Affinage

TRIM69

E3 ubiquitin-protein ligase TRIM69 · UniProt Q86WT6

Length
500 aa
Mass
57.4 kDa
Annotated
2026-04-28
100 papers in source corpus 5 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIM69 is an interferon-stimulated E3 ubiquitin ligase that restricts viral replication through mechanistically distinct pathways and ubiquitinates cellular substrates involved in apoptosis and ferroptosis. Its RING domain-dependent K48-linked polyubiquitination targets dengue virus NS3 at Lys104 for proteasomal degradation (PMID:30142214), whereas it inhibits vesicular stomatitis virus (VSV) pioneer transcription by physically associating with the viral phosphoprotein P and forming higher-order multimers, without degrading P (PMID:31578292). TRIM69 also ubiquitinates and promotes degradation of the cellular substrates p53 and ferroptosis suppressor protein 1 (FSP1), linking it to suppression of UVB-induced apoptosis and modulation of ferroptosis sensitivity in hepatocellular carcinoma (PMID:30844644, PMID:36423520).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2018 High

    Establishing TRIM69 as a direct antiviral effector resolved how an ISG could target a flavivirus replication protein: TRIM69 ubiquitinates and degrades dengue virus NS3 via K48-linked chains at Lys104, using its RING E3 ligase domain, without modulating IFN signaling itself.

    Evidence Co-IP, ubiquitination assays, K104 mutagenesis, RING deletion mutants, and in vivo mouse dengue infection model

    PMID:30142214

    Open questions at the time
    • E2 ubiquitin-conjugating enzyme partner not identified
    • Structural basis of TRIM69–NS3 recognition unknown
    • Whether TRIM69 restricts other flaviviruses beyond dengue not tested
  2. 2019 High

    Demonstrating that TRIM69 inhibits VSV through a degradation-independent mechanism showed the protein has two distinct antiviral modes: it blocks pioneer transcription of VSV genomic RNA by binding the phosphoprotein P and multimerizing, with a single P mutation conferring resistance, indicating direct and specific targeting.

    Evidence Arrayed ISG screen, Co-IP, viral RNA synthesis assays, multimerization studies, resistance-conferring P mutant, and evolutionary positive-selection analysis across two independent studies

    PMID:31375575 PMID:31578292

    Open questions at the time
    • Molecular interface between TRIM69 multimer and P protein unresolved
    • Whether TRIM69 multimerization is required for dengue NS3 degradation not addressed
    • TRIM69 did not inhibit influenza A, HIV-1, RVFV, or dengue in the VSV-focused screen, leaving the full spectrum of antiviral activity unclear
  3. 2019 Medium

    Identifying p53 as a cellular ubiquitination substrate of TRIM69 expanded its role beyond antiviral defense: TRIM69 ubiquitinates p53 to suppress UVB-induced apoptosis and ROS in lens epithelial cells, under transcriptional control by Foxo3a.

    Evidence Co-IP, ubiquitination assay, Foxo3a promoter-reporter assay, overexpression/knockdown, flow cytometry for apoptosis and ROS in human lens epithelial cells

    PMID:30844644

    Open questions at the time
    • No in vitro reconstitution of TRIM69-mediated p53 ubiquitination
    • Ubiquitin chain type on p53 not determined
    • Findings from a single lab without independent replication
  4. 2022 Medium

    Identification of FSP1 as another TRIM69 degradation substrate linked the E3 ligase to ferroptosis regulation: TRIM69 polyubiquitinates FSP1, and the lncRNA lncFAL competitively blocks this interaction to protect hepatocellular carcinoma cells from ferroptosis.

    Evidence Co-IP, ubiquitination assay, RNA pulldown for lncFAL–FSP1 interaction, overexpression/knockdown in HCC cells, in vivo xenograft assays

    PMID:36423520

    Open questions at the time
    • Ubiquitin chain linkage type on FSP1 not specified
    • Whether TRIM69-FSP1 axis operates in non-cancer contexts unknown
    • Findings from a single lab without independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Unresolved: how TRIM69 achieves substrate selectivity across diverse viral and cellular targets, what structural features govern the switch between degradation-dependent (NS3, p53, FSP1) and degradation-independent (VSV P) mechanisms, and what E2 conjugating enzymes cooperate with TRIM69.
  • No structural data for TRIM69 or any of its substrate complexes
  • E2 partner(s) remain unidentified
  • Relative physiological importance of antiviral vs. cellular substrate functions not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3
Pathway
R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 2
Partners
FSP1NS3TP53

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 TRIM69 is an interferon-stimulated gene that directly interacts with dengue virus nonstructural protein 3 (NS3) and mediates its K48-linked polyubiquitination and proteasomal degradation, with Lys104 of NS3 identified as the target residue. The RING domain of TRIM69, which confers E3 ubiquitin ligase activity, is required for this antiviral function. TRIM69 does not modulate IFN signaling itself. Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (Lys104 of NS3), RING domain deletion mutants, in vivo mouse infection model PLoS pathogens High 30142214
2019 TRIM69 inhibits vesicular stomatitis Indiana virus (VSIV) replication in an IFN-induced antiviral state. TRIM69 physically associates with the VSIV phosphoprotein (P) through a specific peptide sequence, and by targeting P (a cofactor of the viral polymerase), TRIM69 inhibits pioneer transcription of incoming virion-associated minus-strand RNA, thereby preventing viral mRNA synthesis. Importantly, TRIM69 does not degrade P but requires higher-order TRIM69 multimerization for antiviral activity. A single amino acid substitution in VSIV P can confer resistance to TRIM69. Arrayed ISG expression screening, loss-of-function experiments, Co-immunoprecipitation, viral RNA synthesis assays, mutagenesis (single amino acid substitution in P protein), multimerization studies Journal of virology High 31578292
2019 TRIM69 inhibits VSIV by a transcriptional inhibition mechanism distinct from degradation. TRIM69 was identified as a potent and specific inhibitor of VSIV (but not influenza A, HIV-1, Rift Valley fever virus, or dengue virus) using arrayed ISG expression screening. TRIM69 exhibits signatures of positive selection consistent with an antiviral role and is highly divergent in human populations. Arrayed ISG expression screening, viral inhibition assays across multiple viruses, evolutionary analysis Journal of virology High 31375575 31578292
2019 TRIM69 interacts with p53 and induces its ubiquitination, thereby suppressing UVB-induced apoptosis and reactive oxygen species production in human lens epithelial cells. Foxo3a acts as a transcription factor that drives TRIM69 promoter activity, establishing a Foxo3a/TRIM69/p53 regulatory axis in cataract formation. Co-immunoprecipitation, ubiquitination assay, overexpression and knockdown experiments, luciferase promoter assay, flow cytometry (apoptosis/ROS) Redox biology Medium 30844644
2022 TRIM69 mediates polyubiquitination and degradation of ferroptosis suppressor protein 1 (FSP1). The long noncoding RNA lncFAL directly binds FSP1 and competitively abolishes TRIM69-dependent FSP1 polyubiquitination, thereby reducing ferroptosis vulnerability in hepatocellular carcinoma cells. Co-immunoprecipitation, ubiquitination assay, RNA pulldown, overexpression/knockdown in HCC cells, in vitro and in vivo functional assays Redox biology Medium 36423520

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science (New York, N.Y.) 2494 12855817
2015 Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science (New York, N.Y.) 1587 25636800
2003 LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. The Journal of experimental medicine 929 14517278
2013 Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. The Journal of biological chemistry 802 24019532
2006 The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nature immunology 414 16964262
2019 Ferroptotic cell death and TLR4/Trif signaling initiate neutrophil recruitment after heart transplantation. The Journal of clinical investigation 387 30830879
2010 Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nature immunology 377 20639876
2005 Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-{kappa}B activation but does not contribute to interferon regulatory factor 3 activation. The Journal of biological chemistry 271 16115877
2017 Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness. Cell stem cell 222 28736216
2008 Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses. Nature immunology 222 18641654
2009 Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production. Nature immunology 213 19734906
2004 Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways. The Journal of biological chemistry 210 14739303
2006 SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type I interferon and proinflammatory cytokine production. Immunity 206 17157040
2008 Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling. Biochemical and biophysical research communications 200 18222170
2016 TRIF-dependent TLR signaling, its functions in host defense and inflammation, and its potential as a therapeutic target. Journal of leukocyte biology 174 27162325
2014 Role of extracellular RNA and TLR3-Trif signaling in myocardial ischemia-reperfusion injury. Journal of the American Heart Association 134 24390148
2006 Suppression of MyD88- and TRIF-dependent signaling pathways of Toll-like receptor by (-)-epigallocatechin-3-gallate, a polyphenol component of green tea. Biochemical pharmacology 127 16890209
2015 CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance. Proceedings of the National Academy of Sciences of the United States of America 112 26106158
2004 Identification of a TLR4- and TRIF-dependent activation program of dendritic cells. European journal of immunology 103 14768061
2010 SARM inhibits both TRIF- and MyD88-mediated AP-1 activation. European journal of immunology 102 20306472
2015 Distinct single-cell signaling characteristics are conferred by the MyD88 and TRIF pathways during TLR4 activation. Science signaling 101 26175492
2009 Suppression of the TRIF-dependent signaling pathway of Toll-like receptors by luteolin. Biochemical pharmacology 94 19426678
2007 Role for MyD88-independent, TRIF pathway in lipid A/TLR4-induced endotoxin tolerance. Journal of immunology (Baltimore, Md. : 1950) 88 17785847
2014 A role for the adaptor proteins TRAM and TRIF in toll-like receptor 2 signaling. The Journal of biological chemistry 87 25505250
2009 Both TRIF- and MyD88-dependent signaling contribute to host defense against pulmonary Klebsiella infection. Journal of immunology (Baltimore, Md. : 1950) 86 19846873
2008 Phosphatase PTP1B negatively regulates MyD88- and TRIF-dependent proinflammatory cytokine and type I interferon production in TLR-triggered macrophages. Molecular immunology 84 18571728
2022 The IRAK4 scaffold integrates TLR4-driven TRIF and MYD88 signaling pathways. Cell reports 80 35977521
2022 HDLBP-stabilized lncFAL inhibits ferroptosis vulnerability by diminishing Trim69-dependent FSP1 degradation in hepatocellular carcinoma. Redox biology 80 36423520
2015 WDFY1 mediates TLR3/4 signaling by recruiting TRIF. EMBO reports 79 25736436
2018 Interferon-stimulated TRIM69 interrupts dengue virus replication by ubiquitinating viral nonstructural protein 3. PLoS pathogens 75 30142214
2010 TRIF mediates Toll-like receptor 5-induced signaling in intestinal epithelial cells. The Journal of biological chemistry 75 20855887
2018 The Synergy between Palmitate and TNF-α for CCL2 Production Is Dependent on the TRIF/IRF3 Pathway: Implications for Metabolic Inflammation. Journal of immunology (Baltimore, Md. : 1950) 71 29632147
2008 Zebrafish TRIF, a Golgi-localized protein, participates in IFN induction and NF-kappaB activation. Journal of immunology (Baltimore, Md. : 1950) 70 18390719
2013 MyD88 and TRIF synergistic interaction is required for TH1-cell polarization with a synthetic TLR4 agonist adjuvant. European journal of immunology 69 23716300
2006 Simultaneous deletion of MyD88 and Trif delays major histocompatibility and minor antigen mismatch allograft rejection. European journal of immunology 69 16874736
2016 STING Requires the Adaptor TRIF to Trigger Innate Immune Responses to Microbial Infection. Cell host & microbe 68 27631700
2015 Differential outcome of TRIF-mediated signaling in TLR4 and TLR3 induced DC maturation. Proceedings of the National Academy of Sciences of the United States of America 68 26508631
2022 ZBP1 promotes inflammatory responses downstream of TLR3/TLR4 via timely delivery of RIPK1 to TRIF. Proceedings of the National Academy of Sciences of the United States of America 67 35666872
2019 Regulation of TRIF-mediated innate immune response by K27-linked polyubiquitination and deubiquitination. Nature communications 67 31511519
2018 TLR4, TRIF, and MyD88 are essential for myelopoiesis and CD11c+ adipose tissue macrophage production in obese mice. The Journal of biological chemistry 67 29636416
2012 Selective TRIF-dependent signaling by a synthetic toll-like receptor 4 agonist. Science signaling 67 22337809
2017 STING and TRIF Contribute to Mouse Sepsis, Depending on Severity of the Disease Model. Shock (Augusta, Ga.) 63 27755506
2017 Chronic ethanol consumption: role of TLR3/TRIF-dependent signaling. Addiction biology 62 28840972
2019 Neutrophil recruitment and activation are differentially dependent on MyD88/TRIF and MAVS signaling during RSV infection. Mucosal immunology 61 31358860
2019 TRIM69 inhibits cataractogenesis by negatively regulating p53. Redox biology 54 30844644
2017 Versican is produced by Trif- and type I interferon-dependent signaling in macrophages and contributes to fine control of innate immunity in lungs. American journal of physiology. Lung cellular and molecular physiology 54 28912382
2017 TRIF Differentially Regulates Hepatic Steatosis and Inflammation/Fibrosis in Mice. Cellular and molecular gastroenterology and hepatology 53 28462384
2011 Kaposi sarcoma-associated herpesvirus degrades cellular Toll-interleukin-1 receptor domain-containing adaptor-inducing beta-interferon (TRIF). The Journal of biological chemistry 52 21212282
2010 CD14 and TRIF govern distinct responsiveness and responses in mouse microglial TLR4 challenges by structural variants of LPS. Brain, behavior, and immunity 52 20951794
2008 Differential induction of MyD88- and TRIF-dependent pathways in equine monocytes by Toll-like receptor agonists. Veterinary immunology and immunopathology 51 19019456
2018 Autocrine-paracrine prostaglandin E2 signaling restricts TLR4 internalization and TRIF signaling. Nature immunology 50 30397349
2012 TLR4 activation under lipotoxic conditions leads to synergistic macrophage cell death through a TRIF-dependent pathway. Journal of immunology (Baltimore, Md. : 1950) 50 23275600
2012 Both TLR2 and TRIF contribute to interferon-β production during Listeria infection. PloS one 49 22432012
2014 PTX3 binds MD-2 and promotes TRIF-dependent immune protection in aspergillosis. Journal of immunology (Baltimore, Md. : 1950) 48 25049357
2013 Liposomal lipopolysaccharide initiates TRIF-dependent signaling pathway independent of CD14. PloS one 48 23565187
2015 TLR4-HMGB1-, MyD88- and TRIF-dependent signaling in mouse intestinal ischemia/reperfusion injury. World journal of gastroenterology 47 26217083
2004 LPS, dsRNA and the interferon bridge to adaptive immune responses: Trif, Tram, and other TIR adaptor proteins. Journal of endotoxin research 47 15120005
2020 Noncoding RNA MaIL1 is an integral component of the TLR4-TRIF pathway. Proceedings of the National Academy of Sciences of the United States of America 46 32241891
2016 Cell-Extrinsic TNF Collaborates with TRIF Signaling To Promote Yersinia-Induced Apoptosis. Journal of immunology (Baltimore, Md. : 1950) 43 27733552
2012 TLR4- and TRIF-dependent stimulation of B lymphocytes by peptide liposomes enables T cell-independent isotype switch in mice. Blood 42 23144170
2019 Oxidized LDL upregulates macrophage DPP4 expression via TLR4/TRIF/CD36 pathways. EBioMedicine 41 30738832
2016 Apolipoproteins L control cell death triggered by TLR3/TRIF signaling in dendritic cells. European journal of immunology 41 27198486
2024 The RIPK1 death domain restrains ZBP1- and TRIF-mediated cell death and inflammation. Immunity 40 38744293
2017 FOSL1 Inhibits Type I Interferon Responses to Malaria and Viral Infections by Blocking TBK1 and TRAF3/TRIF Interactions. mBio 40 28049150
2018 Hepatitis C virus NS4B induces the degradation of TRIF to inhibit TLR3-mediated interferon signaling pathway. PLoS pathogens 39 29782532
2017 Functional interfaces between TICAM-2/TRAM and TICAM-1/TRIF in TLR4 signaling. Biochemical Society transactions 39 28630139
2022 Neutrophils and macrophages drive TNF-induced lethality via TRIF/CD14-mediated responses. Science immunology 38 36563168
2019 TRIM69 Inhibits Vesicular Stomatitis Indiana Virus. Journal of virology 38 31375575
2015 Prothymosin-alpha preconditioning activates TLR4-TRIF signaling to induce protection of ischemic retina. Journal of neurochemistry 38 26364961
2004 PIASy represses TRIF-induced ISRE and NF-kappaB activation but not apoptosis. FEBS letters 38 15251447
2019 Inhibition of TLR4/TRIF/IRF3 Signaling Pathway by Curcumin in Breast Cancer Cells. Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 37 31287789
2015 Unexpected Roles for Toll-Like Receptor 4 and TRIF in Intraocular Infection with Gram-Positive Bacteria. Infection and immunity 35 26195555
2011 Disruption of downstream MyD88 or TRIF Toll-like receptor signaling does not protect against cerebral ischemia. Brain research 34 21376021
2022 Cardioprotective Effect of circ_SMG6 Knockdown against Myocardial Ischemia/Reperfusion Injury Correlates with miR-138-5p-Mediated EGR1/TLR4/TRIF Inactivation. Oxidative medicine and cellular longevity 33 35126807
2018 TRIF is a key inflammatory mediator of acute sickness behavior and cancer cachexia. Brain, behavior, and immunity 33 29852290
2020 Anti-inflammatory effects of nobiletin on TLR4/TRIF/IRF3 and TLR9/IRF7 signaling pathways in prostate cancer cells. Immunopharmacology and immunotoxicology 32 32048561
2019 Vesicular Stomatitis Virus Transcription Is Inhibited by TRIM69 in the Interferon-Induced Antiviral State. Journal of virology 32 31578292
2016 Salmonella Suppresses the TRIF-Dependent Type I Interferon Response in Macrophages. mBio 32 26884434
2016 The role of MyD88- and TRIF-dependent signaling in monophosphoryl lipid A-induced expansion and recruitment of innate immunocytes. Journal of leukocyte biology 32 27354411
2013 TRIF-mediated TLR3 and TLR4 signaling is negatively regulated by ADAM15. Journal of immunology (Baltimore, Md. : 1950) 32 23365087
2012 CD16 regulates TRIF-dependent TLR4 response in human monocytes and their subsets. Journal of immunology (Baltimore, Md. : 1950) 32 22427642
2024 Key roles for phosphorylation and the Coiled-coil domain in TRIM56-mediated positive regulation of TLR3-TRIF-dependent innate immunity. The Journal of biological chemistry 31 38556084
2017 The TLR4-TRIF pathway can protect against the development of experimental allergic asthma. Immunology 31 28502093
2015 Phosphatase PTPN4 preferentially inhibits TRIF-dependent TLR4 pathway by dephosphorylating TRAM. Journal of immunology (Baltimore, Md. : 1950) 31 25825441
2014 TRIF signaling drives homeostatic intestinal epithelial antimicrobial peptide expression. Journal of immunology (Baltimore, Md. : 1950) 31 25210121
2023 SARS-CoV-2 NSP7 inhibits type I and III IFN production by targeting the RIG-I/MDA5, TRIF, and STING signaling pathways. Journal of medical virology 30 36755358
2023 Bacterial vesicles block viral replication in macrophages via TLR4-TRIF-axis. Cell communication and signaling : CCS 30 36978183
2021 TRAF6-IRF5 kinetics, TRIF, and biophysical factors drive synergistic innate responses to particle-mediated MPLA-CpG co-presentation. Science advances 30 33523878
2020 Methamphetamine induced neuroinflammation in mouse brain and microglial cell line BV2: Roles of the TLR4/TRIF/Peli1 signaling axis. Toxicology letters 30 32768653
2019 TLR9/MyD88/TRIF signaling activates host immune inhibitory CD200 in Leishmania infection. JCI insight 30 31092731
2017 Expression and functional characterization of TRIF in orange-spotted grouper (Epinephelus coioides). Fish & shellfish immunology 30 28964858
2013 TLR4-mediated pro-inflammatory dendritic cell differentiation in humans requires the combined action of MyD88 and TRIF. Innate immunity 30 23941760
2020 Leptospiral LPS escapes mouse TLR4 internalization and TRIF‑associated antimicrobial responses through O antigen and associated lipoproteins. PLoS pathogens 29 32790743
2009 The toll-Like receptor adaptor TRIF contributes to otitis media pathogenesis and recovery. BMC immunology 28 19656404
2009 Suppression of the TRIF-dependent signaling pathway of toll-like receptors by isoliquiritigenin in RAW264.7 macrophages. Molecules and cells 27 19809799
2014 Differential requirements of MyD88 and TRIF pathways in TLR4-mediated immune responses in murine B cells. Immunology letters 26 25448706
2012 A unique host defense pathway: TRIF mediates both antiviral and antibacterial immune responses. Microbes and infection 26 23116944
2023 SARS-CoV-2 NSP8 suppresses type I and III IFN responses by modulating the RIG-I/MDA5, TRIF, and STING signaling pathways. Journal of medical virology 25 36929724
2018 Regulator of calcineurin 1 differentially regulates TLR-dependent MyD88 and TRIF signaling pathways. PloS one 25 29799862
2013 Reduced expression of TRIF in chronic HBV infected Iranian patients. Clinics and research in hepatology and gastroenterology 25 23433963