lab findings without independent replication
    • Mechanism of how TRIM15 promotes TAK1 K63-chain turnover (recruitment of DUB vs. direct editing) unresolved
    • APOA1 ubiquitin linkage type not defined
  4. 2022 Medium

    Connected TRIM15 to the antioxidant axis by showing it degrades Keap1 to stabilize Nrf2, extending its substrate repertoire to a redox master regulator in lung cancer.

    Evidence Co-IP, immunofluorescence co-localization, in vitro ubiquitination, gain/loss-of-function, and xenograft models

    PMID:35534896

    Open questions at the time
    • Keap1 ubiquitin linkage type not specified
    • Single lab
    • Direct vs. indirect engagement of Keap1 not fully resolved
  5. 2023 Medium

    Identified a positive feedback loop in which AKT/FOXO1 induces TRIM15, which in turn K63-ubiquitinates LASP1 to drive its nuclear translocation and further AKT phosphorylation, linking TRIM15 to TKI resistance.

    Evidence Co-IP, ubiquitination assay, nuclear/cytoplasmic fractionation, pathway inhibition, knockdown/overexpression in HCC

    PMID:36670097

    Open questions at the time
    • LASP1 acceptor lysines not mapped
    • Single lab
    • Mechanism by which nuclear LASP1 increases AKT phosphorylation unresolved
  6. 2024 Medium

    Expanded TRIM15 substrates into RNA-binding regulation by showing it ubiquitinates IGF2BP2 to enhance its phase separation and stabilize TLR4 mRNA, linking the ligase to post-transcriptional control.

    Evidence Transcriptomics/proteomics, Co-IP, ubiquitination assay, orthotopic transplantation in pancreatic cancer

    PMID:38657551

    Open questions at the time
    • IGF2BP2 ubiquitin linkage type not defined
    • Mechanistic link between ubiquitination and phase separation not structurally resolved
    • Single lab
  7. 2025 High

    Multiple 2025 studies broadened TRIM15 into Hippo, Wnt, AKT, and lipid-metabolism control, establishing it as a hub whose transcription is driven by HIF-1α and Wnt and validating roles in vivo via conditional knockouts.

    Evidence Site-specific lysine mutagenesis (YAP K254, AKT PH domain), coiled-coil-dependent Axin1 polymerization disruption assays, Wnt reporters, ChIP/promoter reporters, proteasome-rescue, and conditional Trim15 knockout mouse models (chondrocyte, AOM/DSS, ApcMin/+)

    PMID:40026037 PMID:40138455 PMID:41237333 PMID:41461634

    Open questions at the time
    • Whether one cell type uses all of these substrate axes simultaneously is unknown
    • How substrate selection among the many targets is governed is unresolved
    • YY2 ubiquitin linkage type not specified
  8. 2026 Medium

    Refined TRIM15's linkage-specific repertoire by defining non-degradative K6 ubiquitination of VDAC3 (autophagy suppression) and K11/K29 ubiquitination of Paxillin coupled to enhanced Paxillin-FAK interaction, tying its catalytic chemistry back to its founding adhesion role.

    Evidence MS substrate ID, Co-IP, linkage-specific ubiquitination assays (K6; K11/K29), autophagy/mitophagy/ROS readouts, phosphorylation assays, and xenograft/migration models

    PMID:41617671 PMID:42192404

    Open questions at the time
    • Single-lab findings
    • Functional consequence of specific K6/K11/K29 linkages at the molecular level not fully resolved
    • Acceptor lysines on Paxillin and VDAC3 not all mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single E3 ligase achieves substrate- and linkage-specificity across degradative (K48), activating (K63), and non-degradative (K6, K11, K29) ubiquitination of structurally unrelated targets, and how this is coordinated in any one cellular context, remains unresolved.
  • No structural basis for linkage selectivity reported
  • No proteome-wide substrate map
  • Relationship between focal-adhesion residence and cytosolic/nuclear substrate engagement not integrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 8 GO:0016874 ligase activity 5 GO:0140096 catalytic activity, acting on a protein 5 GO:0098772 molecular function regulator activity 2
Localization
GO:0005856 cytoskeleton 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 1 R-HSA-9612973 Autophagy 1
Partners
AKT1AXIN1KEAP1LASP1PXNTAK1VDAC3YAP1
Complex memberships
focal adhesion

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 TRIM15 acts as a K63-linked polyubiquitin E3 ligase for ERK1/2, modifying defined lysine residues. This K63-linked ubiquitination enhances ERK interaction with and activation by MEK. CYLD serves as the opposing deubiquitinase of ERK1/2, and TRIM15 and CYLD regulate ERK ubiquitination through mutually exclusive interactions. Co-immunoprecipitation, in vitro ubiquitination assay, mutagenesis of ubiquitin acceptor lysines, ERK-MEK interaction assays, TRIM15/CYLD knockdown with ERK activation readouts Nature cell biology High 34497368
2021 TRIM15 interacts with APOA1 through its PRY/SPRY domain and promotes APOA1 polyubiquitination and degradation via its RING domain, leading to enhanced lipid anabolism and lipid droplet accumulation in pancreatic cancer cells. Mass spectrometry, co-immunoprecipitation, domain mapping, ubiquitination assay, lipid droplet staining, knockdown experiments Biochimica et biophysica acta. Molecular basis of disease Medium 34311082
2014 TRIM15 localizes to focal adhesions via homo-dimerization; B-box2 and PRY domains are essential for focal adhesion localization and inhibition of cell migration. TRIM15 interacts with integrin adhesome proteins including coronin 1B, cortactin, filamin binding LIM protein1, and VASP. Fluorescence microscopy localization, domain deletion mapping, protein-protein interaction screen (co-immunoprecipitation), cell migration assay, knockdown Biochimica et biophysica acta Medium 25450970
2014 TRIM15 localizes to focal contacts via an interaction between its coiled-coil domain and the LD2 motif of paxillin, independently of myosin-II. TRIM15 forms oligomers conferring restricted mobility (stable focal adhesion component), and its depletion impairs focal adhesion disassembly and cell migration, resulting in enlarged focal adhesions. Co-immunoprecipitation, domain mapping (coiled-coil domain to LD2 of paxillin), live imaging, FRAP, siRNA knockdown with focal adhesion turnover and migration readouts Journal of cell science High 25015296
2021 TRIM15 is a TNF-α-induced late-response gene that inhibits the TNF-α-induced NF-κB pathway by interacting with TAK1 and promoting turnover of K63-linked ubiquitin chains on TAK1, in a PRY/SPRY domain-dependent manner. TRIM15 also interacts with TRIM8 and inhibits TRIM8 cytosolic translocation, thereby antagonizing TRIM8-modulated NF-κB activation. Co-immunoprecipitation, ubiquitination assay, domain mutants (PRY/SPRY), NF-κB reporter assays, knockdown/overexpression in multiple cell lines Cellular signalling Medium 34871740
2022 TRIM15 directly targets Keap1 for ubiquitination and degradation via its E3 ligase activity, preventing Keap1-mediated degradation of Nrf2 and leading to activation of the antioxidant response and promotion of NSCLC progression. Co-immunoprecipitation, immunofluorescence co-localization, in vitro ubiquitination assay, gain/loss-of-function experiments, in vivo xenograft models Cell communication and signaling : CCS Medium 35534896
2023 TRIM15 mediates K63-linked polyubiquitination of LASP1, inducing its nuclear translocation, which increases AKT phosphorylation and Snail expression. TRIM15 expression is upregulated by AKT/FOXO1 signaling, forming a positive feedback loop that promotes TKI resistance in HCC. Co-immunoprecipitation, ubiquitination assay, nuclear/cytoplasmic fractionation, pathway inhibition, knockdown/overexpression experiments Cell death & disease Medium 36670097
2025 TRIM15 binds YAP and mediates K48-linked ubiquitination of YAP at K254, which disrupts the interaction between YAP and angiomotin, leading to enhanced YAP nuclear translocation. This TRIM15-YAP axis promotes chondrocyte senescence and osteoarthritis progression. Conditional Trim15 deletion in mouse chondrocytes impairs skeletal growth and embryonic chondrocyte senescence. Co-immunoprecipitation, ubiquitination assay with lysine site mutagenesis (K254), conditional knockout mouse model, in vivo OA models (surgery-induced and aging), AAV-shRNA knockdown, nuclear translocation imaging Science translational medicine High 40138455
2024 TRIM15 ubiquitinates IGF2BP2 to enhance its phase separation function and stabilize TLR4 mRNA, thereby upregulating TLR4 and promoting pancreatic cancer progression. Transcriptomics, proteomics, co-immunoprecipitation, ubiquitination assay, orthotopic mouse transplantation model, knockdown/overexpression Biochimica et biophysica acta. Molecular basis of disease Medium 38657551
2025 TRIM15 induces K63-linked ubiquitination of AKT at its pleckstrin homology (PH) domain via the RING domain, activating AKT signaling. HIF-1α promotes TRIM15 transcription by binding hypoxia response elements in the TRIM15 promoter. Co-immunoprecipitation, ubiquitination assay, RING domain mutant, domain mapping (PH domain of AKT), ChIP/promoter reporter for HIF-1α binding, in vivo xenograft models International journal of cancer Medium 40026037
2025 TRIM15 interacts with Axin1 through its coiled-coil domain and disrupts Axin1 polymerization, thereby preventing assembly of the β-catenin destruction complex and promoting Wnt/β-catenin signaling activation and colorectal cancer growth. TRIM15 is itself a Wnt target gene, forming a positive feedback loop. Conditional Trim15 genetic ablation in mice inhibits tumor formation in AOM/DSS-induced and ApcMin/+ CRC models. Co-immunoprecipitation, domain mapping (coiled-coil), Axin1 polymerization assay, Wnt reporter assay, conditional knockout mouse models (AOM/DSS and ApcMin/+), tumor growth assays Cell death & disease High 41461634
2025 TRIM15 promotes degradation of the transcription factor YY2 through the ubiquitin-proteasome system, leading to dysregulation of lipid metabolism (reduced FOXRED1 expression) and enhanced proliferation of esophageal adenocarcinoma cells. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor rescue, knockdown/overexpression, gene expression analysis Advanced science Medium 41237333
2026 TRIM15 (Trim15) stabilizes VDAC3 via K6-linked ubiquitination (non-degradative), suppressing autophagy and mitophagy and elevating reactive oxygen species levels in hypopharyngeal squamous cell carcinoma cells. Co-immunoprecipitation, ubiquitination assay (K6-linked), VDAC3 knockdown, autophagy/mitophagy assays, ROS measurement, xenograft models Cell death discovery Medium 41617671
2026 TRIM15 interacts with Paxillin and mediates its ubiquitination via Lys11- and Lys29-linked polyubiquitin chains. TRIM15 also enhances the interaction between Paxillin and FAK, promoting Paxillin phosphorylation and ovarian cancer cell migration and proliferation. Mass spectrometry substrate identification, co-immunoprecipitation, ubiquitination assay (K11- and K29-linkage), phosphorylation assay, siRNA knockdown, colony formation and Transwell migration assays Cancer cell international Medium 42192404

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 TRIM15 and CYLD regulate ERK activation via lysine-63-linked polyubiquitination. Nature cell biology 76 34497368
2021 TRIM15 promotes the invasion and metastasis of pancreatic cancer cells by mediating APOA1 ubiquitination and degradation. Biochimica et biophysica acta. Molecular basis of disease 45 34311082
2014 Role of the focal adhesion protein TRIM15 in colon cancer development. Biochimica et biophysica acta 44 25450970
2022 E3 ligase TRIM15 facilitates non-small cell lung cancer progression through mediating Keap1-Nrf2 signaling pathway. Cell communication and signaling : CCS 37 35534896
2014 TRIM15 is a focal adhesion protein that regulates focal adhesion disassembly. Journal of cell science 25 25015296
2018 TRIM15 Exerts Anti-Tumor Effects Through Suppressing Cancer Cell Invasion in Gastric Adenocarcinoma. Medical science monitor : international medical journal of experimental and clinical research 23 30412518
2021 TNF-α-induced E3 ligase, TRIM15 inhibits TNF-α-regulated NF-κB pathway by promoting turnover of K63 linked ubiquitination of TAK1. Cellular signalling 20 34871740
2023 TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIs. Cell death & disease 18 36670097
2021 Knockdown of TRIM15 inhibits the proliferation, migration and invasion of esophageal squamous cell carcinoma cells through inactivation of the Wnt/β-catenin signaling pathway. Journal of bioenergetics and biomembranes 15 33515345
2025 TRIM15 drives chondrocyte senescence and osteoarthritis progression. Science translational medicine 10 40138455
2024 Ubiquitin ligase TRIM15 promotes the progression of pancreatic cancer via the upregulation of the IGF2BP2-TLR4 axis. Biochimica et biophysica acta. Molecular basis of disease 8 38657551
2021 Knockdown of TRIM15 inhibits the activation of hepatic stellate cells. Journal of molecular histology 5 34142270
2025 Targeting TRIM15-mediated Axin1 depolymerization suppresses Wnt signaling and inhibits colorectal cancer growth. Cell death & disease 2 41461634
2025 Hypoxia-mediated high expression of TRIM15 promotes malignant progression of high-grade serous ovarian cancer through activation of AKT signaling pathway by K63 ubiquitination. International journal of cancer 1 40026037
2025 Obesity-Associated TRIM15 Promotes the Proliferation of Esophageal Adenocarcinoma Through the YY2/FOXRED1 Axis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 1 41237333
2026 Trim15 stabilizes VDAC3 via ubiquitination to suppress autophagy and enhance chemosensitivity in hypopharyngeal squamous cell carcinoma. Cell death discovery 0 41617671
2026 TRIM15 Mediates ubiquitination of Paxillin to facilitate the progression of ovarian cancer. Cancer cell international 0 42192404
2025 Exploring the TRIM15 protein interaction network as a drug target using machine learning in pancreatic cancer. Discover oncology 0 41296246

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