Affinage

TRIM15

E3 ubiquitin-protein ligase TRIM15 · UniProt Q9C019

Length
465 aa
Mass
52.1 kDa
Annotated
2026-04-28
17 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIM15 is a RING-domain E3 ubiquitin ligase that functions as a context-dependent signaling regulator by catalyzing linkage-specific polyubiquitination of diverse substrates across multiple cellular pathways. It localizes to focal adhesions through coiled-coil-mediated interaction with paxillin and B-box2/PRY domain-dependent oligomerization, where it promotes focal adhesion disassembly and regulates cell migration (PMID:25015296, PMID:25450970). TRIM15 activates MAPK signaling via K63-linked ubiquitination of ERK1/2 (PMID:34497368), activates PI3K/AKT signaling via K63-linked ubiquitination of AKT (PMID:40026037), promotes Wnt/β-catenin signaling by disrupting Axin1 polymerization (PMID:41461634), and modulates the Keap1-Nrf2 antioxidant axis and NF-κB signaling through targeted ubiquitin-dependent degradation or inhibition of key pathway components (PMID:35534896, PMID:34871740). It also ubiquitinates YAP via K48-linked chains to promote chondrocyte senescence and osteoarthritis progression, as demonstrated by conditional knockout mouse models (PMID:40138455), and stabilizes VDAC3 via K6-linked ubiquitination to suppress autophagy and mitophagy (PMID:41617671).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2014 High

    Establishing that TRIM15 is a stable focal adhesion component resolved its subcellular site of action: it localizes to focal contacts via coiled-coil interaction with paxillin's LD2 motif and oligomerization, and its depletion impairs focal adhesion disassembly and cell migration.

    Evidence FRAP, live imaging, Co-IP with domain mapping, siRNA knockdown with focal adhesion disassembly measurements, and fluorescence co-localization with adhesome proteins (coronin 1B, cortactin, VASP) in cultured cells

    PMID:25015296 PMID:25450970

    Open questions at the time
    • Whether TRIM15 E3 ligase activity is required for its focal adhesion function was not tested
    • Identity of ubiquitination substrates at focal adhesions unknown
    • In vivo relevance of focal adhesion phenotype not established
  2. 2021 High

    Identification of ERK1/2 as a direct substrate for TRIM15-catalyzed K63-linked polyubiquitination established TRIM15 as a bona fide E3 ligase that activates MAPK signaling by enhancing ERK-MEK interaction, with CYLD acting as the opposing deubiquitinase.

    Evidence In vitro ubiquitination assay, site-specific lysine mutagenesis, Co-IP, and functional rescue experiments

    PMID:34497368

    Open questions at the time
    • Whether K63-linked ubiquitination of ERK occurs at focal adhesions specifically
    • Physiological contexts beyond cancer cell proliferation not explored
  3. 2021 Medium

    TRIM15 was shown to negatively regulate NF-κB by interacting with TAK1 via its PRY/SPRY domain and reducing TAK1 K63-linked ubiquitination, and separately by sequestering TRIM8, revealing TRIM15 as a TNF-α-induced negative feedback regulator of inflammation.

    Evidence Co-IP, ubiquitination assay, domain mapping with PRY/SPRY mutant, NF-κB luciferase reporter, siRNA knockdown

    PMID:34871740

    Open questions at the time
    • Whether TRIM15 directly ubiquitinates TAK1 or acts indirectly was not resolved
    • In vivo inflammatory phenotype not tested
    • No independent replication
  4. 2021 Medium

    Discovery that TRIM15 ubiquitinates APOA1 via its RING/PRY-SPRY domains leading to APOA1 degradation and lipid droplet accumulation expanded the substrate repertoire to metabolic regulators in pancreatic cancer.

    Evidence Mass spectrometry, reciprocal Co-IP, domain mapping, ubiquitination assay, migration/invasion assays in pancreatic cancer cells

    PMID:34311082

    Open questions at the time
    • Ubiquitin chain linkage type on APOA1 not determined
    • In vivo metabolic consequences not validated
    • No independent replication
  5. 2022 Medium

    Demonstrating that TRIM15 targets Keap1 for proteasomal degradation, thereby stabilizing Nrf2 and activating antioxidant gene expression, linked TRIM15 E3 ligase activity to oxidative stress defense.

    Evidence Co-IP, in vitro ubiquitination assay, gain- and loss-of-function in NSCLC cells with Nrf2 target gene readout

    PMID:35534896

    Open questions at the time
    • Ubiquitin chain linkage type on Keap1 not specified
    • In vivo antioxidant phenotype not tested
    • No independent replication
  6. 2023 Medium

    TRIM15 was found to K63-ubiquitinate LASP1 to promote its nuclear translocation and activate AKT/Snail signaling, with TRIM15 itself upregulated via AKT/FOXO1, establishing a positive feedback loop driving TKI resistance.

    Evidence Co-IP, K63-specific ubiquitination assay, nuclear fractionation, gain/loss-of-function in TKI-treated cancer cells

    PMID:36670097

    Open questions at the time
    • Specific ubiquitination sites on LASP1 not mapped
    • Feedback loop not validated in vivo
    • No independent replication
  7. 2024 Medium

    TRIM15 ubiquitination of IGF2BP2 was shown to enhance its phase separation capacity, stabilizing TLR4 mRNA and promoting pancreatic cancer, linking TRIM15 to RNA metabolism via liquid-liquid phase separation.

    Evidence Multi-omics, Co-IP, ubiquitination assay, mRNA stability assay, orthotopic mouse transplantation model

    PMID:38657551

    Open questions at the time
    • Ubiquitin chain type on IGF2BP2 not specified
    • Direct structural basis for phase separation enhancement unknown
    • No independent replication
  8. 2025 High

    Three studies collectively broadened TRIM15's substrate repertoire and in vivo significance: K48-linked ubiquitination of YAP at K254 disrupts YAP-angiomotin interaction and drives chondrocyte senescence/osteoarthritis (validated in conditional KO mice); TRIM15 disrupts Axin1 polymerization via coiled-coil interaction to activate Wnt/β-catenin signaling in colorectal cancer (validated in two genetic mouse models); and TRIM15 K63-ubiquitinates AKT at its PH domain under HIF-1α transcriptional control.

    Evidence Site-specific mutagenesis, conditional Trim15 KO mice (Col2a1-CreER; Trim15flox/flox), AOM/DSS and ApcMin/+ mouse models, polymerization assays, domain-specific ubiquitination with ChIP for HIF-1α

    PMID:40026037 PMID:40138455 PMID:41461634

    Open questions at the time
    • Whether Axin1 is also a direct ubiquitination substrate is unclear
    • Relationship between focal adhesion localization and Wnt/YAP/AKT signaling functions not resolved
    • Tissue-specific hierarchy among TRIM15 substrates unknown
  9. 2025 Medium

    TRIM15 was shown to target YY2 for proteasomal degradation, linking it to ferroptosis sensitivity through dysregulated lipid metabolism (FOXRED1) and SLC3A2/GPX4 pathway modulation in esophageal adenocarcinoma.

    Evidence Co-IP, ubiquitination assay, gain/loss-of-function, transcriptional reporter for FOXRED1

    PMID:41237333

    Open questions at the time
    • Ubiquitin chain type on YY2 not specified
    • In vivo ferroptosis relevance not validated
    • No independent replication
  10. 2026 Medium

    Discovery of K6-linked (non-degradative) ubiquitination of VDAC3 by TRIM15 that suppresses autophagy and mitophagy while elevating ROS demonstrated that TRIM15 employs atypical ubiquitin chain types for stabilizing functions.

    Evidence K6-linkage-specific ubiquitination assay, siRNA knockdown of VDAC3, autophagy/mitophagy flux assays, ROS measurement, xenograft model

    PMID:41617671

    Open questions at the time
    • Structural basis for K6 linkage specificity unknown
    • Relationship to TRIM15's other mitochondrial or metabolic functions unexplored
    • No independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified model explaining how TRIM15 selects among K6, K48, and K63 ubiquitin chain linkages for different substrates, and how its focal adhesion localization relates to its diverse signaling functions, remains to be established.
  • No structural model of TRIM15 RING domain explaining linkage selectivity
  • No systematic in vivo phenotyping of Trim15 knockout across tissues
  • Substrate prioritization under physiological versus pathological conditions unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016874 ligase activity 5
Localization
GO:0005856 cytoskeleton 2
Pathway
R-HSA-392499 Metabolism of proteins 8 R-HSA-162582 Signal Transduction 5 R-HSA-8953897 Cellular responses to stimuli 1 R-HSA-9612973 Autophagy 1
Partners
AKT1AXIN1ERK1ERK2KEAP1LASP1PAXILLINYAP1

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 TRIM15 functions as an E3 ubiquitin ligase that adds K63-linked polyubiquitin chains to ERK1/2 at defined lysine residues, enhancing ERK interaction with and activation by MEK; the deubiquitinase CYLD opposes this modification through mutually exclusive interactions with ERK1/2. Co-immunoprecipitation, ubiquitination assays, mutagenesis of ERK lysine residues, in vitro ubiquitination assay, loss-of-function studies Nature cell biology High 34497368
2021 TRIM15 interacts with APOA1 through its PRY/SPRY domain and promotes APOA1 polyubiquitination via its RING domain, leading to APOA1 degradation, enhanced lipid anabolism, and lipid droplet accumulation in pancreatic cancer cells. Mass spectrometry, co-immunoprecipitation, domain mapping, ubiquitination assay, loss-of-function migration/invasion assays Biochimica et biophysica acta. Molecular basis of disease Medium 34311082
2014 TRIM15 localizes to focal adhesions through 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 protein 1, and VASP. Fluorescence co-localization, domain mapping, protein-protein interaction screen, loss-of-function migration assays, in vivo tumor growth Biochimica et biophysica acta Medium 25450970
2014 TRIM15 localizes to focal contacts by an interaction between its coiled-coil domain and the LD2 motif of paxillin in a myosin-II-independent manner; TRIM15 is a stable focal adhesion component due to oligomer formation; TRIM15 depletion impairs focal adhesion disassembly and cell migration, and results in enlarged focal adhesions. FRAP, live imaging, co-immunoprecipitation, domain mapping, siRNA knockdown with focal adhesion disassembly rate measurement Journal of cell science High 25015296
2021 TRIM15 acts as a TNF-α-induced late-response E3 ligase that inhibits NF-κB activation by interacting with TAK1 and reducing its K63-linked ubiquitination; this function depends on the PRY/SPRY domain. TRIM15 also interacts with TRIM8 and inhibits TRIM8-mediated cytosolic translocation that normally promotes NF-κB activity. Co-immunoprecipitation, ubiquitination assay, domain mapping (PRY/SPRY mutant), NF-κB reporter assay, siRNA knockdown Cellular signalling Medium 34871740
2022 TRIM15 directly targets Keap1 for ubiquitination and proteasomal degradation via its E3 ligase activity, preventing Keap1-mediated degradation of Nrf2 and activating the antioxidant response in NSCLC cells. Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination assay in vitro, gain- and loss-of-function experiments Cell communication and signaling : CCS Medium 35534896
2023 TRIM15 mediates K63-linked polyubiquitination of LASP1, promoting its nuclear translocation; nuclear LASP1 increases AKT phosphorylation and Snail expression, contributing to TKI resistance. TRIM15 expression is upregulated after TKI treatment via the AKT/FOXO1 axis, forming a feedback loop. Co-immunoprecipitation, ubiquitination assay, nuclear fractionation, loss-of-function and gain-of-function experiments, immunofluorescence Cell death & disease Medium 36670097
2025 TRIM15 binds YAP and mediates K48-linked ubiquitination of YAP at K254, disrupting the YAP-angiomotin interaction and promoting YAP nuclear translocation, thereby facilitating chondrocyte senescence and osteoarthritis progression. Co-immunoprecipitation, ubiquitination assay with specific lysine mutagenesis (K254), conditional knockout mouse model (Col2a1-CreER; Trim15flox/flox), in vivo OA models, AAV-mediated shRNA Science translational medicine High 40138455
2025 TRIM15 interacts with Axin1 through its coiled-coil domain to disrupt Axin1 polymerization, thereby inhibiting assembly of the β-catenin destruction complex and promoting Wnt/β-catenin signaling in colorectal cancer. TRIM15 is itself a Wnt target gene, forming a positive feedback loop. Co-immunoprecipitation, domain mapping (coiled-coil domain), polymerization assays, conditional Trim15 knockout mice in AOM/DSS and ApcMin/+ models, gain- and loss-of-function experiments Cell death & disease High 41461634
2025 TRIM15 induces K63-linked ubiquitination of AKT specifically at the pleckstrin homology (PH) domain via its RING domain, activating AKT signaling; TRIM15 transcription is activated by HIF-1α binding to hypoxia response elements in the TRIM15 promoter. Co-immunoprecipitation, ubiquitination assay (site-specific, RING domain mutant), ubiquitin proteomic analysis, promoter-binding assay (HIF-1α ChIP/reporter), gain- and loss-of-function experiments International journal of cancer Medium 40026037
2024 TRIM15 ubiquitinates IGF2BP2, enhancing its phase separation function and stabilizing TLR4 mRNA, thereby upregulating TLR4 expression and promoting pancreatic cancer progression. Transcriptomics, proteomics, co-immunoprecipitation, ubiquitination assay, mRNA stability assay, orthotopic mouse transplantation model Biochimica et biophysica acta. Molecular basis of disease Medium 38657551
2025 TRIM15 promotes ubiquitin-proteasome-mediated degradation of YY2, dysregulating lipid metabolism (via FOXRED1) and modulating ferroptosis sensitivity (via SLC3A2/GPX4 through mTOR/c-MYC) in esophageal adenocarcinoma cells. Co-immunoprecipitation, ubiquitination assay, gain- and loss-of-function, transcriptional reporter assay for FOXRED1 Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 41237333
2026 TRIM15 stabilizes VDAC3 via K6-linked ubiquitination (non-degradative), suppressing autophagy and mitophagy while elevating ROS levels; VDAC3 knockdown reverses these effects. Co-immunoprecipitation, ubiquitination assay (K6-linked), siRNA knockdown, autophagy/mitophagy flux assays, ROS measurement, xenograft model Cell death discovery Medium 41617671

Source papers

Stage 0 corpus · 17 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 73 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 43 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 19 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 16 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 14 33515345
2025 TRIM15 drives chondrocyte senescence and osteoarthritis progression. Science translational medicine 9 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 7 38657551
2021 Knockdown of TRIM15 inhibits the activation of hepatic stellate cells. Journal of molecular histology 5 34142270
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
2025 Targeting TRIM15-mediated Axin1 depolymerization suppresses Wnt signaling and inhibits colorectal cancer growth. Cell death & disease 1 41461634
2026 Trim15 stabilizes VDAC3 via ubiquitination to suppress autophagy and enhance chemosensitivity in hypopharyngeal squamous cell carcinoma. Cell death discovery 0 41617671
2025 Exploring the TRIM15 protein interaction network as a drug target using machine learning in pancreatic cancer. Discover oncology 0 41296246