Affinage

TRIM25

E3 ubiquitin/ISG15 ligase TRIM25 · UniProt Q14258

Length
630 aa
Mass
71.0 kDa
Annotated
2026-04-28
100 papers in source corpus 38 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIM25 is a RING-type E3 ubiquitin and ISG15 ligase that serves as a central hub in innate antiviral immunity, stress granule-based signaling, and diverse protein turnover pathways. Its RING domain dimerizes to catalyze K63-linked polyubiquitination of RIG-I at K172, an event essential for RIG-I–MAVS interaction and type I interferon induction, while multiple viral antagonists (influenza NS1, dengue sfRNA, SARS-CoV-2 N, HPV E6, EBV BPLF1) converge on TRIM25 to block this pathway by disrupting its coiled-coil-mediated oligomerization, RNA binding via the PRY/SPRY domain, or protein stability (PMID:18948594, PMID:27425606, PMID:29739942, PMID:26138103, PMID:29263274, PMID:31710640). Beyond RIG-I signaling, TRIM25 ubiquitinates substrates including Keap1 (K48-linked, activating Nrf2 antioxidant defense), PTEN (K63-linked, activating AKT/mTOR), RIP3 (K48-linked, inhibiting necroptosis), PPARγ (suppressing adipogenesis), and 14-3-3σ, and it cooperates with ZAP to restrict viral RNA translation through SPRY-mediated interaction and ligase-dependent ZAP activation (PMID:31953436, PMID:33931764, PMID:33953350, PMID:30323259, PMID:12075357, PMID:28060952). TRIM25 also possesses ubiquitin-ligase-independent antiviral functions: it binds and destabilizes viral mRNAs directly, restricts influenza vRNP RNA chain elongation in the nucleus, and undergoes dsRNA-dependent liquid–liquid phase separation with G3BP1 at stress granules to enhance its catalytic output (PMID:35736141, PMID:29107643, PMID:38750080).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2002 High

    Establishing TRIM25 as a RING-dependent E3 ubiquitin ligase resolved the question of whether this TRIM family member possessed intrinsic catalytic activity and identified 14-3-3σ as its first substrate linking it to cell proliferation.

    Evidence In vitro ubiquitination reconstitution with RING mutagenesis and mouse xenograft tumor model

    PMID:12075357

    Open questions at the time
    • Ubiquitin chain linkage type on 14-3-3σ not determined
    • E2 enzyme specificity not identified
  2. 2005 High

    Demonstrating that TRIM25 also functions as an ISG15 E3 ligase for 14-3-3σ revealed dual modifier specificity, connecting TRIM25 to interferon-stimulated pathways beyond canonical ubiquitination.

    Evidence siRNA knockdown in 293T and MCF-7 cells with interferon treatment and RING domain mutagenesis

    PMID:16352599

    Open questions at the time
    • Physiological contexts in which ISGylation vs. ubiquitination is favored were unclear
    • Auto-ISGylation consequences not yet known
  3. 2007 High

    Discovery that TRIM25 auto-ISGylates at K117 as a negative-feedback mechanism, and that it ubiquitinates ERα to paradoxically enhance transcription, expanded the substrate repertoire and revealed automodification as a regulatory switch.

    Evidence K117R mutagenesis with ISGylation assay; co-IP and ubiquitination assay with dominant-negative RING for ERα

    PMID:17222803 PMID:17418098

    Open questions at the time
    • Other auto-modification sites not mapped
    • Structural basis for ERα recognition unknown
  4. 2008 High

    Identification of TRIM25 as the E3 ligase that K63-polyubiquitinates RIG-I CARD at K172 to enable MAVS interaction established the central axis of TRIM25 in antiviral innate immunity.

    Evidence Reciprocal co-IP, K172R and T55I mutagenesis, IFN-β reporter assay

    PMID:18948594

    Open questions at the time
    • Whether unanchored K63-Ub chains also contribute was unresolved
    • Structural basis for CARD recognition not determined
  5. 2011 High

    Discovery that LUBAC targets TRIM25 for K48-linked degradation and that HOIL-1L competes for RIG-I binding revealed a dedicated negative regulatory circuit controlling TRIM25 protein levels and substrate access.

    Evidence Domain mapping, genetic deletion, IFN production assay

    PMID:21292167

    Open questions at the time
    • Quantitative threshold of TRIM25 degradation needed to suppress IFN unknown
    • Whether other E3 ligases compensate in LUBAC absence untested
  6. 2014 High

    USP15 was identified as the deubiquitylase that counteracts LUBAC-mediated K48 ubiquitination of TRIM25, establishing a stabilizing DUB–E3 axis that sustains RIG-I signaling; separately, TRIM25 was found to act as an RNA-binding cofactor for Lin28a/TuT4-mediated pre-let-7 uridylation, revealing a non-immune RNA regulatory function.

    Evidence Endogenous interaction by mass spectrometry with catalytic-dead USP15 mutant; RNA pulldown with quantitative MS and in vitro uridylation reconstitution

    PMID:24399297 PMID:25457611

    Open questions at the time
    • Whether USP15 regulation is tissue-specific was unknown
    • Full spectrum of TRIM25's RNA targets not mapped
  7. 2015 High

    Dengue sfRNA was shown to bind TRIM25 directly and prevent its deubiquitylation, establishing the first viral RNA antagonist of TRIM25 and explaining sfRNA-mediated immune evasion.

    Evidence RNA-protein binding assay, TRIM25 deubiquitylation assay, IFN suppression, epidemiological validation

    PMID:26138103

    Open questions at the time
    • Exact binding site on TRIM25 for sfRNA not mapped
    • Whether other flavivirus sfRNAs use the same mechanism unknown
  8. 2016 High

    Crystal structure of the TRIM25 RING dimer demonstrated that dimerization is essential for E2 engagement and catalysis, and that SPRY domain binding to RIG-I allosterically promotes RING dimerization, providing the first structural framework for TRIM25 activation.

    Evidence X-ray crystallography of RING dimer, RING dimerization mutants in ubiquitination and IFN assays

    PMID:27425606

    Open questions at the time
    • Full-length TRIM25 structure not available
    • How coiled-coil antiparallel architecture positions two SPRY domains relative to RING dimer unresolved
  9. 2017 High

    A cluster of studies revealed that TRIM25 partners with ZAP via its SPRY domain to restrict viral RNA translation, that RNA binding by the PRY/SPRY domain is required for TRIM25 ligase activity, that influenza NS1 disrupts TRIM25 by binding its coiled-coil to misposition the SPRY domain, and that nuclear TRIM25 directly inhibits vRNP RNA elongation independently of ubiquitin ligase activity — collectively showing TRIM25 operates through both ligase-dependent and ligase-independent antiviral mechanisms in distinct subcellular compartments.

    Evidence Crystal structures of TRIM25 CC-SPRY and CC-NS1 complex; CLIP-seq; genome-wide RNAi screen; vRNP binding with ligase-dead mutant; BiFC and super-resolution imaging in infected cells

    PMID:27807226 PMID:28060952 PMID:29107643 PMID:29117863 PMID:29739942

    Open questions at the time
    • How nuclear vs. cytoplasmic TRIM25 pools are regulated remained unclear
    • Whether TRIM25 RNA binding activates ligase by an allosteric or proximity mechanism was unresolved
    • Full repertoire of ZAP-targeted viral RNAs requiring TRIM25 not defined
  10. 2018 High

    Multiple viral antagonists were shown to converge on TRIM25: HPV16 E6 promotes K48-linked TRIM25 degradation through a complex with USP15, while TRIM25 was also demonstrated to ubiquitinate PPARγ for proteasomal degradation, expanding its non-immune substrate repertoire to adipocyte differentiation.

    Evidence Co-IP, ubiquitination assay, CRISPR KO; in vitro ubiquitination with TRIM25-KO MEFs and adipocyte differentiation assay

    PMID:29263274 PMID:30323259

    Open questions at the time
    • Whether E6-mediated TRIM25 suppression contributes to HPV-driven oncogenesis in vivo untested
    • Ubiquitin chain type on PPARγ not determined
  11. 2019 High

    New regulatory layers were uncovered: NLRP12 blocks TRIM25-mediated RIG-I ubiquitination, MAP3K13 phosphorylates TRIM25 at S12 to stabilize it and enable FBXW7α ubiquitination (increasing Myc), EBV BPLF1 uses 14-3-3 proteins to sequester TRIM25 into inactive aggregates, and lncRNA Lnczc3h7a scaffolds the RIG-I–TRIM25 complex.

    Evidence KO mice with viral infection; phosphorylation site mutagenesis and xenograft; BPLF1 catalytic mutants with p62 colocalization; RNA pulldown and in vivo knockdown

    PMID:30902577 PMID:31036902 PMID:31186535 PMID:31710640

    Open questions at the time
    • Interplay between these multiple regulators under physiological infection conditions not modeled
    • Whether MAP3K13-S12 phosphorylation affects antiviral functions of TRIM25 unknown
  12. 2021 High

    TRIM25's substrate repertoire was further expanded to include RIP3 (K48-linked ubiquitination at K501 inhibiting necroptosis), PTEN (K63-linked at K266 activating AKT/mTOR), and IBDV VP3 (K27-linked at K854), while viral antagonism was extended to SARS-CoV-2 N protein and JCV small t antigen targeting TRIM25 RNA-binding activity.

    Evidence In vitro ubiquitination with site-directed mutagenesis and KO cells; co-IP and domain mapping with IFN readout

    PMID:33849980 PMID:33931764 PMID:33953350 PMID:34452305 PMID:34516573

    Open questions at the time
    • K27-linked ubiquitination mechanism by TRIM25 is unusual and structural basis unknown
    • Whether PTEN ubiquitination is relevant outside NSCLC not tested
  13. 2022 High

    Substrate-trapping (R54P mutant) combined with mass spectrometry identified G3BP1/2, UPF1, NME1, and PABPC4 as direct TRIM25 substrates mediating IFN-independent antiviral activity against alphaviruses, and separate work showed TRIM25 destabilizes IAV mRNAs through a mechanism independent of both its ligase and canonical RNA-binding domain.

    Evidence Catalytic trap mutant interactome by MS with siRNA validation; RNA tethering assay with ΔRING and ΔRBD mutants

    PMID:35736141 PMID:36067236

    Open questions at the time
    • Ubiquitin chain type and sites on G3BP1/2 and UPF1 not mapped
    • Molecular mechanism of ligase-independent RNA destabilization unclear
  14. 2024 High

    TRIM25 was shown to undergo dsRNA-dependent liquid–liquid phase separation and co-condense with G3BP1 in antiviral stress granules, with phase separation significantly enhancing its ubiquitination activity, providing a biophysical mechanism for spatiotemporal activation of TRIM25 during infection.

    Evidence Live-cell imaging, in vitro LLPS reconstitution with dsRNA titration, ubiquitination assay in condensates

    PMID:38750080

    Open questions at the time
    • Which TRIM25 domains drive phase separation not fully mapped
    • Whether LLPS is required for all TRIM25 antiviral functions or only RIG-I signaling is unknown
    • Post-translational modifications regulating LLPS not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length structural model of TRIM25 showing how the B-box, coiled-coil, and SPRY domains coordinate RING dimerization, RNA binding, substrate engagement, and phase separation remains unresolved, as does the in vivo hierarchy among its many substrates and the tissue-specific regulation of its immune versus non-immune functions.
  • No full-length structure available
  • In vivo substrate hierarchy and competition not determined
  • Tissue-specific regulation of immune vs. metabolic TRIM25 functions not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0003723 RNA binding 4 GO:0016874 ligase activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 1
Pathway
R-HSA-168256 Immune System 11 R-HSA-392499 Metabolism of proteins 8 R-HSA-162582 Signal Transduction 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-5357801 Programmed Cell Death 1
Partners
14-3-3G3BP1MAVSNLRP12NS1RIG-IUSP15ZAP

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 TRIM25 (EFP/estrogen-responsive finger protein) is a RING-finger-dependent E3 ubiquitin ligase that targets 14-3-3 sigma for proteasomal degradation, promoting cell cycle progression and breast tumor growth. In vitro ubiquitination assay, RING domain mutagenesis, antisense knockdown, mouse xenograft model Nature High 12075357
2005 TRIM25 (EFP) functions as an ISG15 E3 ligase for 14-3-3 sigma in a RING domain-dependent manner, identifying it as a dual ubiquitin and ISG15 E3 ligase. siRNA knockdown in 293T and MCF-7 cells, interferon treatment, RING domain mutagenesis, in vivo ISGylation assay The Journal of biological chemistry High 16352599
2007 TRIM25 (EFP) auto-ISGylates at K117 via its RING domain, and this autoISGylation negatively regulates its ISG15 E3 ligase activity toward 14-3-3 sigma. Site-directed mutagenesis (K117R), in vivo ISGylation assay, E2 enzyme identification (UbcH6 and UbcH8) Biochemical and biophysical research communications High 17222803
2007 TRIM25 (EFP) interacts with and ubiquitylates estrogen receptor alpha (ERα), promoting its ligand-dependent degradation, which paradoxically enhances ERα transcriptional activity through recruitment of the coactivator Tip60. Co-immunoprecipitation, in vitro and in vivo ubiquitylation assay, dominant-negative RING mutant, reporter assay Biochemical and biophysical research communications High 17418098
2008 TRIM25 binds the first CARD of RIG-I and mediates K63-linked polyubiquitination of the second CARD at K172, which is required for RIG-I interaction with MAVS and downstream IFN-beta production. Reciprocal co-immunoprecipitation, site-directed mutagenesis (T55I, K172R), IFN-beta reporter assay, RIG-I splice variant analysis Proceedings of the National Academy of Sciences of the United States of America High 18948594
2011 LUBAC (HOIL-1L/HOIP) suppresses TRIM25 by inducing its K48-linked polyubiquitination and proteasomal degradation via RBR ligase domains, and HOIL-1L NZF domain competes with TRIM25 for RIG-I binding, thereby inhibiting RIG-I ubiquitination and antiviral IFN production. Co-immunoprecipitation, domain mapping, genetic deletion/depletion, IFN production assay Molecular cell High 21292167
2012 TRIM25 ubiquitinates MAVS on K7 and K10, marking it for proteasomal degradation, which is required to release the TBK1/NEMO signaling complex from mitochondria and allow IRF3 phosphorylation. Co-immunoprecipitation, proteasome inhibitor treatment, IRF3 activation assay, site mapping BMC biology Medium 22626058
2014 USP15 deubiquitylates TRIM25, removing K48-linked ubiquitin chains added by LUBAC and thereby stabilizing TRIM25 to sustain RIG-I-mediated type I IFN production. Protein purification, mass spectrometry, co-immunoprecipitation, catalytically inactive USP15 mutant, siRNA knockdown, IFN production assay Science signaling High 24399297
2014 TRIM25 acts as an RNA-specific cofactor for Lin28a/TuT4-mediated pre-let-7 uridylation by binding the conserved terminal loop of pre-let-7 and activating TuT4, providing substrate specificity for this non-let-7 pre-miRNA. RNA pulldown coupled with quantitative mass spectrometry, co-immunoprecipitation, in vitro uridylation assay Cell reports High 25457611
2015 Dengue virus subgenomic flavivirus RNA (sfRNA) binds TRIM25 in a sequence-dependent manner and prevents its deubiquitylation, thereby blocking TRIM25-dependent sustained RIG-I activation and type I IFN expression. RNA-protein binding assay, TRIM25 deubiquitylation assay, IFN expression measurement, viral fitness comparison Science (New York, N.Y.) High 26138103
2016 TRIM25 RING domain forms a dimer that engages ubiquitin-charged E2 enzymes; RING dimerization is required for catalysis, K63-linked polyubiquitin synthesis, RIG-I ubiquitination, and IFN induction. Binding of TRIM25 SPRY domain to the RIG-I effector domain promotes RING dimerization and E3 ligase activity. Crystal structure of RING dimer, in vitro ubiquitination assay with RING dimerization mutants, IFN reporter assay, antiviral activity assay Cell reports High 27425606
2017 TRIM25 interacts with ZAP (zinc-finger antiviral protein) through its SPRY domain, and both TRIM25 RING domain (ligase activity) and coiled-coil domain (oligomerization) are required for TRIM25 to enhance ZAP's translational inhibition of incoming viral RNA. Co-immunoprecipitation, genome-wide RNAi screen, TRIM25 RING/coiled-coil deletion mutants, antiviral activity assay, polyubiquitin linkage analysis PLoS pathogens High 28060952
2017 TRIM25 RNA-binding activity is mediated by its PRY/SPRY domain; this RNA-binding activity is required for TRIM25's ubiquitin ligase activity toward itself (autoubiquitination) and its substrate ZAP. CLIP-seq, SILAC co-immunoprecipitation, RNA-binding domain mutagenesis, in vitro ubiquitination assay BMC biology High 29117863
2017 Nuclear TRIM25 directly binds influenza A virus ribonucleoproteins (vRNPs) via a ubiquitin ligase-independent mechanism and blocks the onset of viral RNA chain elongation without affecting initiation of capped-RNA-primed mRNA synthesis. Subcellular fractionation, vRNP binding assay, viral RNA synthesis assay with ubiquitin ligase-dead mutant, NS1 antagonism assay Cell host & microbe High 29107643
2017 Influenza A NS1 protein binds the TRIM25 coiled-coil domain, sterically preventing correct positioning of the PRYSPRY domain required for substrate ubiquitination without affecting unanchored K63-linked polyubiquitin chain synthesis or RING dimerization. Crystal structures of TRIM25 coiled-coil-PRYSPRY and TRIM25-NS1 complex, in vitro ubiquitination assay Nature communications High 29739942
2017 TRIM25 is redistributed to cytoplasmic stress granules upon viral infection; TRIM25 forms homo-complexes and heterocomplexes with RIG-I, and influenza NS1 inhibits TRIM25 homo-complex formation but not RIG-I/TRIM25 heterocomplex formation, preventing downstream RIG-I/MAVS complex assembly. Bimolecular fluorescence complementation (BiFC), super-resolution microscopy, co-localization analysis in virus-infected cells Journal of virology Medium 27807226
2017 TRIM25 is required for ZAP's antiviral activity; TRIM25 E3 ligase activity mediates ZAP ubiquitination and modulates ZAP's target RNA binding activity. siRNA knockdown of TRIM25, overexpression of deubiquitinase OTUB1, RNA binding assay, antiviral activity assay Journal of virology Medium 28202764
2018 HPV16 E6 oncoprotein forms a complex with TRIM25 and USP15, increasing K48-linked ubiquitination and proteasomal degradation of TRIM25, thereby suppressing TRIM25-mediated K63-linked RIG-I ubiquitination and CARD-dependent RIG-I/MAVS interaction. Co-immunoprecipitation in human cells, ubiquitination assay, IFN-beta reporter assay, CRISPR-Cas9 gene targeting Journal of virology High 29263274
2018 TRIM25 directly ubiquitinates PPARγ, leading to its proteasome-dependent degradation and suppression of adipocyte differentiation; TRIM25 expression is inversely correlated with PPARγ during differentiation. In vitro ubiquitination assay, TRIM25 stable overexpression, siRNA knockdown, TRIM25-KO MEFs, adipocyte differentiation assay Experimental & molecular medicine High 30323259
2019 NLRP12 interacts with TRIM25 via its nucleotide-binding domain to prevent TRIM25-mediated K63-linked ubiquitination of RIG-I, and also enhances RNF125-mediated K48-linked degradative ubiquitination of RIG-I, thereby dampening antiviral signaling. Co-immunoprecipitation, ubiquitination assay, Nlrp12-KO mice, VSV infection model Cell host & microbe High 30902577
2019 14-3-3 proteins bind the coiled-coil domain of TRIM25 and mediate Epstein-Barr virus BPLF1 deubiquitinase positioning to induce TRIM25 mono/di-ubiquitination and sequestration into inactive cytosolic aggregates decorated by p62/SQSTM1, suppressing IFN responses. Co-immunoprecipitation, in vitro pulldown, BPLF1 catalytic and 14-3-3-binding mutants, p62 colocalization, IFN suppression assay PLoS pathogens High 31710640
2019 The lncRNA Lnczc3h7a acts as a molecular scaffold that simultaneously binds TRIM25 and activated RIG-I, stabilizing the RIG-I-TRIM25 complex at early stages of infection and facilitating TRIM25-mediated K63-linked ubiquitination of RIG-I. RNA pulldown, co-immunoprecipitation, Lnczc3h7a depletion in vitro and in vivo, ubiquitination assay Nature immunology High 31036902
2019 MAP3K13 phosphorylates TRIM25 at Ser12 to stabilize it by reducing its polyubiquitination and proteasomal degradation; stabilized TRIM25 then directly ubiquitinates FBXW7α at K412 to block Myc ubiquitination, thereby increasing Myc protein levels. Phosphorylation assay, ubiquitination assay, co-immunoprecipitation, site-directed mutagenesis, tumor xenograft model Cell death and differentiation High 31186535
2020 TRIM25 directly targets Keap1 for K48-linked ubiquitination and proteasomal degradation, leading to Nrf2 nuclear activation, upregulation of antioxidant defense, reduction of IRE1 UPR signaling, and promotion of ER-associated degradation. Co-immunoprecipitation, in vitro ubiquitination assay, TRIM25 knockdown/overexpression, TRIM25 KO cell lines, xenograft model Nature communications High 31953436
2020 RIG-I binds TRIM25 mRNA via its helicase and C-terminal regulatory domains, enhancing TRIM25 transcript stability, and activates ISGylation pathway genes via CARD domain through ISRE, promoting the RIG-I-TRIM25-ISGylation axis required for myeloid differentiation. RNA immunoprecipitation, mRNA stability assay, domain-deletion mutants, TRIM25 and ISG15 knockdown, ATRA-induced differentiation assay Proceedings of the National Academy of Sciences of the United States of America Medium 32513696
2020 TRIM25 interacts with ZAP through its PRY/SPRY domain and controls the cellular level of ZAP; RNA binding by the PRY/SPRY domain is required for TRIM25 ubiquitin ligase activity toward ZAP (autoubiquitination and ZAP ubiquitination). CLIP-seq, SILAC co-immunoprecipitation, RNA-binding deficient mutant, in vitro ubiquitination assay BMC biology High 29117863
2021 TRIM25 directly interacts with RIP3 through its SPRY domain and mediates K48-linked polyubiquitination of RIP3 at K501 via its RING domain, promoting proteasomal degradation of RIP3 and inhibiting TNF-induced cell necrosis. Co-immunoprecipitation, in vitro ubiquitination assay, site-directed mutagenesis (K501R), TRIM25 KO/knockdown, necrosis assay Cell death and differentiation High 33953350
2021 TRIM25 activates the AKT/mTOR pathway by mediating K63-linked ubiquitination of PTEN at K266, which prevents PTEN plasma membrane translocation and reduces its phosphatase activity. Co-immunoprecipitation, ubiquitination assay with K266R mutant, membrane fractionation, PTEN phosphatase activity assay, NSCLC cell xenograft Acta pharmacologica Sinica High 33931764
2021 SARS-CoV-2 nucleocapsid (N) protein interacts with TRIM25 at its SPRY domain, masking TRIM25's RNA-binding activity and suppressing TRIM25-mediated K63-linked ubiquitination of RIG-I and IFN-beta secretion. Co-immunoprecipitation, IFN-beta reporter assay, ubiquitination assay, domain mapping Viruses Medium 34452305
2021 JCV small t antigen interacts with TRIM25 and prevents its RNA-binding activity, thereby inhibiting K63-linked ubiquitination of RIG-I and downstream antiviral signaling. Co-immunoprecipitation, RNA binding assay, ubiquitination assay, IFN reporter assay mBio Medium 33849980
2021 TRIM25 promotes ubiquitination of IBDV structural protein VP3 at K854 via K27-linked polyubiquitination, targeting it for proteasomal degradation and inhibiting IBDV replication. Immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K854), TRIM25 overexpression/knockdown, in vitro and in vivo viral replication assay PLoS pathogens High 34516573
2022 TRIM25 R54P mutation traps substrates including G3BP1/2, UPF1, NME1, and PABPC4, and TRIM25's antiviral activity against alphaviruses is independent of host interferon response, being directly mediated by ubiquitination of these substrates. Substrate trapping with R54P mutant, mass spectrometry interactome, siRNA knockdown of substrates, antiviral assay independent of IFN PLoS pathogens High 36067236
2022 TRIM25 binds IAV mRNAs and destabilizes them in a manner independent of its ubiquitin ligase or canonical RNA-binding domain activity; direct tethering of TRIM25 to RNA is sufficient to downregulate the targeted RNA. RNA binding assay with TRIM25ΔRBD and TRIM25ΔRING mutants, IAV replication assay, RNA tethering assay Nucleic acids research High 35736141
2024 TRIM25 undergoes liquid-liquid phase separation (LLPS) and co-condenses with G3BP1 in a dsRNA-dependent manner at antiviral stress granules, and this co-condensation significantly enhances TRIM25's ubiquitination activity toward multiple antiviral proteins and is critical for activating the RIG-I signaling pathway. Live-cell imaging, LLPS assay, co-condensation with dsRNA titration, ubiquitination assay in condensates, RIG-I signaling readout Nature communications High 38750080
2016 TRIM25 polyubiquitinates ERG (ETS-related gene) in vitro, and TRIM25 inactivation reduces ERG polyubiquitination and stabilizes ERG protein; ERG in turn upregulates TRIM25 expression, creating a regulatory feedback. In vitro polyubiquitination assay, TRIM25 inactivation, co-immunoprecipitation of full-length and truncated ERG Oncotarget Medium 27626314
2014 TRIM25 cooperates with gp78 in polyubiquitylation of AMF/PGI: TRIM25 mediates the initial ubiquitylation while gp78 catalyzes poly-extension; TRIM25 also ubiquitylates gp78 itself, controlling gp78 steady-state levels. In vitro polyubiquitylation assay with Ub-DHFR model substrate, co-immunoprecipitation, overexpression/degradation assay Oncotarget Medium 24810856
2011 EFP (TRIM25) interacts with and ubiquitylates KLF5, promoting its degradation in an estrogen-dependent manner; only unubiquitinated EFP can interact with KLF5, and auto-ubiquitination of EFP disrupts its interaction with KLF5. Co-immunoprecipitation, in vitro ubiquitylation, cycloheximide chase, siRNA knockdown and overexpression The Biochemical journal Medium 21542805
2012 EFP (TRIM25) interacts with and ubiquitinates ATBF1, promoting its estrogen-induced proteasomal degradation in breast cancer cells. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown and overexpression of EFP, protein half-life analysis The Biochemical journal Medium 22452784
2023 TRIM25 interacts with HBx protein and promotes its K90-site ubiquitination via both RING and SPRY domains, leading to proteasomal degradation; additionally, TRIM25 acts as an adaptor (via SPRY domain, independently of RING) to enhance RIG-I recognition of HBV pregenomic RNA and IFN production. Co-immunoprecipitation, immunofluorescence colocalization, Western blotting with RING and SPRY mutants, RNA-binding protein immunoprecipitation, ELISA for HBV antigens Chinese medical journal Medium 36975005

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Interaction of lifestyle, behaviour or systemic diseases with dental caries and periodontal diseases: consensus report of group 2 of the joint EFP/ORCA workshop on the boundaries between caries and periodontal diseases. Journal of clinical periodontology 372 28266114
2013 Diabetes and periodontal diseases: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. Journal of periodontology 364 23631572
2013 Periodontitis and atherosclerotic cardiovascular disease: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. Journal of periodontology 364 23631582
2015 Dengue subgenomic RNA binds TRIM25 to inhibit interferon expression for epidemiological fitness. Science (New York, N.Y.) 337 26138103
2002 Efp targets 14-3-3 sigma for proteolysis and promotes breast tumour growth. Nature 322 12075357
2013 Diabetes and periodontal diseases: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. Journal of clinical periodontology 305 23627322
2013 Periodontitis and atherosclerotic cardiovascular disease: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. Journal of clinical periodontology 261 23627332
2005 The interferon-inducible ubiquitin-protein isopeptide ligase (E3) EFP also functions as an ISG15 E3 ligase. The Journal of biological chemistry 240 16352599
2020 TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway. Nature communications 224 31953436
2013 Periodontitis and atherosclerotic cardiovascular disease: consensus report of the Joint EFP/AAPWorkshop on Periodontitis and Systemic Diseases. Journal of periodontology 220 29537596
2008 Roles of RIG-I N-terminal tandem CARD and splice variant in TRIM25-mediated antiviral signal transduction. Proceedings of the National Academy of Sciences of the United States of America 209 18948594
2011 Linear ubiquitin assembly complex negatively regulates RIG-I- and TRIM25-mediated type I interferon induction. Molecular cell 185 21292167
2012 MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I interferon production after activation of the antiviral RIG-I-like receptors. BMC biology 180 22626058
2017 TRIM25 Enhances the Antiviral Action of Zinc-Finger Antiviral Protein (ZAP). PLoS pathogens 173 28060952
2019 The long noncoding RNA Lnczc3h7a promotes a TRIM25-mediated RIG-I antiviral innate immune response. Nature immunology 158 31036902
2018 Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition. Nature communications 155 29739942
2014 The ubiquitin-specific protease USP15 promotes RIG-I-mediated antiviral signaling by deubiquitylating TRIM25. Science signaling 139 24399297
2017 RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC biology 133 29117863
2017 Structural Basis for Polyproline-Mediated Ribosome Stalling and Rescue by the Translation Elongation Factor EF-P. Molecular cell 124 29100052
2018 The Human Papillomavirus E6 Oncoprotein Targets USP15 and TRIM25 To Suppress RIG-I-Mediated Innate Immune Signaling. Journal of virology 123 29263274
2017 TRIM25 Is Required for the Antiviral Activity of Zinc Finger Antiviral Protein. Journal of virology 122 28202764
2017 TRIM25 in the Regulation of the Antiviral Innate Immunity. Frontiers in immunology 121 29018447
2016 Mechanism of TRIM25 Catalytic Activation in the Antiviral RIG-I Pathway. Cell reports 115 27425606
2017 Nuclear TRIM25 Specifically Targets Influenza Virus Ribonucleoproteins to Block the Onset of RNA Chain Elongation. Cell host & microbe 101 29107643
2019 RIPLET, and not TRIM25, is required for endogenous RIG-I-dependent antiviral responses. Immunology and cell biology 84 31335993
2019 NLRP12 Regulates Anti-viral RIG-I Activation via Interaction with TRIM25. Cell host & microbe 82 30902577
2015 Maintenance of protein synthesis reading frame by EF-P and m(1)G37-tRNA. Nature communications 82 26009254
2017 Subcellular Localizations of RIG-I, TRIM25, and MAVS Complexes. Journal of virology 78 27807226
2023 EETs alleviate alveolar epithelial cell senescence by inhibiting endoplasmic reticulum stress through the Trim25/Keap1/Nrf2 axis. Redox biology 73 37269686
2014 Trim25 Is an RNA-Specific Activator of Lin28a/TuT4-Mediated Uridylation. Cell reports 71 25457611
2018 Paramyxovirus V Proteins Interact with the RIG-I/TRIM25 Regulatory Complex and Inhibit RIG-I Signaling. Journal of virology 69 29321315
1979 Peptide bond formation stimulated by protein synthesis factor EF-P depends on the aminoacyl moiety of the acceptor. European journal of biochemistry 68 383483
2018 Human Respiratory Syncytial Virus NS 1 Targets TRIM25 to Suppress RIG-I Ubiquitination and Subsequent RIG-I-Mediated Antiviral Signaling. Viruses 67 30558248
2015 Stall no more at polyproline stretches with the translation elongation factors EF-P and IF-5A. Molecular microbiology 66 26416626
2020 A RIG-I-like receptor directs antiviral responses to a bunyavirus and is antagonized by virus-induced blockade of TRIM25-mediated ubiquitination. The Journal of biological chemistry 64 32471869
2019 The MAP3K13-TRIM25-FBXW7α axis affects c-Myc protein stability and tumor development. Cell death and differentiation 63 31186535
2021 SARS-CoV-2 N Protein Targets TRIM25-Mediated RIG-I Activation to Suppress Innate Immunity. Viruses 61 34452305
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2017 Type I IFN augments IL-27-dependent TRIM25 expression to inhibit HBV replication. Cellular & molecular immunology 59 28194021
2017 An eFP browser for visualizing strawberry fruit and flower transcriptomes. Horticulture research 55 28674614
2016 TRIM25 blockade by RNA interference inhibited migration and invasion of gastric cancer cells through TGF-β signaling. Scientific reports 54 26754079
2020 TRIM25 and its emerging RNA-binding roles in antiviral defense. Wiley interdisciplinary reviews. RNA 49 31990130
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2007 Negative regulation of ISG15 E3 ligase EFP through its autoISGylation. Biochemical and biophysical research communications 48 17222803
2021 TRIM25 activates AKT/mTOR by inhibiting PTEN via K63-linked polyubiquitination in non-small cell lung cancer. Acta pharmacologica Sinica 47 33931764
2020 RIG-I regulates myeloid differentiation by promoting TRIM25-mediated ISGylation. Proceedings of the National Academy of Sciences of the United States of America 47 32513696
2020 JP3, an antiangiogenic peptide, inhibits growth and metastasis of gastric cancer through TRIM25/SP1/MMP2 axis. Journal of experimental & clinical cancer research : CR 47 32576271
2015 Overexpression of TRIM25 in Lung Cancer Regulates Tumor Cell Progression. Technology in cancer research & treatment 46 26113559
2015 Regulation of MDA5-MAVS Antiviral Signaling Axis by TRIM25 through TRAF6-Mediated NF-κB Activation. Molecules and cells 45 26299329
2021 E3 ligase TRIM25 ubiquitinates RIP3 to inhibit TNF induced cell necrosis. Cell death and differentiation 44 33953350
2021 TRIM25 inhibits infectious bursal disease virus replication by targeting VP3 for ubiquitination and degradation. PLoS pathogens 44 34516573
2020 OTUD5 cooperates with TRIM25 in transcriptional regulation and tumor progression via deubiquitination activity. Nature communications 44 32826889
2019 NDR2 promotes the antiviral immune response via facilitating TRIM25-mediated RIG-I activation in macrophages. Science advances 43 30775439
2019 14-3-3 scaffold proteins mediate the inactivation of trim25 and inhibition of the type I interferon response by herpesvirus deconjugases. PLoS pathogens 43 31710640
2021 Long noncoding RNA AVAN promotes antiviral innate immunity by interacting with TRIM25 and enhancing the transcription of FOXO3a. Cell death and differentiation 41 33990776
2018 The E3 ubiquitin ligase TRIM25 regulates adipocyte differentiation via proteasome-mediated degradation of PPARγ. Experimental & molecular medicine 40 30323259
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2019 RNA Helicase LGP2 Negatively Regulates RIG-I Signaling by Preventing TRIM25-Mediated Caspase Activation and Recruitment Domain Ubiquitination. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 39 31237466
2007 Ligand-dependent transcription of estrogen receptor alpha is mediated by the ubiquitin ligase EFP. Biochemical and biophysical research communications 39 17418098
2021 LncRNA XIST upregulates TRIM25 via negatively regulating miR-192 in hepatitis B virus-related hepatocellular carcinoma. Molecular medicine (Cambridge, Mass.) 38 33858324
2019 An 'eFP-Seq Browser' for visualizing and exploring RNA sequencing data. The Plant journal : for cell and molecular biology 38 31350781
2016 RING domain is essential for the antiviral activity of TRIM25 from orange spotted grouper. Fish & shellfish immunology 37 27276113
2024 Suppression of ITPKB degradation by Trim25 confers TMZ resistance in glioblastoma through ROS homeostasis. Signal transduction and targeted therapy 36 38438346
2022 TRIM25 inhibits influenza A virus infection, destabilizes viral mRNA, but is redundant for activating the RIG-I pathway. Nucleic acids research 36 35736141
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2024 Morusin Alleviates Aortic Valve Calcification by Inhibiting Valve Interstitial Cell Senescence Through Ccnd1/Trim25/Nrf2 Axis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 30 38502885
2022 Elucidation of TRIM25 ubiquitination targets involved in diverse cellular and antiviral processes. PLoS pathogens 30 36067236
2019 Zebrafish TRIM25 Promotes Innate Immune Response to RGNNV Infection by Targeting 2CARD and RD Regions of RIG-I for K63-Linked Ubiquitination. Frontiers in immunology 29 31849979
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2024 TRIM25 promotes glioblastoma cell growth and invasion via regulation of the PRMT1/c-MYC pathway by targeting the splicing factor NONO. Journal of experimental & clinical cancer research : CR 26 38303029
2017 Nitroxoline shows antimyeloma activity by targeting the TRIM25/p53 axle. Anti-cancer drugs 26 28301380
2024 Neddylation activated TRIM25 desensitizes triple-negative breast cancer to paclitaxel via TFEB-mediated autophagy. Journal of experimental & clinical cancer research : CR 25 38926803
2017 TRIM25 is associated with cisplatin resistance in non-small-cell lung carcinoma A549 cell line via downregulation of 14-3-3σ. Biochemical and biophysical research communications 24 28867193
2024 TRIM25 predominately associates with anti-viral stress granules. Nature communications 23 38750080
2023 Hepatitis B virus X protein promotes MAN1B1 expression by enhancing stability of GRP78 via TRIM25 to facilitate hepatocarcinogenesis. British journal of cancer 23 36635499
2022 The Role of ZAP and TRIM25 RNA Binding in Restricting Viral Translation. Frontiers in cellular and infection microbiology 23 35800389
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2019 Suppressor mutations in ribosomal proteins and FliY restore Bacillus subtilis swarming motility in the absence of EF-P. PLoS genetics 22 31237868
2021 TRIM25 and DEAD-Box RNA Helicase DDX3X Cooperate to Regulate RIG-I-Mediated Antiviral Immunity. International journal of molecular sciences 21 34445801
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2022 Human metapneumovirus M2-2 protein inhibits RIG-I signaling by preventing TRIM25-mediated RIG-I ubiquitination. Frontiers in immunology 18 36045682
2021 Attenuation of Antiviral Immune Response Caused by Perturbation of TRIM25-Mediated RIG-I Activation under Simulated Microgravity. Cell reports 18 33406425
2019 Identification of TRIM25 as a Negative Regulator of Caspase-2 Expression Reveals a Novel Target for Sensitizing Colon Carcinoma Cells to Intrinsic Apoptosis. Cells 18 31842382
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