Affinage

TRIM45

E3 ubiquitin-protein ligase TRIM45 · UniProt Q9H8W5

Length
580 aa
Mass
64.4 kDa
Annotated
2026-06-10
17 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIM45 is a RBCC/TRIM-family RING-finger E3 ubiquitin ligase that controls cell signaling and protein fate through linkage-specific polyubiquitination, with distinct outputs depending on the substrate and lysine-chain topology it assembles (PMID:15351693, PMID:28542145). It acts as a brake on growth and inflammatory signaling: early work showed it represses MAPK-driven ELK-1/AP-1 and TNFα-induced NF-κB transcription, in part independently of its RING domain, and that it interacts with the PKC scaffold RACK1 within a negative feedback loop activated by mitogenic stimuli (PMID:15351693, PMID:22634006, PMID:24681954). As an E3 ligase its functional duality is most clearly seen at its substrates. It stabilizes p53 by conjugating K63-linked chains to C-terminal lysines, competitively excluding degradative K48-linked ubiquitination and underlying tumor-suppressor activity in glioblastoma (PMID:28542145). At TAB2, TRIM45 either builds K63-linked chains that promote TAB1-TAK1-TAB2 complex assembly and NF-κB activation, or assembles K48-linked chains at TAB2 K611 to drive proteasomal degradation and dampen TLR-driven NF-κB/MAPK inflammatory signaling (PMID:35217833, PMID:36681779). It also drives FABP5 nuclear translocation via K33/K63 ubiquitination of the FABP5 NLS, where nuclear FABP5 engages PPARγ to upregulate lipid-synthesis genes (PMID:38755308). In antiviral defense, TRIM45 K48-ubiquitinates calpain-1 for degradation, sparing LAMP-2A from cleavage and promoting chaperone-mediated autophagic degradation of influenza PB2 via a conserved PB2 QMRDV motif (PMID:41129599). TRIM45 is also required for normal diencephalon and eye development in zebrafish (PMID:32489689).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2004 Medium

    Establishing TRIM45's domain architecture and first function answered whether this novel RBCC protein had a role in signaling, identifying it as a candidate transcriptional repressor in the MAPK pathway.

    Evidence Molecular cloning, luciferase reporter assays for ELK-1/AP-1, and immunostaining localization in COS-7 cells

    PMID:15351693

    Open questions at the time
    • No direct substrate or ubiquitination activity demonstrated
    • Repression mechanism not resolved at the molecular level
    • Based on overexpression only
  2. 2012 Medium

    Testing whether NF-κB repression required E3 activity showed a RING-deletion mutant retained inhibition, establishing that some TRIM45 functions are ligase-independent.

    Evidence Luciferase reporter assays with RING-domain deletion mutant and cell growth assays

    PMID:22634006

    Open questions at the time
    • Mechanism of RING-independent NF-κB repression unknown
    • Direct binding partner not identified
    • Overexpression-based
  3. 2014 Medium

    Identifying RACK1 as a direct partner placed TRIM45 within a defined PKC/MAPK negative feedback circuit, explaining its MAPK-repressive activity.

    Evidence Co-immunoprecipitation of TRIM45-RACK1, MAPK pathway readouts, overexpression/knockdown

    PMID:24681954

    Open questions at the time
    • Whether RACK1 is a ubiquitination substrate not established
    • Reciprocal validation limited to one lab
  4. 2017 High

    Defining p53 as a substrate resolved how TRIM45 functions as a tumor suppressor: K63-linked chains block degradative K48 ubiquitination, demonstrating chain-topology-based stabilization.

    Evidence Reciprocal Co-IP, K63/K48 linkage-specific ubiquitination assays, p53 lysine mutagenesis, CRISPR knockout, in vivo glioblastoma tumorigenicity

    PMID:28542145

    Open questions at the time
    • Whether the same mechanism operates outside glioma not tested
    • Regulation of TRIM45 chain-type choice unknown
  5. 2022 High

    Showing TRIM45 K63-ubiquitinates TAB2 to assemble the TAK1 complex established it as a positive driver of NF-κB inflammation in microglia, contrasting its earlier repressive role.

    Evidence Co-IP of TRIM45-TAB2, K63-linkage-specific ubiquitination, microglia-specific AAV-shRNA knockdown in mice, OGD/R model

    PMID:35217833

    Open questions at the time
    • Does not reconcile activating vs repressive NF-κB roles across cell types
    • Determinants of K63 vs K48 chain choice on TAB2 unresolved
  6. 2023 High

    Demonstrating K48-linked degradation of TAB2 at K611 in macrophages revealed that the same substrate can be degraded rather than stabilized, defining cell-type-dependent ubiquitin output.

    Evidence Co-IP, K48-linkage-specific ubiquitination, TAB2 K611 mutagenesis, RNF99 knockout mice, LPS/DSS inflammation models

    PMID:36681779

    Open questions at the time
    • What switches TRIM45 between K48 and K63 ubiquitination of TAB2 unknown
    • Microglia vs macrophage divergence not mechanistically reconciled
  7. 2023 Medium

    Linking TRIM45 to NLRP3 inflammasome and pyroptosis via Atg5/autophagic flux broadened its inflammatory role to programmed cell death in septic encephalopathy.

    Evidence AAV-shTRIM45 in vivo, BV2 gain/loss-of-function, ROS flow cytometry, JC-1 mitochondrial potential, LPS/ATP pyroptosis model

    PMID:38037161

    Open questions at the time
    • No direct biochemical TRIM45-Atg5 interaction shown
    • Whether effect depends on E3 activity not tested
  8. 2024 High

    Identifying FABP5 as an MS-defined substrate showed TRIM45 controls subcellular localization through K33/K63 ubiquitination of an NLS, coupling it to PPARγ-driven lipogenesis in HCC.

    Evidence IP-tandem MS, K33/K63 linkage-specific ubiquitination, nuclear fractionation, FABP5 knockdown/overexpression, in vivo HCC/NASH models

    PMID:38755308

    Open questions at the time
    • How NLS ubiquitination promotes import mechanistically unresolved
    • Reader of the K33/K63 mark not identified
  9. 2024 Low

    Reporting TRAF6 as an additional K48-degradation target extended the TLR-suppressive role but rests on indirect ubiquitination evidence.

    Evidence Western blot of TRAF6/TAK1, ubiquitination upon RNF99 knockdown, forsythiaside A acute lung injury model

    PMID:39094364

    Open questions at the time
    • No direct Co-IP or linkage specificity reported
    • Single lab, indirect knockdown-plus-blot evidence
  10. 2025 High

    Defining the calpain-1/LAMP-2A/PB2 axis revealed an antiviral mechanism in which TRIM45 degrades a protease to protect a CMA receptor, channeling viral protein into chaperone-mediated autophagy.

    Evidence Multiple Co-IPs (TRIM45-PB2, PB2-LAMP-2A, PB2-HSC70), K48 ubiquitination of CAPN1, PB2 QMRDV mutagenesis, mutant virus pathogenicity in mice, CMA inhibition

    PMID:41129599

    Open questions at the time
    • Whether this CMA-promoting role applies to non-viral substrates unknown
    • Regulation of TRIM45 induction during infection not defined
  11. 2026 Low

    A proposed cervical-cancer role via cGAS/STING suppression and ANXA2-driven glycolysis extends TRIM45's tumor associations but lacks direct biochemical linkage.

    Evidence Single-cell sequencing, proliferation/metastasis assays, TRIM45/ANXA2 overexpression/knockdown

    PMID:42186236

    Open questions at the time
    • E3-activity link to ANXA2 not demonstrated
    • Mechanism inferred from expression correlation
  12. 2026 Low

    Identifying IGF2BP1-mediated m6A control of TRIM45 mRNA addresses how TRIM45 is upregulated to amplify NLRP3-driven microglial inflammation after ischemia.

    Evidence meRIP and RIP assays, Western blot, ELISA, IGF2BP1 manipulation, MCAO mouse model

    PMID:41639535

    Open questions at the time
    • Link to TRIM45 protein function is indirect
    • Small replicate number noted by authors
  13. 2026 Medium

    A natural-compound (Ginkgolide B) study confirmed TRIM45 is mechanistically required for K63-TAB2 ubiquitination and downstream NF-κB activation in stroke models.

    Evidence Molecular docking, K63 ubiquitination assay, TRIM45 gain/loss-of-function in BV2 cells, tMCAO rat model

    PMID:41921864

    Open questions at the time
    • GB-TRIM45 binding is computational, not biochemically confirmed
    • Pocket 279 binding not validated structurally

Open questions

Synthesis pass · forward-looking unresolved questions
  • What determines whether TRIM45 assembles stabilizing (K63/K33) versus degradative (K48) chains on a given substrate, and how its opposing pro- vs anti-inflammatory roles are partitioned across cell types, remains unresolved.
  • No structural basis for chain-type selectivity
  • Upstream signals controlling TRIM45 activity/output not defined
  • Cross-tissue reconciliation of opposing phenotypes lacking

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 3 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 2 R-HSA-1430728 Metabolism 1 R-HSA-9612973 Autophagy 1
Partners
CAPN1FABP5PB2RACK1TAB2TP53TRAF6

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 TRIM45 was identified as a novel RBCC/TRIM protein with a RING finger, two B-boxes, coiled-coil domain, and C-terminal filamin-type immunoglobulin (IG-FLMN) domain. Overexpression of TRIM45 in COS-7 cells inhibits transcriptional activities of ELK-1 and AP-1, suggesting it acts as a transcriptional repressor in the MAPK signaling pathway. Luciferase reporter assay (transcriptional activity), subcellular localization by immunostaining, Northern blot for expression, molecular cloning Biochemical and biophysical research communications Medium 15351693
2012 TRIM45 negatively regulates TNFα-induced NF-κB-mediated transcription; importantly, a TRIM45 mutant lacking the RING domain retains this inhibitory activity, indicating the repression of NF-κB is independent of E3 ligase activity. TRIM45 overexpression also suppresses cell growth. Luciferase reporter assay, RING-domain deletion mutant overexpression, cell growth assay Biochemical and biophysical research communications Medium 22634006
2014 TRIM45 directly interacts with RACK1 (receptor for activated C-kinase 1), a scaffolding protein in the PKC signaling pathway, and negatively regulates MAPK signal transduction. TRIM45 expression is induced by growth-promoting extracellular stimuli that activate MAPK, acting as part of a negative feedback loop. Co-immunoprecipitation (TRIM45–RACK1 interaction), signal pathway activity assays (MAPK readouts), overexpression/knockdown Oncogene Medium 24681954
2017 TRIM45 interacts with p53 and stabilizes it by conjugating K63-linked polyubiquitin chains to the C-terminal six lysine residues of p53, thereby competitively blocking K48-linked polyubiquitination at those sites and preventing proteasomal degradation of p53. This E3 ligase activity underlies its tumor-suppressor function in glioblastoma. Co-immunoprecipitation, ubiquitination assays (K63- vs K48-linkage-specific), CRISPR/Cas9 knockout, overexpression in vitro and in vivo tumorigenicity assays, site-directed mutagenesis of p53 lysine residues Cell death & disease High 28542145
2022 TRIM45 constitutively interacts with TAB2 in microglia and facilitates K63-linked polyubiquitination of TAB2, promoting formation of the TAB1-TAK1-TAB2 complex and activation of TAK1, which leads to NF-κB pathway activation and proinflammatory cytokine/chemokine production. TRIM45 knockdown reduces neuroinflammation and neuronal apoptosis after cerebral ischemia-reperfusion injury. Co-immunoprecipitation (TRIM45–TAB2 interaction), K63-linkage-specific ubiquitination assay, microglia-specific AAV-shRNA knockdown in mice, OGD/R primary microglia model, Transwell coculture system Experimental & molecular medicine High 35217833
2023 RNF99 (TRIM45) interacts with TAB2 and mediates its K48-linked polyubiquitin-proteasomal degradation specifically at lysine 611 of TAB2, thereby suppressing TLR-mediated NF-κB and MAPK pathway activation and inflammatory cytokine production in macrophages. RNF99 knockout mice show enhanced LPS-induced septic shock and DSS-induced colitis. Co-immunoprecipitation, K48-linkage-specific ubiquitination assay, site-directed mutagenesis (K611 of TAB2), RNF99 knockout mice, bone marrow transplantation, TLR4-stably transfected HEK293 cells Cell death and differentiation High 36681779
2023 TRIM45 regulates NLRP3 inflammasome activation and microglial pyroptosis via modulation of Atg5 and autophagic flux in septic encephalopathy; TRIM45 overexpression activates NLRP3 and downstream Gsdmd-N, and alters ROS levels and mitochondrial membrane potential, while TRIM45 knockdown reduces pyroptosis and neuronal damage. AAV-shTRIM45 in vivo knockdown, overexpression and siRNA in BV2 cells, Western blot, flow cytometry (ROS), JC-1 staining (mitochondrial membrane potential), LPS/ATP in vitro pyroptosis model Journal of neuroinflammation Medium 38037161
2024 TRIM45 directly adds K33-type and K63-type poly-ubiquitin chains to the NLS domain of FABP5, promoting FABP5 nuclear translocation. Nuclear FABP5 interacts with PPARγ to upregulate lipid synthesis gene expression, driving fatty acid synthesis and HCC progression in the context of NASH. IP-tandem mass spectrometry (identifying FABP5 as substrate), ubiquitination assay (K33/K63 linkage-specific), nuclear fractionation/localization studies, FABP5 knockdown and overexpression, transcriptome analysis, in vitro and in vivo HCC models Oncogene High 38755308
2024 TRIM45 (RNF99) mediates K48-linked polyubiquitination and proteasomal degradation of TRAF6 (in addition to TAB2) in the context of TLR signaling; RNF99 knockdown increased ubiquitinated TRAF6 protein, and forsythiaside A exerts anti-inflammatory effects by upregulating RNF99 to suppress TRAF6/TAK1/NF-κB signaling in acute lung injury. Western blot for TRAF6 and TAK1 levels, ubiquitination assay of TRAF6 upon RNF99 knockdown, in vivo ALI mouse model International immunopharmacology Low 39094364
2025 TRIM45 restricts influenza virus replication by promoting chaperone-mediated autophagy (CMA)-dependent degradation of viral PB2 protein. TRIM45 interacts with PB2 and enhances its binding to LAMP-2A; mechanistically, TRIM45 uses its E3 ligase activity to mediate K48-linked polyubiquitination and proteasomal degradation of calpain 1 (CAPN1), preventing CAPN1-mediated cleavage of LAMP-2A. A conserved QMRDV motif (aa 602–606) in PB2 is required for its interaction with LAMP-2A/HSC70 and for TRIM45-mediated degradation. Co-immunoprecipitation (TRIM45-PB2, PB2-LAMP-2A, PB2-HSC70), K48-linkage-specific ubiquitination assay (CAPN1), site-directed mutagenesis (PB2 QMRDV motif), mutant virus generation and pathogenicity in mice, CMA inhibition experiments PLoS pathogens High 41129599
2026 TRIM45 promotes cervical cancer progression by suppressing the cGAS/STING signaling pathway through mediation of ANXA2, which subsequently upregulates glycolytic enzymes HK2 and ENO2, enhancing aerobic glycolysis in tumor cells. Single-cell sequencing, functional proliferation/metastasis assays, molecular profiling, overexpression/knockdown of TRIM45 and ANXA2 Integrative biology : quantitative biosciences from nano to macro Low 42186236
2026 IGF2BP1 promotes TRIM45 expression through m6A methylation modification of TRIM45 mRNA, thereby enhancing NLRP3 inflammasome activation and pro-inflammatory phenotype in microglia-like cells after OGD/R injury. Methylated RNA immunoprecipitation (meRIP) assay, RIP assay, Western blot, ELISA, IGF2BP1 overexpression/knockdown, MCAO mouse model Neurotoxicity research Low 41639535
2026 Ginkgolide B (GB) directly binds to pocket 279 of TRIM45 (by molecular docking), downregulates TRIM45 expression, reduces K63-linked ubiquitination of TAB2, disrupts TAB2-TAK1-TAB1 complex formation, and blocks NF-κB pathway activation. TRIM45 overexpression reversed GB's regulatory effects, while TRIM45 knockdown mimicked them, confirming TRIM45 is mechanistically required for GB's neuroprotective action. Molecular docking (GB-TRIM45 binding), K63-linkage-specific ubiquitination assay, TRIM45 overexpression/knockdown gain/loss-of-function in BV2 cells, tMCAO rat model, Western blot Brain research bulletin Medium 41921864
2020 In zebrafish, trim45 is required for normal development of the diencephalon and eye: ectopic trim45 expression expands diencephalon and eye fields, while morpholino knockdown reduces their size. Markers olig2 (midbrain) and rx1/rx3 (eye) are decreased in trim45 morphants. mRNA microinjection (gain-of-function), antisense morpholino knockdown, in situ hybridization for marker genes (olig2, rx1/rx3), zebrafish embryo model Animal cells and systems Medium 32489689

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 TRIM45 causes neuronal damage by aggravating microglia-mediated neuroinflammation upon cerebral ischemia and reperfusion injury. Experimental & molecular medicine 81 35217833
2017 TRIM45 functions as a tumor suppressor in the brain via its E3 ligase activity by stabilizing p53 through K63-linked ubiquitination. Cell death & disease 57 28542145
2023 TRIM45 aggravates microglia pyroptosis via Atg5/NLRP3 axis in septic encephalopathy. Journal of neuroinflammation 55 38037161
2004 TRIM45, a novel human RBCC/TRIM protein, inhibits transcriptional activities of ElK-1 and AP-1. Biochemical and biophysical research communications 50 15351693
2012 TRIM45 negatively regulates NF-κB-mediated transcription and suppresses cell proliferation. Biochemical and biophysical research communications 41 22634006
2014 The TRIM-FLMN protein TRIM45 directly interacts with RACK1 and negatively regulates PKC-mediated signaling pathway. Oncogene 36 24681954
2023 E3 ligase RNF99 negatively regulates TLR-mediated inflammatory immune response via K48-linked ubiquitination of TAB2. Cell death and differentiation 18 36681779
2024 TRIM45 facilitates NASH-progressed HCC by promoting fatty acid synthesis via catalyzing FABP5 ubiquitylation. Oncogene 17 38755308
2025 Trim45: An emerging E3 ubiquitin ligases in cancer. Cellular signalling 15 40466841
2020 TRIM45 Suppresses the Development of Non-small Cell Lung Cancer. Current molecular medicine 14 31663468
2020 Trim45 is essential to the development of the diencephalon and eye in zebrafish embryos. Animal cells and systems 9 32489689
2024 Identification and characterization of chicken TRIM45 and its role as a negative regulator of ALV-J replication in vitro. Avian pathology : journal of the W.V.P.A 4 39417776
2025 TRIM45 restricts influenza virus infection through modulating the chaperone-mediated autophagic degradation of viral PB2 protein. PLoS pathogens 2 41129599
2024 Forsythiaside A alleviates acute lung injury via the RNF99/TRAF6/NF-κB signaling pathway. International immunopharmacology 1 39094364
2026 IGF2BP1 Aggravates NLRP3 Inflammasome Activation and Pro-Inflammatory Phenotype in Microglia-like Cells by Promoting TRIM45 Expression. Neurotoxicity research 0 41639535
2026 Ginkgolide B alleviates cerebral ischemia-reperfusion injury by antagonizing TRIM45 to reduce microglia-mediated neuronal damage. Brain research bulletin 0 41921864
2026 Trim45 promotes the occurrence and development of cervical cancer by inhibiting the cGAS/STING signaling pathway. Integrative biology : quantitative biosciences from nano to macro 0 42186236

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