Affinage

TLR3

Toll-like receptor 3 · UniProt O15455

Length
904 aa
Mass
103.8 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TLR3 is a double-stranded RNA receptor that initiates innate antiviral and inflammatory programs, recognizing viral dsRNA as well as self-derived ligands and driving an IRF3-dependent type I IFN response that selectively restricts viral replication (PMID:12354379, PMID:16517751). Ligand engagement triggers cooperative receptor assembly: cryo-EM shows TLR3 homodimers cluster along long dsRNA helices with uniform ~103 Å spacing, with longer duplexes nucleating higher-order multimers, providing the structural basis for length-dependent activation; the transmembrane and intracellular domains are dispensable for this clustering (PMID:36371424, PMID:36631495). Productive signaling requires proteolytic and trafficking maturation — the cathepsin-cleaved N-terminal ectodomain fragment remains associated with the C-terminal fragment, and both are needed for IFN-β and NF-κB activation (PMID:25305318) — together with accessory factors that promote ligand binding and TRIF recruitment, including the FYVE-domain proteins ZFYVE1 and WDFY1, ZCCHC3, and the endosomal maturation factor S100A9 (PMID:25736436, PMID:32133501, PMID:31388100, PMID:26385519). Downstream, TLR3 phosphorylation on specific tyrosines bifurcates signaling into a TBK1/IRF3 branch and a PI3K/Akt branch required for full IRF3 phosphorylation and target-gene promoter binding (PMID:15502848), and the TLR3-TRIF complex engages LUBAC for gene activation versus RIPK1/ZBP1 for inflammatory and death signaling (PMID:27810922, PMID:35666872). Beyond canonical antiviral defense, TLR3 controls a basal constitutive IFN-β tone that establishes a standing antiviral state in human fibroblasts and cortical neurons (PMID:33393505), and acts on diverse self-ligands — UVB-damaged self-RNA, extracellular RNA released during ischemia, and tumor-derived endogenous retroviral RNA — to drive immune suppression, cardiac injury, angiogenesis suppression, or pro-metastatic SLIT2 induction in endothelium (PMID:22772463, PMID:24390148, PMID:18368052, PMID:32999457). A TRIF/MyD88-independent branch through c-Src biphasically regulates cell migration, adhesion, and proliferation (PMID:22323545), and MyD88-dependent TLR3 signaling shapes neuronal dendritic arborization and pruning (PMID:27979975, PMID:29777026).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2002 High

    Established that TLR3 signaling converges on IRF3 to drive a specific antiviral transcriptional program, defining the receptor's core output as type I IFN induction rather than generic inflammation.

    Evidence Genetic loss-of-function, expression profiling, and viral replication assays in macrophages/fibroblasts

    PMID:12354379

    Open questions at the time
    • Did not resolve receptor-proximal events linking dsRNA binding to IRF3
    • Did not distinguish viral from endogenous ligand recognition
  2. 2004 High

    Resolved how TLR3 bifurcates signaling, showing tyrosine phosphorylation drives separable TBK1/IRF3 and PI3K/Akt branches, the latter required for full IRF3 activation and promoter binding.

    Evidence Tyrosine phosphosite mutagenesis, PI3K inhibition, and promoter-binding assays

    PMID:15502848

    Open questions at the time
    • Identity of the kinase phosphorylating TLR3 tyrosines not established
    • How PI3K recruitment is spatially organized at the receptor unclear
  3. 2006 High

    Demonstrated CNS-intrinsic TLR3 function by showing microglia mount poly(I:C) responses via TLR3, extending its role beyond classical immune cells.

    Evidence WT and TLR3-/- primary microglia and intracerebroventricular poly(I:C) injection

    PMID:16517751

    Open questions at the time
    • Endogenous CNS ligand not defined
    • Downstream effector program in microglia not fully mapped
  4. 2008 High

    Revealed a cell-surface, sequence-independent TLR3 activity by which long extracellular siRNAs suppress neovascularization, with a length threshold matching a modeled 2:1 receptor stoichiometry.

    Evidence Mouse CNV models, siRNA length series, TLR3/TRIF KO mice, and pharmacogenetic 412FF variant analysis

    PMID:18368052

    Open questions at the time
    • Mechanism coupling cell-surface TLR3 to anti-angiogenic effectors incomplete
    • Generality of surface vs endosomal signaling not resolved
  5. 2009 High

    Confirmed direct cell-surface TLR3 activation on endothelium, showing 21-nt but not 7-nt siRNA phosphorylates surface TLR3 and triggers apoptosis to suppress hem- and lymphangiogenesis.

    Evidence Mouse neovascularization models with surface TLR3 phosphorylation and internalization controls

    PMID:19359485

    Open questions at the time
    • Adaptor usage at the cell surface vs endosome not delineated
    • Apoptotic effector pathway not defined
  6. 2012 High

    Identified TLR3 as a sensor of UVB-damaged self-RNA acting as a DAMP, broadening its ligand repertoire to endogenous noncoding RNA driving sterile inflammation and UV immunosuppression.

    Evidence TLR3/TRIF KO mice, purified UVB-irradiated noncoding RNA stimulation, in vivo UVB model

    PMID:22772463

    Open questions at the time
    • Structural features of UVB-modified RNA recognized by TLR3 unclear
    • Whether other damaged self-RNAs share this activity unaddressed
  7. 2012 High

    Uncovered a TRIF/MyD88-independent branch in which dsRNA-bound TLR3 recruits c-Src to biphasically control migration, adhesion, and proliferation, decoupling some TLR3 outputs from canonical adaptors.

    Evidence Co-IP of Src with TLR3, lipid raft fractionation, TRIF/MyD88-deficient cells, migration/adhesion assays

    PMID:22323545

    Open questions at the time
    • Direct vs indirect TLR3-Src association not fully resolved
    • Physiological context of this branch in vivo unaddressed
  8. 2014 Medium

    Defined the post-translational and trafficking requirements for TLR3 activation: the ectodomain dictates plasma-membrane localization (UNC93B1-dependent), the TIR domain selects adaptors, and cathepsin cleavage yields associated N/C fragments both needed for signaling.

    Evidence Chimeric receptor and domain-deletion constructs, cleavage-site mapping, UNC93B1 manipulation, confocal localization

    PMID:24651829 PMID:25305318

    Open questions at the time
    • Functional consequence of cleavage for ligand binding vs signaling not separated
    • Surface vs endosomal pool contributions to signaling unresolved
  9. 2014 High

    Established TLR3-TRIF as a driver of cardiac ischemia-reperfusion injury via extracellular RNA, acting upstream of and independent of autocrine type I IFN.

    Evidence TLR3-/-, TRIF-/-, IFNAR1-/- I/R mouse models with RNase/DNase treatment and apoptosis readouts

    PMID:24390148

    Open questions at the time
    • Cell-death effector pathway downstream of TRIF in cardiomyocytes not detailed
    • Source and identity of injurious extracellular RNA not fully defined
  10. 2014 Medium

    Identified FYVE-domain adaptor WDFY1 as a positive regulator bridging TRIF recruitment to TLR3 (and TLR4), implicating endosomal phosphoinositide-binding proteins in signal assembly.

    Evidence Reciprocal co-IP with gain/loss-of-function reporter and cytokine assays

    PMID:25736436

    Open questions at the time
    • Whether WDFY1 acts at the receptor or adaptor level not fully resolved
    • Single-lab finding without in vivo validation
  11. 2015 High

    Showed S100A9 is required for maturation of TLR3-containing endosomes into late endosomes where TLR3 meets its dsRNA ligand, placing endosomal trafficking control upstream of signaling.

    Evidence S100A9-KO macrophages with colocalization microscopy, co-IP, endosomal fractionation, in vivo poly(I:C) challenge

    PMID:26385519

    Open questions at the time
    • Molecular basis of S100A9-TLR3 interaction not defined
    • Whether S100A9 acts generally for endosomal TLRs unaddressed
  12. 2015 Medium

    Identified additional accessory factors (ZCCHC3, scavenger receptor SREC-I) that facilitate TRIF recruitment and dsRNA-mediated TLR3 activation, refining the assembly machinery of the signaling complex.

    Evidence Co-IP, KO cells/mice, colocalization, and cytokine/reporter assays

    PMID:25641411 PMID:32133501

    Open questions at the time
    • Hierarchy and redundancy among accessory factors not established
    • Direct vs scaffolded interactions not fully resolved
  13. 2016 High

    Resolved a key signaling decision point by showing LUBAC engagement of the TLR3 complex routes signaling toward gene activation and restrains assembly of a death-inducing complex, with loss of LUBAC driving TLR3-dependent autoinflammatory pathology.

    Evidence Co-IP of LUBAC with TLR3 complex, LUBAC-deficient mice, and Tlr3/cpdm double-KO genetic epistasis

    PMID:27810922

    Open questions at the time
    • Molecular switch toggling gene-activation vs death complexes not fully defined
    • Ubiquitin linkage architecture on the TLR3 complex not resolved
  14. 2016 Medium

    Demonstrated non-immune developmental roles for TLR3, including MyD88-dependent control of neuronal dendritic arborization via DISC1 and RelA-dependent control of cardiomyocyte maturation gene expression.

    Evidence MyD88-KO epistasis and DISC1 rescue in neurons; TLR3 inhibition with RelA ChIP at maturation gene promoters

    PMID:27979975 PMID:29676038

    Open questions at the time
    • Ligand driving these developmental TLR3 functions unidentified
    • How a dsRNA receptor couples to developmental transcription unclear
  15. 2019 Medium

    Identified ZFYVE1 as a FYVE-domain factor that binds the TLR3 ectodomain and enhances ligand-binding affinity, providing a mechanism for positively tuning TLR3 antiviral signaling.

    Evidence Co-IP with domain mapping, ligand-binding affinity assays, and Zfyve1-/- mice

    PMID:31388100

    Open questions at the time
    • Structural mode of ZFYVE1-TLR3 binding not resolved
    • Relationship to WDFY1 function not clarified
  16. 2020 High

    Placed TLR3 in a pro-metastatic circuit, showing endogenous retroviral dsRNA activates endothelial TLR3 to induce SLIT2, which signals via ROBO1 on cancer cells to promote intravasation.

    Evidence Mouse tumor models, endothelial ribosome-tagging RNA-seq, endothelial Slit2 conditional KO, and dsRNA/TLR3 epistasis

    PMID:32999457

    Open questions at the time
    • Adaptor branch coupling endothelial TLR3 to SLIT2 transcription not defined
    • Therapeutic tractability of the axis unaddressed
  17. 2021 High

    Revealed a homeostatic function in which human TLR3 sustains constitutive basal IFN-β and baseline ISG expression, establishing a standing antiviral state in fibroblasts and cortical neurons against multiple virus families.

    Evidence TLR3-deficient human fibroblasts and iPSC-derived neurons, Tlr3-/- MEFs, IFN-β ELISA, ISG quantification, WT rescue

    PMID:33393505

    Open questions at the time
    • Endogenous ligand maintaining basal IFN-β not identified
    • How basal vs induced TLR3 signaling are distinguished mechanistically unclear
  18. 2022 High

    Provided the structural logic of TLR3 activation, showing cooperative homodimer clustering at 103 Å spacing along long dsRNA, with the TM/intracellular domains dispensable for clustering, explaining length-dependent signaling.

    Evidence Cryo-EM of full-length TLR3 with ~400-bp poly(I:C) plus domain-deletion validation

    PMID:36371424 PMID:36631495

    Open questions at the time
    • How ectodomain clustering templates intracellular adaptor assembly not directly visualized
    • Stoichiometry of TRIF recruitment per cluster unknown
  19. 2022 Medium

    Clarified how the TLR3 complex sustains inflammatory output, with ZBP1 delivering RIPK1 to TRIF and promoting RIPK1 M1-ubiquitination, and PKR cooperating with TLR3/TRIF to license caspase-8-dependent apoptosis.

    Evidence ZBP1-KO and PKR/TLR3-KO systems with RIPK1-TRIF interaction, ubiquitination, caspase-8, and in vivo readouts

    PMID:35666872 PMID:35970851

    Open questions at the time
    • Switch between inflammatory and apoptotic TRIF complexes not fully defined
    • In vivo relevance of PKR-TLR3 synergy beyond cell models unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ligand-induced ectodomain clustering is mechanically transmitted across the membrane to template ordered TRIF/LUBAC versus RIPK1/ZBP1 adaptor complexes — and what endogenous ligand sustains constitutive basal IFN-β and developmental TLR3 functions — remains unresolved.
  • No structure of the assembled intracellular TLR3-TRIF signaling complex
  • Endogenous ligand(s) for basal and developmental signaling unidentified
  • Determinants choosing gene-activation vs death outputs not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0060089 molecular transducer activity 3 GO:0038024 cargo receptor activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005764 lysosome 2 GO:0005768 endosome 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
S100A9SRCTRIFUNC93B1WDFY1ZBP1ZCCHC3ZFYVE1
Complex memberships
LUBAC (associated)TLR3-TRIF signaling complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 TLR3 and TLR4, but not TLR2 or TLR9, activate IRF3, which mediates a specific antiviral gene program including IFN-β induction; IRF3 confers TLR3/TLR4 specificity and selectively inhibits viral replication. Genetic loss-of-function, gene expression profiling, pathway epistasis in macrophages/fibroblasts Immunity High 12354379
2004 dsRNA-activated phosphorylation of two specific tyrosine residues of TLR3 is essential for initiating two distinct signaling pathways: one activating TBK-1 (leading to IRF-3 Ser/Thr phosphorylation) and one recruiting and activating PI3 kinase/Akt (required for full IRF-3 phosphorylation and target gene promoter binding). Without PI3K recruitment to TLR3, IRF-3 is only partially phosphorylated and fails to bind target gene promoters. Tyrosine phosphorylation site mutagenesis, PI3K inhibition, in vitro signaling assays, promoter binding assays Nature structural & molecular biology High 15502848
2008 TLR3 mediates sequence- and target-independent suppression of choroidal neovascularization by extracellular siRNAs (≥21 nt) acting on the cell surface. This requires TLR3 and its adaptor TRIF, and induces IFN-γ and IL-12. A minimum siRNA length of 21 nucleotides is required, consistent with a modeled 2:1 TLR3-RNA complex. The TLR3 coding variant 412FF renders endothelial cells refractory to extracellular siRNA-induced cytotoxicity. Mouse CNV models, siRNA length-series experiments, TLR3-deficient mice, TRIF-deficient mice, cell-surface TLR3 detection, pharmacogenetic variant analysis Nature High 18368052
2009 21-nt siRNA activates cell-surface TLR3 on lymphatic endothelial cells (phosphorylation of surface TLR3 demonstrated), induces apoptosis, and suppresses both hemangiogenesis and lymphangiogenesis in mouse models. A 7-nt siRNA too short to activate TLR3 has no such effect. siRNA is not internalized unless cell-permeating moieties are used. Mouse corneal suture and hindlimb ischemia neovascularization models, TLR3 phosphorylation assays, siRNA internalization controls, apoptosis assays Proceedings of the National Academy of Sciences of the United States of America High 19359485
2012 UVB-damaged self noncoding RNA (e.g., UVB-irradiated U1 RNA) is recognized by TLR3 (and adaptor TRIF) to induce TNF-α and IL-6 from keratinocytes and PBMCs. Tlr3-/- mice fail to upregulate TNF-α in skin after UVB exposure and lack UVB-induced immune suppression, establishing TLR3 as a sensor of UV-damaged self-RNA acting as a DAMP. TLR3 KO mice, purified noncoding RNA stimulation, whole-transcriptome sequencing, TRIF-deficient cells, in vivo UVB model Nature medicine High 22772463
2012 A TRIF-independent branch of TLR3 signaling, mediated by the proto-oncoprotein c-Src (which binds TLR3 after dsRNA stimulation), controls cell migration, adhesion, and proliferation in a biphasic manner: immediate increase in motility via Src phosphorylation/activation, followed by strong inhibition via Src sequestration in lipid rafts. MyD88 is also not required for this pathway. dsRNA stimulation, Src binding to TLR3 (co-IP), lipid raft fractionation, TLR3/TRIF/MyD88-deficient cells, cell migration and adhesion assays Journal of immunology High 22323545
2014 The N-terminal TLR3 ectodomain fragment (TLR3N, cleaved by cathepsins in endolysosomes starting at 343S) remains associated with the C-terminal fragment (TLR3C); both are required for dsRNA-induced activation of IFN-β and NF-κB promoters. Cell-surface TLR3 is highly expressed on splenic CD8+ DCs and marginal zone B cells in a UNC93B1-dependent manner. Cleavage site mapping, promoter activation assays with TLR3N/C domain deletion mutants, new monoclonal antibodies to mouse TLR3, flow cytometry, UNC93B1-deficient cells Journal of immunology High 25305318
2014 WDFY1 (WD repeat and FYVE domain-containing protein) is a crucial adaptor that interacts with TLR3 and TLR4 and mediates the recruitment of TRIF to these receptors. WDFY1 overexpression potentiates TLR3/4-mediated NF-κB, IRF3 activation and type I IFN production; WDFY1 depletion has the opposite effect. Co-immunoprecipitation, overexpression/knockdown, NF-κB/IRF3 reporter assays, cytokine ELISA EMBO reports Medium 25736436
2015 ZCCHC3 promotes TLR3-mediated signaling by facilitating the recruitment of TRIF to TLR3 after poly(I:C) stimulation. ZCCHC3 deficiency specifically inhibits TLR3- but not TLR4-mediated type I IFN and proinflammatory cytokine induction; Zcchc3-/- mice are more resistant to poly(I:C)-induced inflammatory death. Co-immunoprecipitation, overexpression/KO cells, Zcchc3-/- mice, cytokine assays Journal of molecular cell biology Medium 32133501
2019 ZFYVE1 (zinc-finger FYVE domain-containing protein, a guanylate-binding protein) interacts with TLR3 via its FYVE domain (binding the TLR3 ectodomain) and enhances TLR3 ligand (poly(I:C)) binding affinity, positively regulating TLR3-mediated antiviral signaling. Zfyve1-/- mice are less susceptible to poly(I:C)-induced inflammatory death. Co-IP, domain mapping, ligand-binding affinity assay, KO mice, gene expression assays Cellular & molecular immunology Medium 31388100
2015 S100A9 is required for maturation of TLR3-containing early endosomes (EE) into late endosomes (LE), enabling TLR3 to colocalize with and sense dsRNA ligands. S100A9 interacts with TLR3 following poly(I:C) treatment; in S100A9-KO macrophages, TLR3 cannot be detected in LE and fails to colocalize with poly(I:C), resulting in dramatically reduced cytokine production. S100A9 KO macrophages, co-localization microscopy, co-immunoprecipitation, endosomal fractionation, in vivo poly(I:C) challenge Journal of immunology High 26385519
2014 The ectodomain of TLR3 (not its transmembrane segment or cytosolic domain) is required for plasma membrane localization. UNC93B1 promotes TLR3 plasma membrane translocation and is itself localized at the plasma membrane. The cytosolic TIR domain determines engagement of signaling adaptors and potentiation by UNC93B1. Endocytosis and endosomal acidification are important for robust TLR3 signaling. TLR3/TLR9 chimeric receptor constructs, confocal microscopy localization, UNC93B1 overexpression, endosomal acidification inhibition PloS one Medium 24651829
2016 TLR3 activation of mesenchymal stromal cells (MSCs) increases Treg induction in co-cultures via cell-contact-dependent Notch signaling; this involves upregulation of the Notch ligand Delta-like 1 in TLR3-activated MSCs. Notch inhibition abrogates the augmented Treg levels, and TLR3 gene silencing abolishes the effect. MSC-lymphocyte co-culture, TLR3/TLR4 gene silencing, Notch inhibitor, gene expression analysis Stem cells Medium 27571579
2016 LUBAC components (SHARPIN, HOIL-1, HOIP) interact with the TLR3 signaling complex and are required for TLR3-mediated gene activation. Absence of LUBAC components increases formation of a TLR3-induced death-inducing signaling complex, leading to enhanced cell death. Excessive TLR3-mediated cell death driven by skin dsRNA is a major contributor to autoinflammatory skin phenotype in SHARPIN-deficient cpdm mice, as genetic TLR3 co-ablation substantially ameliorates cpdm dermatitis. Co-IP of LUBAC with TLR3 SC, LUBAC-deficient mice, Tlr3/cpdm double KO genetic epistasis, NF-κB/IRF3 activation assays The Journal of experimental medicine High 27810922
2016 TLR3 signals through MYD88 to negatively regulate Disc1 expression in neurons, causing impaired dendritic arborization; cytokines are not involved. TLR3 activation at neonatal stage also increases dendritic spine density but narrows spine heads at P21, indicating lasting spinogenesis effects. The dendritic arborization impairment is rescued by MYD88 deficiency or DISC1 overexpression. Cultured neurons and in vivo mouse brain studies (in utero electroporation), MYD88-deficient cells, DISC1 overexpression rescue, cytokine neutralization EMBO reports Medium 27979975
2018 TLR8, TLR7, and TLR3 each promote dendritic pruning via MYD88 signaling in neurons but induce different transcriptomic profiles. TLR7 and TLR3 (but not TLR8) also control axonal growth. MAPK signaling is specifically implicated in TLR8-mediated dendritic pruning. In vitro neuronal cultures, in utero electroporation, transcriptomic profiling, pathway analyses, TLR-specific agonist treatment The Journal of cell biology Medium 29777026
2018 TLR3 inhibition blocks cardiomyocyte maturation; committed precursor cells fail to express maturation genes and sarcomeres do not develop. TLR3's effect on cardiomyocyte maturation is dependent on the RelA subunit of NF-κB, which becomes enriched at promoters of cardiomyocyte maturation genes under conditions promoting cardiomyocyte development. TLR3 inhibition, NF-κB RelA knockdown/analysis, chromatin immunoprecipitation for NF-κB at maturation gene promoters, cardiac differentiation assays Stem cells Medium 29676038
2019 Angiotensin II-induced hypertension requires the TLR3-TRIF pathway but not TLR4, while cardiac hypertrophy requires both TLR3-TRIF and TLR4-TRIF pathways, demonstrating nonredundant roles for these two TLRs downstream of TRIF. TLR3-/- and TLR4-/- mice, ANG II infusion model, blood pressure and cardiac hypertrophy measurements, proinflammatory gene expression in heart and kidney American journal of physiology. Heart and circulatory physiology Medium 30793936
2020 Double-stranded RNA (including endogenous retroviral element RNAs upregulated in metastatic tumor cells) activates TLR3 on endothelial cells to induce SLIT2 expression, which in turn signals via ROBO1 on cancer cells to promote intravasation and metastasis. Deletion of endothelial Slit2 suppresses metastasis. Mouse breast/lung cancer models, endothelial ribosome-tagging/RNA-seq, endothelial Slit2 conditional KO, dsRNA/TLR3 epistasis experiments Nature High 32999457
2021 Human TLR3 controls constitutive (basal) levels of IFNB mRNA and secreted IFN-β protein in fibroblasts and iPSC-derived cortical neurons, thereby maintaining baseline ISG expression. TLR3-deficient fibroblasts and cortical neurons are vulnerable to multiple virus families, not just HSV-1, due to loss of basal IFN-β immunity. Tlr3-/- mouse embryonic fibroblasts also have lower basal ISG levels. TLR3-deficient human fibroblasts and iPSC-derived cortical neurons, Tlr3-/- MEFs, IFN-β protein measurement (ELISA), ISG mRNA quantification, viral susceptibility assays, WT TLR3 rescue The Journal of clinical investigation High 33393505
2022 Cryo-EM structure of full-length TLR3 complexed with ~400-bp poly(I:C) reveals that TLR3 homodimers cluster along the dsRNA helix in a highly organized, cooperative fashion with a uniform inter-dimer spacing of 103 Å. The intracellular and transmembrane domains are dispensable for cluster formation; ligand-induced clustering is proposed to drive ordered assembly of intracellular signaling adaptors for robust signaling. Cryo-electron microscopy structural determination of full-length TLR3 + long dsRNA complex; deletion mutant analysis confirming transmembrane/intracellular domains dispensable for clustering Nature communications High 36371424
2023 Cryo-EM analyses show that TLR3 dimers laterally form a higher-order multimeric complex along longer dsRNA (beyond the minimum 40-50 bp for dimerization), providing the structural basis for cooperative binding and explaining the length-dependent activation of TLR3. Cryo-electron microscopy of TLR3 in complex with longer dsRNA Nature communications High 36631495
2022 ZBP1 promotes the timely delivery of RIPK1 to the TLR3/4 adaptor TRIF and M1-ubiquitination of RIPK1, sustaining inflammatory signaling downstream of TLR3. Zbp1-/- mice show reduced TLR3-mediated inflammatory responses and prolonged survival in septic shock. ZBP1 KO mice, RIPK1-TRIF interaction assays, ubiquitination assays, in vivo LPS-induced septic shock model Proceedings of the National Academy of Sciences of the United States of America Medium 35666872
2022 PKR and TLR3 trigger distinct signals that synergize to induce rapid apoptosis in response to intracellular long dsRNA. PKR induces translational arrest reducing cellular FLICE-inhibitory protein levels, which then enables TLR3/TRIF-dependent caspase-8 activation; both PKR and TLR3 are essential for virus-induced apoptosis and arrest of viral production. Cytoplasmic RNA injection, PKR KO and TLR3 KO cells, caspase-8 activation assays, translational arrest measurements, apoptosis quantification Cell death & disease Medium 35970851
2014 Extracellular RNA released during myocardial ischemia-reperfusion (I/R) activates TLR3-TRIF signaling to promote cardiomyocyte apoptosis and cardiac injury, independent of inflammatory cytokine production and neutrophil recruitment. RNase (but not DNase) treatment reduces serum RNA levels and confers cardiac protection. IFNAR1 deletion had no effect on infarct size, placing this TLR3-TRIF pathway's injurious effect upstream of autocrine type I IFN. TLR3-/-, TRIF-/-, IFNAR1-/- mouse I/R models, infarct size measurement, apoptosis quantification, RNase/DNase in vivo treatment, cardiomyocyte necrosis RNA stimulation assays Journal of the American Heart Association High 24390148
2011 PLIC-1 (ubiquilin 1) is a negative regulator of TLR3-TRIF signaling. PLIC-1 interacts with TRIF (confirmed by co-IP and GST pull-down), colocalizes with TRIF and autophagosome marker LC3, and reduces TRIF protein abundance in a Nocodazole-sensitive manner; shRNA knockdown of PLIC-1 enhances TLR3 activation. Yeast-two-hybrid, co-IP, GST pull-down, shRNA knockdown, confocal microscopy, luciferase reporter assay PloS one Medium 21695056
2014 Scavenger receptor SREC-I directly interacts with TLR3 in the presence of poly(I:C) and co-localizes with TLR3 and internalized dsRNA in endosomes, promoting dsRNA-mediated TLR3 activation through NFκB, MAPK, and IRF3 pathways and enhancing cytokine (IL-8, IFN-β) production in macrophages. Co-IP of SREC-I with TLR3, confocal colocalization, cytokine ELISA, NFκB/IRF3 activation assays in THP1 cells and BMDMs Immunobiology Medium 25641411
2015 TLR3 activation in keratinocytes drives IRF6-dependent IL-23p19 expression and formation of a novel IL-23p19/EBI3 heterodimer (confirmed by co-IP and proximity ligation assay). IRF6 silencing inhibits poly(I:C)-inducible IL-23p19 but enhances IFN-β expression. Co-expression of IL-23p19 and EBI3 increases secreted IL-23p19 levels. siRNA silencing of IRF6, reporter assays, co-immunoprecipitation, proximity ligation assay, cytokine secretion measurement in primary keratinocytes Immunology and cell biology Medium 26303210
2013 TLR3 activation by poly(I:C) induces upregulation of miR-29b, -29c, -148b, and -152, which target DNA methyltransferases, leading to demethylation and re-expression of the oncosuppressor RARβ; cancer cells then become sensitive to retinoic acid and undergo apoptosis both in vitro and in vivo. miRNA profiling, luciferase reporter assays, DNA methylation assays, in vitro and in vivo tumor models, RARβ expression rescue Proceedings of the National Academy of Sciences of the United States of America Medium 23716670
2006 Microglia recognize dsRNA through TLR3 and mount an innate immune response; TLR3-/- microglia show diminished cytokine secretion and delayed MAPK activation in response to poly(I:C). In vivo intracerebroventricular poly(I:C) injection causes microgliosis in WT but not TLR3-/- mice. Primary cultured WT and TLR3-/- microglia, poly(I:C) stimulation, MAPK activation time-course, ICV injection in vivo model, cell surface marker immunofluorescence Journal of immunology High 16517751
2009 MDA5 and TLR3 activate NK cells indirectly through different accessory cell types: MDA5 acts primarily through stromal cells inducing IFN-α, while TLR3 acts predominantly through hematopoietic cells inducing IL-12. TLR3 has a minor independent role; MDA5 is the primary driver of poly(I:C)-mediated NK cell activation. MDA5-/-, TLR3-/-, MDA5-/-TLR3-/- mice, bone marrow chimeras, NK cell activation assays, cytokine measurement The Journal of experimental medicine High 19995959
2017 RKIP preferentially regulates TLR3-mediated (but not TLR4 or TLR9-mediated) immune responses by interacting with TBK1 and promoting TBK1/IRF3 activation, and by enhancing interaction between TAK1 and MKK3, promoting p38 activation. Poly(I:C) but not LPS induces RKIP phosphorylation at S109, required for these TBK1- and MKK3-activating functions. RKIP KO mice, co-IP, phosphorylation site mutagenesis (S109), IRF3/p38 activation assays, cytokine production assays, TLR specificity comparison Journal of immunology Medium 28411188
2021 RNase T2 in endosomes/lysosomes negatively regulates TLR3 responses in macrophages: RNase T2 degrades dsRNA, and RNase T2-deficient macrophages show upregulated TLR3 responses. Enzymatic mutants demonstrate a positive correlation between RNA degradation activity and rescue of altered TLR responses, indicating degradation is mechanistically responsible. RNase T2-deficient macrophages, enzymatic mutant analysis, RNA degradation assays, TLR3/TLR7 response assays, colocalization of RNase T2 with poly(I:C) International immunology Medium 34161582

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 739 18368052
2002 IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 681 12354379
2008 TLR3: interferon induction by double-stranded RNA including poly(I:C). Advanced drug delivery reviews 565 18262679
2012 Ultraviolet radiation damages self noncoding RNA and is detected by TLR3. Nature medicine 331 22772463
2004 Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling. Nature structural & molecular biology 290 15502848
2005 Transcriptional signaling by double-stranded RNA: role of TLR3. Cytokine & growth factor reviews 203 15733829
2010 Study of TLR3, TLR4 and TLR9 in breast carcinomas and their association with metastasis. BMC cancer 194 21129170
2021 Toll-like receptor 3 (TLR3) regulation mechanisms and roles in antiviral innate immune responses. Journal of Zhejiang University. Science. B 181 34414698
2009 Distinct and complementary functions of MDA5 and TLR3 in poly(I:C)-mediated activation of mouse NK cells. The Journal of experimental medicine 173 19995959
2005 TLR3 in antiviral immunity: key player or bystander? Trends in immunology 172 16027039
2006 Microglia recognize double-stranded RNA via TLR3. Journal of immunology (Baltimore, Md. : 1950) 162 16517751
2021 TLR3 and TLR7 RNA Sensor Activation during SARS-CoV-2 Infection. Microorganisms 152 34576716
2011 Antiviral responses induced by the TLR3 pathway. Reviews in medical virology 146 21312311
2013 TLR3 immunity to infection in mice and humans. Current opinion in immunology 142 23290562
2005 TLR3-induced activation of mast cells modulates CD8+ T-cell recruitment. Blood 138 15840693
2014 Role of extracellular RNA and TLR3-Trif signaling in myocardial ischemia-reperfusion injury. Journal of the American Heart Association 135 24390148
2009 Small interfering RNA-induced TLR3 activation inhibits blood and lymphatic vessel growth. Proceedings of the National Academy of Sciences of the United States of America 128 19359485
2020 Tumoural activation of TLR3-SLIT2 axis in endothelium drives metastasis. Nature 123 32999457
2010 Study of TLR3, TLR4, and TLR9 in prostate carcinomas and their association with biochemical recurrence. Cancer immunology, immunotherapy : CII 122 20978888
2016 TLR3 or TLR4 Activation Enhances Mesenchymal Stromal Cell-Mediated Treg Induction via Notch Signaling. Stem cells (Dayton, Ohio) 119 27571579
2014 dsRNA-activation of TLR3 and RLR signaling: gene induction-dependent and independent effects. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 116 24905199
2011 Overexpression of TLR3, TLR4, TLR7 and TLR9 in esophageal squamous cell carcinoma. World journal of gastroenterology 108 21990957
2008 Upregulation of the TLR3 pathway by Kaposi's sarcoma-associated herpesvirus during primary infection. Journal of virology 108 18367536
2011 MDA5 and TLR3 initiate pro-inflammatory signaling pathways leading to rhinovirus-induced airways inflammation and hyperresponsiveness. PLoS pathogens 105 21637773
2021 TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons. The Journal of clinical investigation 90 33393505
2020 Trial watch: TLR3 agonists in cancer therapy. Oncoimmunology 89 32934877
2015 WDFY1 mediates TLR3/4 signaling by recruiting TRIF. EMBO reports 79 25736436
2016 --LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation. The Journal of experimental medicine 77 27810922
2008 Inhibition of TLR3 and TLR4 function and expression in human dendritic cells by helminth parasites. Blood 76 18541719
2016 Immune biomarkers PD-1/PD-L1 and TLR3 in malignant pleural mesotheliomas. Human pathology 71 26980049
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
2008 TLR3 and TLR4 expression in healthy and diseased human endometrium. Reproductive biology and endocrinology : RB&E 66 18775079
2018 TLR3 agonist and CD40-targeting vaccination induces immune responses and reduces HIV-1 reservoirs. The Journal of clinical investigation 65 30148455
2017 Chronic ethanol consumption: role of TLR3/TRIF-dependent signaling. Addiction biology 64 28840972
2019 Angiotensin II-induced hypertension and cardiac hypertrophy are differentially mediated by TLR3- and TLR4-dependent pathways. American journal of physiology. Heart and circulatory physiology 59 30793936
2018 Endosomal TLR3, TLR7, and TLR8 control neuronal morphology through different transcriptional programs. The Journal of cell biology 59 29777026
2005 TLR3 activation inhibits human mast cell attachment to fibronectin and vitronectin. Molecular immunology 59 16280166
2021 TLR3 agonists: RGC100, ARNAX, and poly-IC: a comparative review. Immunologic research 58 34145551
2015 TLR3 triggering regulates PD-L1 (CD274) expression in human neuroblastoma cells. Cancer letters 57 25697485
2013 Toll-like receptor 3 (TLR3) activation induces microRNA-dependent reexpression of functional RARβ and tumor regression. Proceedings of the National Academy of Sciences of the United States of America 57 23716670
2015 EBV-encoded RNA via TLR3 induces inflammation in nasopharyngeal carcinoma. Oncotarget 55 26172457
2014 TLR3 and MDA5 signalling, although not expression, is impaired in asthmatic epithelial cells in response to rhinovirus infection. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 55 24131248
2015 TLR3 agonist and Sorafenib combinatorial therapy promotes immune activation and controls hepatocellular carcinoma progression. Oncotarget 54 26287667
2015 TLR3 drives IRF6-dependent IL-23p19 expression and p19/EBI3 heterodimer formation in keratinocytes. Immunology and cell biology 50 26303210
2016 TLR3 Agonist Poly-IC Induces IL-33 and Promotes Myelin Repair. PloS one 49 27022724
2014 TLR3 plays significant roles against hepatitis B virus. Molecular biology reports 48 24477590
2022 TLR3 forms a highly organized cluster when bound to a poly(I:C) RNA ligand. Nature communications 46 36371424
2015 Interferon-Gamma Enhances TLR3 Expression and Anti-Viral Activity in Keratinocytes. The Journal of investigative dermatology 45 25822580
2012 TLR3/TICAM-1 signaling in tumor cell RIP3-dependent necroptosis. Oncoimmunology 45 23162759
2017 LncRNA CRNDE triggers inflammation through the TLR3-NF-κB-Cytokine signaling pathway. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 42 28621230
2016 Apolipoproteins L control cell death triggered by TLR3/TRIF signaling in dendritic cells. European journal of immunology 42 27198486
2014 Roles of the cleaved N-terminal TLR3 fragment and cell surface TLR3 in double-stranded RNA sensing. Journal of immunology (Baltimore, Md. : 1950) 42 25305318
2010 Dissecting TLR3 signalling in dendritic cells. Immunobiology 42 20561711
2023 TLR3 forms a laterally aligned multimeric complex along double-stranded RNA for efficient signal transduction. Nature communications 41 36631495
2017 Functional failure of TLR3 and its signaling components contribute to herpes simplex encephalitis. Journal of neuroimmunology 41 29305044
2016 TLR3 downregulates expression of schizophrenia gene Disc1 via MYD88 to control neuronal morphology. EMBO reports 41 27979975
2018 Cardiomyocyte Maturation Requires TLR3 Activated Nuclear Factor Kappa B. Stem cells (Dayton, Ohio) 39 29676038
2017 TLR4 signaling induces TLR3 up-regulation in alveolar macrophages during acute lung injury. Scientific reports 39 28198368
2023 Extracellular RNAs-TLR3 signaling contributes to cognitive impairment after chronic neuropathic pain in mice. Signal transduction and targeted therapy 36 37544956
2019 A Toll-like receptor 3 (TLR3) agonist ARNAX for therapeutic immunotherapy. Advanced drug delivery reviews 36 31302192
2015 Regulation of TLR3 Activation by S100A9. Journal of immunology (Baltimore, Md. : 1950) 34 26385519
2009 Characterization of equine and other vertebrate TLR3, TLR7, and TLR8 genes. Immunogenetics 34 19568743
2023 A novel defined TLR3 agonist as an effective vaccine adjuvant. Frontiers in immunology 32 36761735
2021 Inborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis. The Journal of experimental medicine 32 34726731
2015 Both MicroRNA-155 and Virus-Encoded MiR-155 Ortholog Regulate TLR3 Expression. PloS one 32 25938551
2009 TLR3 gene polymorphisms and liver disease manifestations in chronic hepatitis C. Journal of medical virology 32 19475618
2009 TLR3 activation inhibits nasopharyngeal carcinoma metastasis via downregulation of chemokine receptor CXCR4. Cancer biology & therapy 32 19652552
2014 FAAH-mediated modulation of TLR3-induced neuroinflammation in the rat hippocampus. Journal of neuroimmunology 31 25245162
2012 A TRIF-independent branch of TLR3 signaling. Journal of immunology (Baltimore, Md. : 1950) 31 22323545
2011 Differential toll-like receptor 3 (TLR3) expression and apoptotic response to TLR3 agonist in human neuroblastoma cells. Journal of biomedical science 31 21861882
2017 Association of TLR3 L412F Polymorphism with Cytomegalovirus Infection in Children. PloS one 28 28046022
2009 TLR3 in human eosinophils: functional effects and decreased expression during allergic rhinitis. International archives of allergy and immunology 28 19752565
2020 ZCCHC3 modulates TLR3-mediated signaling by promoting recruitment of TRIF to TLR3. Journal of molecular cell biology 27 32133501
2018 TLR2 and TLR3 expression as a biomarker for the risk of doxorubicin-induced heart failure. Toxicology letters 27 29959987
2023 The effect of TLR3 priming conditions on MSC immunosuppressive properties. Stem cell research & therapy 26 38031182
2015 Necrosis-induced TLR3 Activation Promotes TLR2 Expression in Gingival Cells. Journal of dental research 26 26045329
2014 Scavenger receptor SREC-I promotes double stranded RNA-mediated TLR3 activation in human monocytes. Immunobiology 25 25641411
2019 TLR3 absence confers increased survival with improved macrophage activity against pneumonia. JCI insight 24 31801911
2018 TRIM56 Suppresses Multiple Myeloma Progression by Activating TLR3/TRIF Signaling. Yonsei medical journal 24 29214775
2020 Shock waves promote spinal cord repair via TLR3. JCI insight 23 32759498
2017 Raf Kinase Inhibitor Protein Preferentially Promotes TLR3-Triggered Signaling and Inflammation. Journal of immunology (Baltimore, Md. : 1950) 23 28411188
2015 Toll-like receptor 3 (TLR3) and the development of type 1 diabetes mellitus. Archives of endocrinology and metabolism 22 25926108
2014 Mannan binding lectin attenuates double-stranded RNA-mediated TLR3 activation and innate immunity. FEBS letters 22 24530528
2013 Targeting TLR3 with no RIG-I/MDA5 activation is effective in immunotherapy for cancer. Expert opinion on therapeutic targets 22 23414438
2012 Association of TLR3-hyporesponsiveness and functional TLR3 L412F polymorphism with recurrent herpes labialis. Human immunology 22 22537752
2022 PKR and TLR3 trigger distinct signals that coordinate the induction of antiviral apoptosis. Cell death & disease 21 35970851
2018 ACTG1 and TLR3 are biomarkers for alcohol-associated hepatocellular carcinoma. Oncology letters 21 30675230
2021 Contemporary evolution of the innate immune receptor gene TLR3 in an isolated vertebrate population. Molecular ecology 20 33949028
2012 TLR3 dsRNA agonist inhibits growth and invasion of HepG2.2.15 HCC cells. Oncology reports 19 22552584
2021 Skewed endosomal RNA responses from TLR7 to TLR3 in RNase T2-deficient macrophages. International immunology 18 34161582
2020 Characterization, expression and function analysis of the TLR3 gene in golden pompano (Trachinotus ovatus). Developmental and comparative immunology 18 33340590
2019 The zinc-finger protein ZFYVE1 modulates TLR3-mediated signaling by facilitating TLR3 ligand binding. Cellular & molecular immunology 18 31388100
2018 Association between Toll-Like Receptor 3 (TLR3) rs3775290, TLR7 rs179008, TLR9 rs352140 and Chronic HCV. Immunological investigations 18 30321082
2022 Pan-Caspase Inhibitor zVAD Induces Necroptotic and Autophagic Cell Death in TLR3/4-Stimulated Macrophages. Molecules and cells 17 34949739
2020 Migration of murine intestinal dendritic cell subsets upon intrinsic and extrinsic TLR3 stimulation. European journal of immunology 17 32383212
2014 The ectodomain of TLR3 receptor is required for its plasma membrane translocation. PloS one 17 24651829
2011 The ubiquitin-like protein PLIC-1 or ubiquilin 1 inhibits TLR3-Trif signaling. PloS one 17 21695056
2020 DEF Cell-Derived Exosomal miR-148a-5p Promotes DTMUV Replication by Negative Regulating TLR3 Expression. Viruses 16 31947624
2015 Astroglial control of neuroinflammation: TLR3-mediated dsRNA-sensing pathways are in the focus. Reviews in the neurosciences 16 25528762
2013 TLR3 impairment in human newborns. Journal of leukocyte biology 16 23901120

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