Toll-like receptor 3 (TLR3, CD283) is a type I transmembrane pattern recognition receptor for double-stranded RNA, a molecular signature of viral replication. Its luminal ectodomain of 23 leucine-rich repeats binds dsRNA of at least 40-50 bp at acidic pH through two sites at opposite ends of the horseshoe (LRR1-3 and LRR17-20, including His539 and Asn541), and ligand binding brings two receptors together into a dimer, the minimal signalling unit. Newly made TLR3 resides in the endoplasmic reticulum and is carried by the chaperone UNC93B1 through the Golgi to endosomes, where cathepsin cleavage generates the signalling-competent receptor; recognition takes place in acidified endosomes/endolysosomes, although some cells also display TLR3 at the cell surface. Unlike the other TLRs, TLR3 does not use MyD88: its cytoplasmic TIR domain recruits the adaptor TRIF (TICAM1), which activates TBK1/IKK-epsilon and IRF3 to induce type I and type III interferons, and RIPK1/TRAF6/TAK1 to activate NF-kappaB and MAP kinases for inflammatory cytokine production; when caspase-8 or cIAPs are inhibited the same route can trigger RIPK3-dependent necroptosis. TLR3 signalling is terminated by c-Src/ZNRF1-mediated ubiquitination and lysosomal degradation. TLR3 is widely expressed, including in fibroblasts, epithelial cells, dendritic cells and CNS-resident cells. Human inherited TLR3 deficiency causes susceptibility to herpes simplex encephalitis and severe influenza pneumonitis, showing that TLR3 is dispensable for defence against most pathogens but essential for cell-intrinsic interferon responses to particular viruses in the CNS and lung.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-1678927 | KEEP AS NON CORE | Summary: TLR3 transits the Golgi apparatus on its way from the ER to endosomes, carried by UNC93B1. Reason: Correct as a biosynthetic transit location: newly made TLR3 passes through the ER and Golgi before reaching endosomes, where it is cleaved and signals. The Golgi is not where TLR3 senses dsRNA or signals, so the location is kept as non-core. Supporting Evidence: PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-1678998 | KEEP AS NON CORE | Summary: TLR3 transits the Golgi apparatus on its way from the ER to endosomes, carried by UNC93B1. Reason: Correct as a biosynthetic transit location: newly made TLR3 passes through the ER and Golgi before reaching endosomes, where it is cleaved and signals. The Golgi is not where TLR3 senses dsRNA or signals, so the location is kept as non-core. Supporting Evidence: PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved |
| GO:0000165 MAPK cascade | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TLR3 engagement by dsRNA activates MAP kinases downstream of TRIF. Reason: Mouse-to-human Ensembl Compara transfer. MAPK activation is a documented output of TLR3 signalling in human cells (IRAK4-independent in fibroblasts), but TLR3 is the receptor that initiates the pathway, not a component of the kinase cascade itself. Kept as a non-core downstream process; GO:0034138 captures the receptor's role. Supporting Evidence: PMID:16286015 Our findings thus indicate that the activation of IRF-3, NF-ΞΊB, and MAPK is IRAK-4 independent in human fibroblasts in response to poly(I:C) stimulation. |
| GO:0002224 toll-like receptor signaling pathway | IDA PMID:18172197 The TLR3 signaling complex forms by cooperative receptor dim... | MODIFY | Summary: TLR3 is the receptor of a Toll-like receptor signalling pathway; the specific child term for TLR3 exists. Reason: Correct but too general. The paper defines how dsRNA binding by the TLR3 ectodomain drives receptor dimerization into the minimal signalling unit, which is the initiating event of the TLR3-specific pathway. GO:0034138 toll-like receptor 3 signaling pathway is the precise term and is already asserted from the same paper. Proposed replacements: toll-like receptor 3 signaling pathway Supporting Evidence: PMID:18172197 We conclude that TLR3 assembles on dsRNA as stable dimers and that the minimal signaling unit is one TLR3 dimer. |
| GO:0002682 regulation of immune system process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Very general ARBA-derived immune regulation term. Reason: Not wrong - TLR3 signalling shapes innate and adaptive immune responses - but uninformative relative to the receptor and pathway terms the gene carries. Retained as non-core rather than removed because the machine-learning rule is broadly consistent with the biology. Supporting Evidence: PMID:12054664 TLR3 recognized dsRNA to activate NF-kappaB and the IFN-beta promoter |
| GO:0003725 double-stranded RNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: TLR3 binds double-stranded RNA through its leucine-rich repeat ectodomain; this is its ligand-recognition activity. Reason: Core function. The IBA node places dsRNA binding on the TLR3 clade; human TLR3 has direct binding data (saturable, specific binding of dsRNA to the ectodomain, with defined binding-site residues H539 and N541). The appearance of TLR3 itself among the IBA sources reflects its own experimental grounding. Supporting Evidence: PMID:18172197 dsRNA binds saturably, specifically, and reversibly to a defined ligand-binding site (or sites) on the TLR3 ectodomain PMID:16720699 only two, H539E and N541A, resulted in the loss of TLR3 activation and ligand binding functions |
| GO:0003725 double-stranded RNA binding | IDA PMID:16111635 Suppression of RNA recognition by Toll-like receptors: the i... | ACCEPT | Summary: RNA lacking nucleoside modifications signals through human TLR3. Reason: The cached record is abstract-only; the abstract shows RNA signalling through TLR3 rather than a binding assay, but dsRNA binding by TLR3 is independently established by direct binding and mutagenesis studies. Deferring to the curator on the full text. Supporting Evidence: PMID:16111635 We show that RNA signals through human TLR3, TLR7, and TLR8 file:human/TLR3/TLR3-deep-research-falcon.md The receptor binds dsRNA through its leucine-rich repeat (LRR) ectodomain, which contacts the ribose-phosphate backbone in the minor grooves of the RNA helix PMID:18172197 dsRNA binds saturably, specifically, and reversibly to a defined ligand-binding site (or sites) on the TLR3 ectodomain |
| GO:0003725 double-stranded RNA binding | NAS PMID:12054664 Establishment of a monoclonal antibody against human Toll-li... | ACCEPT | Summary: dsRNA recognition by TLR3 in reporter assays; the antibody blocks dsRNA-induced signalling. Reason: Consistent with direct binding evidence. The paper itself left open whether binding was direct, but later biochemistry settled it. Supporting Evidence: PMID:12054664 TLR3 recognized dsRNA to activate NF-kappaB and the IFN-beta promoter PMID:18172197 dsRNA binds saturably, specifically, and reversibly to a defined ligand-binding site (or sites) on the TLR3 ectodomain |
| GO:0004888 transmembrane signaling receptor activity | IDA PMID:12471095 Cutting edge: a novel Toll/IL-1 receptor domain-containing a... | ACCEPT | Summary: TLR3 is a single-pass transmembrane receptor that transduces dsRNA recognition across the endosomal membrane to the adaptor TRIF. Reason: Core function. The TRIF identification paper shows TLR3-dependent NF-kappaB and IFN-beta promoter activation through TRIF, and TRIF associating with TLR3. TLR3 has a luminal LRR ectodomain, one transmembrane helix and a cytoplasmic TIR domain, the architecture of a transmembrane signalling receptor. Supporting Evidence: PMID:12471095 Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters. PMID:12471095 TRIF associated with TLR3 and IFN regulatory factor 3. |
| GO:0004888 transmembrane signaling receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic transfer of transmembrane signaling receptor activity. Reason: Consistent with the experimental evidence for human TLR3. Supporting Evidence: PMID:12471095 Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters. |
| GO:0004888 transmembrane signaling receptor activity | NAS PMID:12054664 Establishment of a monoclonal antibody against human Toll-li... | ACCEPT | Summary: Author statement that TLR3 is a dsRNA-signalling receptor. Reason: Consistent with the experimental evidence. Supporting Evidence: PMID:12054664 TLR3 recognized dsRNA to activate NF-kappaB and the IFN-beta promoter |
| GO:0005515 protein binding | IPI PMID:16858407 Toll-like receptor 3 associates with c-Src tyrosine kinase o... | REMOVE | Summary: Interaction with PIK3R1 (p85 regulatory subunit of PI3K) reported in IntAct from the c-Src paper. Reason: Generic protein binding is uninformative. The cached record is abstract-only and the abstract concerns recruitment of c-Src to TLR3; it does not describe the PIK3R1 interaction, so no more informative activity can be justified from it. Removal does not dispute the interaction. Supporting Evidence: PMID:16858407 c-Src tyrosine kinase is activated by dsRNA in human monocyte-derived dendritic cells, and is recruited to TLR3 in a dsRNA-dependent manner |
| GO:0005515 protein binding | IPI PMID:25736436 WDFY1 mediates TLR3/4 signaling by recruiting TRIF. | REMOVE | Summary: Interaction with the adaptor TRIF (TICAM1), enhanced by WDFY1. Reason: Generic protein binding is uninformative. Recruitment of TRIF is part of TLR3's transmembrane signalling receptor activity, which is captured by GO:0004888. The cached text does not map the interaction to specific domains, so a TIR-domain binding term is not asserted from it. Removal does not dispute the interaction. Supporting Evidence: PMID:25736436 Engagement of TLR3 by double-stranded RNA (dsRNA) causes dimerization and tyrosine phosphorylation of TLR3, which then recruits TRIF PMID:25736436 WDFY1 interacts with TLR3 and TLR4 and mediates the recruitment of TRIF to these receptors. |
| GO:0005515 protein binding | IPI PMID:25736436 WDFY1 mediates TLR3/4 signaling by recruiting TRIF. | REMOVE | Summary: Interaction with WDFY1, an endosomal FYVE-domain protein that bridges TLR3 and TRIF. Reason: Generic protein binding is uninformative and no specific TLR3 activity follows from the interaction; WDFY1 is the bridging factor. Removal does not dispute the interaction. Supporting Evidence: PMID:25736436 WDFY1 interacts with TLR3 and TLR4 and mediates the recruitment of TRIF to these receptors. |
| GO:0005515 protein binding | IPI PMID:33432245 Cryo-EM structures of Toll-like receptors in complex with UN... | REMOVE | Summary: Cryo-EM structure of TLR3 bound to its trafficking chaperone UNC93B1. Reason: Generic protein binding is uninformative. TLR3 is the client of UNC93B1; the relevant biology (UNC93B1-dependent ER exit) is a location and trafficking matter, not an activity of TLR3. Removal does not dispute the interaction. Supporting Evidence: PMID:33432245 Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions |
| GO:0005737 cytoplasm | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | KEEP AS NON CORE | Summary: Intracellular TLR3 staining in cultured melanocytes. Reason: Correct in the broad sense (GO cytoplasm includes the endomembrane system) but uninformative: TLR3 is an integral membrane protein of the ER and endosomes, which the gene carries as specific terms. The cached record is abstract-only. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | KEEP AS NON CORE | Summary: Found in a proteomic survey of placental lysosomal membranes. Reason: Plausible: signalling-competent TLR3 resides in acidic endolysosomes and is later sorted to lysosomes for degradation. The high-throughput identification does not distinguish signalling from degradation, so it is kept as non-core. Supporting Evidence: PMID:17897319 In membranes purified from placental lysosomes, we identified 58 proteins PMID:37158982 c-Src kinase activated by TLR3 engagement phosphorylates ZNRF1 at tyrosine 103, which mediates K63-linked ubiquitination of TLR3 at lysine 813 and promotes TLR3 lysosomal trafficking and degradation |
| GO:0005769 early endosome | EXP PMID:25736436 WDFY1 mediates TLR3/4 signaling by recruiting TRIF. | ACCEPT | Summary: TLR3 in early endosomes, where it recruits TRIF via WDFY1. Reason: Consistent with dsRNA-induced movement of TLR3 from the ER to endosomes and with its colocalisation with the early endosome marker EEA1 after poly(I:C). The cached full text is partial; UniProt cites this paper for the early endosome location. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:37158982 suggesting that ZNRF1 is not involved in TLR3 transport from the ER to endosomes but controls its trafficking beyond the early endosome |
| GO:0005769 early endosome | IDA PMID:17982077 Spatiotemporal mobilization of Toll/IL-1 receptor domain-con... | ACCEPT | Summary: TLR3 transiently colocalises with TICAM1 in response to dsRNA. Reason: TLR3 is active in early endosomes after dsRNA uptake, where it recruits TRIF before TRIF forms signalling speckles. Supporting Evidence: PMID:17982077 a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA |
| GO:0005769 early endosome | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping to early endosome. Reason: Consistent with experimental data. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: TLR3 resides in the ER membrane before UNC93B1-dependent export to endosomes. Reason: The ER is the steady-state location of newly synthesised, unstimulated TLR3 and the site of its association with UNC93B1. It is a biosynthetic rather than a signalling compartment, but it is a well-established location of the protein. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1678921 | ACCEPT | Summary: TLR3 resides in the ER membrane before UNC93B1-dependent export to endosomes. Reason: The ER is the steady-state location of newly synthesised, unstimulated TLR3 and the site of its association with UNC93B1. It is a biosynthetic rather than a signalling compartment, but it is a well-established location of the protein. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1678998 | ACCEPT | Summary: TLR3 resides in the ER membrane before UNC93B1-dependent export to endosomes. Reason: The ER is the steady-state location of newly synthesised, unstimulated TLR3 and the site of its association with UNC93B1. It is a biosynthetic rather than a signalling compartment, but it is a well-established location of the protein. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-5607838 | ACCEPT | Summary: TLR3 resides in the ER membrane before UNC93B1-dependent export to endosomes. Reason: The ER is the steady-state location of newly synthesised, unstimulated TLR3 and the site of its association with UNC93B1. It is a biosynthetic rather than a signalling compartment, but it is a well-established location of the protein. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Plasma membrane as the active location, inherited from the Toll-like receptor family node. Reason: TLR3 signals from acidic endosomal compartments, not from the cell surface. Surface-expressed TLR3 exists in fibroblasts and epithelial cells, but signalling requires endosomal maturation and acidic pH. The IBA reflects the surface TLRs (TLR1/2/4/5/6) in the family; TLR3 is among the nucleic-acid-sensing TLRs that relocated their active site to endosomes, so 'is active in plasma membrane' overstates its biology. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: GO_REF:0000033 Β· Toll-like receptor family PAINT node UNRESOLVED IBA for 'is active in plasma membrane' inherited from the Toll-like receptor family node. The family node fits the cell-surface TLRs (TLR1/2/4/5/6), but TLR3 is a nucleic-acid-sensing TLR that recognises dsRNA and signals from acidified endosomes/endolysosomes, not the plasma membrane. The specific PANTHER:PTN node for this row was not reliably recovered from the cached data. Supporting Evidence: PMID:21266579 TLR3 signaling arises from an intracellular compartment in both cell types and requires endosomal maturation. PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0005886 plasma membrane | IDA PMID:27830702 Hyperglycaemia inhibits REG3A expression to exacerbate TLR3-... | MARK AS OVER ANNOTATED | Summary: Plasma membrane given as the active location of TLR3 in keratinocytes. Reason: The cached full text describes TLR3-dependent JNK2 activation and inflammation in skin wounds but contains no statement localising active TLR3 to the plasma membrane; the supporting detail may be in a supplementary figure. TLR3 signals from acidic endosomes, so 'is active in plasma membrane' overstates its biology even where surface TLR3 is detectable. Supporting Evidence: PMID:27830702 Here we show that REG3A induces the negative regulator SHP-1 to inhibit TLR3-activated JNK2 phosphorylation, thus limiting TLR3 signalling. PMID:21266579 TLR3 signaling arises from an intracellular compartment in both cell types and requires endosomal maturation. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Electronic plasma membrane active location. Reason: As for the IBA row: TLR3 is expressed at the surface of some cell types but signals from acidic endosomes. Supporting Evidence: PMID:21266579 TLR3 signaling arises from an intracellular compartment in both cell types and requires endosomal maturation. |
| GO:0005886 plasma membrane | TAS PMID:9435236 A family of human receptors structurally related to Drosophi... | KEEP AS NON CORE | Summary: Plasma membrane location stated in the original cloning paper for the human TLR family. Reason: TLR3 is detected at the cell surface of fibroblasts and some epithelial cells, so 'located in' is defensible, but this is not its signalling compartment. The 1998 paper inferred receptor topology from sequence. Supporting Evidence: PMID:21266579 Human TLR3 localizes to the endosomal compartments in myeloid DCs, whereas it localizes to both the cell surface and endosomes of fibroblasts, macrophages, and epithelial cells PMID:12054664 the mAb to TLR3 suppressed poly(I):poly(C)-mediated IFN-beta production by human fibroblasts naturally expressing TLR3 on their surface |
| GO:0006972 hyperosmotic response | NAS PMID:12054664 Establishment of a monoclonal antibody against human Toll-li... | REMOVE | Summary: Hyperosmotic response attributed from a paper on a TLR3-blocking antibody. Reason: The cited abstract contains nothing about osmotic stress, and no other evidence links TLR3 to responses to hyperosmolarity. The annotation appears to be an error. Supporting Evidence: PMID:12054664 TLR3 recognized dsRNA to activate NF-kappaB and the IFN-beta promoter |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping from the TIR domain. Reason: General but correct: TLR3 is a signalling receptor whose TIR domain engages TRIF. Supporting Evidence: PMID:12471095 Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters. |
| GO:0007165 signal transduction | TAS PMID:10426995 Host defense mechanisms triggered by microbial lipoproteins ... | ACCEPT | Summary: Signal transduction, cited to a paper on TLR2-dependent lipoprotein responses. Reason: General but correct for TLR3. The cited abstract concerns lipoprotein signalling through TLRs, not TLR3 specifically; the term is accepted on the strength of other evidence rather than this reference. Supporting Evidence: PMID:12471095 Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters. |
| GO:0007165 signal transduction | TAS PMID:9435236 A family of human receptors structurally related to Drosophi... | ACCEPT | Summary: Signal transduction, from the original cloning of the human TLR family. Reason: General but correct; TLR3 was proposed as a Toll-like signalling receptor on the basis of its architecture and later shown to signal. Supporting Evidence: PMID:9435236 We report the molecular cloning of a class of putative human receptors with a protein architecture that is similar to Drosophila Toll in both intra- and extracellular segments. PMID:12471095 Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters. |
| GO:0007250 activation of NF-kappaB-inducing kinase activity | NAS PMID:12054664 Establishment of a monoclonal antibody against human Toll-li... | MODIFY | Summary: Activation of NIK kinase activity asserted from a paper showing TLR3-dependent NF-kappaB activation. Reason: The paper shows TLR3 activates NF-kappaB, but not that it activates NF-kappaB-inducing kinase (MAP3K14), which is a component of the non-canonical NF-kappaB pathway. TLR3 signals to canonical NF-kappaB through TRIF, RIPK1, TRAF6 and TAK1. The supported claim is positive regulation of canonical NF-kappaB signalling. Proposed replacements: positive regulation of canonical NF-kappaB signal transduction Supporting Evidence: PMID:12054664 TLR3 recognized dsRNA to activate NF-kappaB and the IFN-beta promoter PMID:12471095 Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters. |
| GO:0007254 JNK cascade | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: JNK cascade, Ensembl Compara transfer from mouse. Reason: TLR3 engagement activates JNK2 (shown in keratinocytes and mouse skin), but TLR3 initiates rather than forms part of the kinase cascade. Kept as a non-core downstream process. Supporting Evidence: PMID:27830702 Here we show that REG3A induces the negative regulator SHP-1 to inhibit TLR3-activated JNK2 phosphorylation, thus limiting TLR3 signalling. |
| GO:0009597 detection of virus | NAS PMID:12054664 Establishment of a monoclonal antibody against human Toll-li... | ACCEPT | Summary: TLR3 detects virus-derived double-stranded RNA. Reason: TLR3 detects dsRNA, a molecular signature of viral replication, and is required for control of HSV-1 in the human CNS. The antibody study shows specific recognition of dsRNA but not ssRNA or DNA. Supporting Evidence: PMID:12054664 TLR3 signaling was not elicited by either single-stranded RNA (ssRNA) or dsDNA PMID:17872438 TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1 |
| GO:0009986 cell surface | IDA NOT PMID:19740627 Cultured human melanocytes express functional toll-like rece... | UNDECIDED | Summary: NOT located at the cell surface of cultured human melanocytes. Reason: The cached record is abstract-only, and the abstract does not state the TLR3 surface-staining result. Cell-surface TLR3 is cell-type dependent: it is absent from the surface of myeloid dendritic cells but present on fibroblasts and epithelial cells, so a gene-level NOT is not straightforward to evaluate without the full text. Supporting Evidence: PMID:21266579 Human TLR3 localizes to the endosomal compartments in myeloid DCs, whereas it localizes to both the cell surface and endosomes of fibroblasts, macrophages, and epithelial cells |
| GO:0010008 endosome membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location: endosome membrane. Reason: Core location: TLR3 recognises dsRNA and signals from the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | ISS PMID:37158982 The Src-ZNRF1 axis controls TLR3 trafficking and interferon ... | ACCEPT | Summary: Endosome membrane as active location, by similarity to mouse Tlr3. Reason: Core location, consistent with human data on dsRNA-induced movement of TLR3 into endosomes and on its signalling from acidic compartments. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:37158982 suggesting that ZNRF1 is not involved in TLR3 transport from the ER to endosomes but controls its trafficking beyond the early endosome |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-168092 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-168929 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-168930 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-177690 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-177692 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-177694 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-450259 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-5602549 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-5602624 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-5602712 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-847070 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013889 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013895 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013963 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013974 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013978 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013979 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013985 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013990 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013992 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9014320 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9014342 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9014343 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9628444 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9828196 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9828200 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9828204 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9828205 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9828209 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9830706 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9830710 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9836763 | ACCEPT | Summary: Reactome places TLR3 and its signalling complexes on the endosome membrane. Reason: Core location. TLR3 binds dsRNA and assembles the TRIF signalling complex on the membrane of acidified endosomes. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA PMID:22611194 newly synthesized endogenous TLR3 is transported through the ER and Golgi apparatus to endosomes, where it is rapidly cleaved PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments |
| GO:0010628 positive regulation of gene expression | IMP PMID:23817958 Proinflammatory stimuli induce galectin-9 in human mesenchym... | KEEP AS NON CORE | Summary: Poly(I:C)-induced galectin-9 expression in mesenchymal stromal cells. Reason: Galectin-9 induction is one of many transcriptional outcomes of TLR3 signalling; TLR3 acts far upstream. The cached record is abstract-only and does not describe the TLR3 perturbation; deferring to the curator on the experimental basis but keeping as non-core. Supporting Evidence: PMID:23817958 ligands of the Toll-like receptors (TLRs) TLR2, TLR3, and TLR4 elicited similar induction of galectin-9 |
| GO:0010628 positive regulation of gene expression | IMP PMID:25754930 Up-regulation of galectin-9 induces cell migration in human ... | KEEP AS NON CORE | Summary: TLR3 knockdown reduces poly(I:C)-induced galectin-9 in dendritic cells. Reason: An indirect downstream transcriptional outcome. In the same paper TLR3 knockdown did not affect dengue-virus-induced galectin-9, so the effect is ligand-specific. Supporting Evidence: PMID:25754930 As controls, knockdown of TLR-3 reduced Poly I:C-induced Gal-9 expression by Western blotting PMID:25754930 effective knockdown of TLR-3 had no effect on DV-induced Gal-9 mRNA and protein expression |
| GO:0016020 membrane | NAS PMID:12054664 Establishment of a monoclonal antibody against human Toll-li... | KEEP AS NON CORE | Summary: Membrane, from an early author statement. Reason: Correct but uninformative; TLR3 is a single-pass membrane protein of the ER and endosomes, captured by specific terms. Supporting Evidence: PMID:16858407 TLR3 is localized in the endoplasmic reticulum of unstimulated cells, moves to dsRNA-containing endosomes in response to dsRNA |
| GO:0032722 positive regulation of chemokine production | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | KEEP AS NON CORE | Summary: TLR ligands including poly(I:C) induce chemokine mRNAs in melanocytes. Reason: Chemokine induction is a downstream output of TLR3-NF-kappaB signalling. Kept as non-core; the abstract reports the TLR panel collectively. Supporting Evidence: PMID:19740627 Stimulation of melanocytes with TLRs ligands resulted in the release of cytokines (IL-8 and IL-6) and the mRNA accumulation of chemokines (CCL2, CCL3 and CCL5) |
| GO:0032722 positive regulation of chemokine production | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic chemokine production term. Reason: Downstream output of TLR3 signalling. Supporting Evidence: PMID:19740627 Stimulation of melanocytes with TLRs ligands resulted in the release of cytokines (IL-8 and IL-6) and the mRNA accumulation of chemokines (CCL2, CCL3 and CCL5) |
| GO:0032727 positive regulation of interferon-alpha production | IDA PMID:16286015 Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/be... | ACCEPT | Summary: Poly(I:C) induces IFN-alpha in human blood cells independently of IRAK4. Reason: Type I interferon induction is the principal output of TLR3 signalling via TRIF-IRF3. The paper shows normal poly(I:C)-induced IFN-alpha in IRAK4-deficient blood cells, consistent with the MyD88/IRAK4-independent TLR3-TRIF route. Supporting Evidence: PMID:16286015 Similar results were obtained for IFN-Ξ± (Figure 1A) and IFN-Ξ» (data not shown) levels determined by ELISA, with normal induction by poly(I:C) |
| GO:0032728 positive regulation of interferon-beta production | IDA PMID:16286015 Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/be... | ACCEPT | Summary: Poly(I:C)-induced IFN-beta in TLR3-only human fibroblasts. Reason: Core output. Human fibroblasts express only TLR3 among TLRs and secrete IFN-beta in response to poly(I:C) independently of IRAK4. Supporting Evidence: PMID:16286015 Human fibroblasts express a single TLR, TLR-3, respond to only one known TLR agonist, poly(I:C), and secrete IFN-Ξ² and IFN-Ξ» (this report). |
| GO:0032728 positive regulation of interferon-beta production | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic IFN-beta production term. Reason: Consistent with the experimental evidence. Supporting Evidence: PMID:16286015 Human fibroblasts express a single TLR, TLR-3, respond to only one known TLR agonist, poly(I:C), and secrete IFN-Ξ² and IFN-Ξ» (this report). |
| GO:0032728 positive regulation of interferon-beta production | IMP PMID:12054664 Establishment of a monoclonal antibody against human Toll-li... | ACCEPT | Summary: A TLR3-blocking antibody suppresses poly(I:C)-induced IFN-beta in human fibroblasts. Reason: Direct loss-of-function evidence for TLR3 in IFN-beta induction. Supporting Evidence: PMID:12054664 the mAb to TLR3 suppressed poly(I):poly(C)-mediated IFN-beta production by human fibroblasts naturally expressing TLR3 on their surface |
| GO:0032728 positive regulation of interferon-beta production | ISS GO_REF:0000024 | ACCEPT | Summary: IFN-beta production by similarity to mouse Tlr3. Reason: Consistent with human experimental evidence. Supporting Evidence: PMID:12054664 the mAb to TLR3 suppressed poly(I):poly(C)-mediated IFN-beta production by human fibroblasts naturally expressing TLR3 on their surface |
| GO:0032729 positive regulation of type II interferon production | IDA PMID:16286015 Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/be... | MARK AS OVER ANNOTATED | Summary: Positive regulation of IFN-gamma production attributed to the IRAK4 study. Reason: In the full text of this paper, IFN-gamma appears only in the introduction, where earlier work is cited showing that IRAK4-deficient blood cells fail to make IFN-gamma in response to several TLR agonists including poly(I:C). The paper's own experiments on poly(I:C) measure type I and type III interferons. IFN-gamma production after poly(I:C) is an indirect, cell-extrinsic effect (for example via NK cells), not a demonstrated TLR3-intrinsic output. Supporting Evidence: PMID:16286015 IRAK-4-deficient blood cells have been shown not to produce the following proinflammatory cytokines: interleukin-1Ξ² (IL-1Ξ²), IL-6, IL-12, tumor necrosis factor-Ξ± (TNF-Ξ±), and interferon-Ξ³ (IFN-Ξ³), in response to IL-1Ξ², IL-18, and all Toll-like receptor (TLR) agonists tested |
| GO:0032735 positive regulation of interleukin-12 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IL-12 production, transferred from mouse Tlr3. Reason: Downstream cytokine output of TLR3 signalling in dendritic cells; non-core. Supporting Evidence: PMID:12054664 TLR3 recognized dsRNA to activate NF-kappaB and the IFN-beta promoter |
| GO:0032735 positive regulation of interleukin-12 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: IL-12 production, by similarity to mouse Tlr3. Reason: Downstream cytokine output; non-core. Supporting Evidence: PMID:12054664 TLR3 recognized dsRNA to activate NF-kappaB and the IFN-beta promoter |
| GO:0032755 positive regulation of interleukin-6 production | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | KEEP AS NON CORE | Summary: TLR ligands including poly(I:C) induce IL-6 release by melanocytes. Reason: Downstream NF-kappaB-dependent cytokine output of TLR3 signalling. Supporting Evidence: PMID:19740627 Stimulation of melanocytes with TLRs ligands resulted in the release of cytokines (IL-8 and IL-6) and the mRNA accumulation of chemokines (CCL2, CCL3 and CCL5) |
| GO:0032755 positive regulation of interleukin-6 production | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic IL-6 production term. Reason: Downstream cytokine output. Supporting Evidence: PMID:19740627 Stimulation of melanocytes with TLRs ligands resulted in the release of cytokines (IL-8 and IL-6) and the mRNA accumulation of chemokines (CCL2, CCL3 and CCL5) |
| GO:0032757 positive regulation of interleukin-8 production | IDA PMID:17128265 Maintenance of colonic homeostasis by distinctive apical TLR... | KEEP AS NON CORE | Summary: IL-8 production, from a study of TLR9 signalling in intestinal epithelial cells. Reason: The abstract concerns TLR9; the TLR3 data are presumably in the full text, which is not cached. IL-8 induction by poly(I:C) is a plausible downstream NF-kappaB output (also seen in melanocytes); deferring to the curator and keeping as non-core. Supporting Evidence: PMID:19740627 Stimulation of melanocytes with TLRs ligands resulted in the release of cytokines (IL-8 and IL-6) and the mRNA accumulation of chemokines (CCL2, CCL3 and CCL5) |
| GO:0032760 positive regulation of tumor necrosis factor production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TNF production, transferred from mouse Tlr3. Reason: Downstream cytokine output of TLR3 signalling. Supporting Evidence: PMID:27830702 Here we show that REG3A induces the negative regulator SHP-1 to inhibit TLR3-activated JNK2 phosphorylation, thus limiting TLR3 signalling. |
| GO:0032760 positive regulation of tumor necrosis factor production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: TNF production, by similarity to mouse Tlr3. Reason: Downstream cytokine output. Supporting Evidence: PMID:27830702 Here we show that REG3A induces the negative regulator SHP-1 to inhibit TLR3-activated JNK2 phosphorylation, thus limiting TLR3 signalling. |
| GO:0034138 toll-like receptor 3 signaling pathway | IDA PMID:17128265 Maintenance of colonic homeostasis by distinctive apical TLR... | ACCEPT | Summary: TLR3 signalling pathway, from a study of TLR9 signalling in intestinal epithelial cells. Reason: The term is correct for TLR3 (it is the receptor that initiates this pathway). The abstract concerns TLR9 and the full text is not cached; the paper reports that apical TLR9 stimulation confers tolerance to subsequent TLR challenges, which presumably included poly(I:C). Accepted on the strength of the biology. Supporting Evidence: PMID:18172197 We conclude that TLR3 assembles on dsRNA as stable dimers and that the minimal signaling unit is one TLR3 dimer. PMID:12471095 Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters. |
| GO:0034138 toll-like receptor 3 signaling pathway | IDA PMID:18172197 The TLR3 signaling complex forms by cooperative receptor dim... | ACCEPT | Summary: dsRNA-induced dimerisation of the TLR3 ectodomain forms the signalling unit. Reason: Core process. TLR3 is the receptor that initiates the TLR3 signalling pathway. Supporting Evidence: PMID:18172197 We conclude that TLR3 assembles on dsRNA as stable dimers and that the minimal signaling unit is one TLR3 dimer. PMID:18172197 dsRNA binds saturably, specifically, and reversibly to a defined ligand-binding site (or sites) on the TLR3 ectodomain |
| GO:0034138 toll-like receptor 3 signaling pathway | IDA PMID:28970238 HCFC2 is needed for IRF1- and IRF2-dependent Tlr3 transcript... | ACCEPT | Summary: Tlr3 transcription is required for poly(I:C) responses in mouse macrophages. Reason: Correct for TLR3. The paper concerns HCFC2-dependent transcription of Tlr3 in mouse macrophages, but the term is accurate for the receptor on any evidence. Supporting Evidence: PMID:28970238 HCFC2 promoted the binding of IRF1 and IRF2 to the Tlr3 promoter, without which inflammatory cytokine and type I IFN responses to the double-stranded RNA analogue poly(I:C) are reduced in mouse macrophages. |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic intracellular signal transduction. Reason: TLR3's cytoplasmic TIR domain initiates intracellular signalling through TRIF, so the term is not wrong, but TLR3 is a transmembrane receptor and the pathway term captures its role better. Supporting Evidence: PMID:12471095 Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-1678927 | ACCEPT | Summary: Reactome: UNC93B1 delivers TLR3 to the endolysosome. Reason: Core location. TLR3 binds dsRNA at acidic pH in endolysosomal compartments after cathepsin cleavage. Supporting Evidence: PMID:16144834 showing that TLR3 interacted with its ligand in acidic subcellular compartments PMID:22611194 Taken together, our data indicate that TLR3 proteolytic processing is essential for its function |
| GO:0038023 signaling receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Signaling receptor activity from the Toll-like receptor family node. Reason: Correct, less specific than transmembrane signaling receptor activity. TLR3 appears among the sources through its own experimental annotations, which is expected. Supporting Evidence: PMID:12471095 Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters. |
| GO:0038023 signaling receptor activity | TAS PMID:10426995 Host defense mechanisms triggered by microbial lipoproteins ... | ACCEPT | Summary: Signaling receptor activity, cited to a paper on TLR2-dependent lipoprotein responses. Reason: Correct for TLR3, though the cited abstract does not address TLR3; accepted on other evidence. Supporting Evidence: PMID:12471095 Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters. |
| GO:0038187 pattern recognition receptor activity | IDA PMID:16720699 The dsRNA binding site of human Toll-like receptor 3. | ACCEPT | Summary: dsRNA binding-site mutations abolish TLR3 activation and ligand binding. Reason: Core function. TLR3 recognises dsRNA, a molecular pattern produced during viral replication, and initiates an innate immune response. Unlike Drosophila Toll, which binds the endogenous cytokine Spaetzle, TLR3 binds the microbial product directly, meeting the pattern recognition receptor definition. Supporting Evidence: PMID:16720699 only two, H539E and N541A, resulted in the loss of TLR3 activation and ligand binding functions PMID:18172197 dsRNA binds saturably, specifically, and reversibly to a defined ligand-binding site (or sites) on the TLR3 ectodomain |
| GO:0038187 pattern recognition receptor activity | IDA PMID:17128265 Maintenance of colonic homeostasis by distinctive apical TLR... | ACCEPT | Summary: Pattern recognition receptor activity, from a study of TLR9 signalling in intestinal epithelial cells. Reason: The abstract concerns TLR9 and the full text is not cached; the term is well supported for TLR3 by direct binding studies, so accepted and deferred to the curator. Supporting Evidence: PMID:16720699 only two, H539E and N541A, resulted in the loss of TLR3 activation and ligand binding functions |
| GO:0038187 pattern recognition receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic pattern recognition receptor activity. Reason: Consistent with the experimental evidence. Supporting Evidence: PMID:16720699 only two, H539E and N541A, resulted in the loss of TLR3 activation and ligand binding functions |
| GO:0042742 defense response to bacterium | TAS PMID:10426995 Host defense mechanisms triggered by microbial lipoproteins ... | REMOVE | Summary: Defense response to bacterium, cited to a paper on TLR2-mediated lipoprotein responses. Reason: The cited paper concerns microbial lipoproteins acting through TLR2, and there is no evidence in it for TLR3. Human genetic evidence indicates TLR3 is largely redundant for defence against most microbes and is needed chiefly for antiviral immunity in the CNS. Bacterial RNA can stimulate TLR3 in vitro, but that does not establish a role in antibacterial defence. Supporting Evidence: PMID:10426995 Here it is shown that microbial lipoproteins are potent stimulators of IL-12 production by human macrophages, and that induction is mediated by Toll-like receptors (TLRs). PMID:17872438 Human TLR3 appears to be redundant in host defense to most microbes but is vital for natural immunity to HSV-1 in the CNS |
| GO:0042802 identical protein binding | IPI PMID:18172197 The TLR3 signaling complex forms by cooperative receptor dim... | MODIFY | Summary: The TLR3 ectodomain forms homodimers on dsRNA. Reason: Ligand-driven homodimerisation is a real and functionally required property of TLR3: one dimer on a 40-50 bp dsRNA is the minimal signalling unit. Protein homodimerization activity describes this more informatively than identical protein binding. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:18172197 We conclude that TLR3 assembles on dsRNA as stable dimers and that the minimal signaling unit is one TLR3 dimer. |
| GO:0042802 identical protein binding | IPI PMID:23155421 Isolated Toll-like receptor transmembrane domains are capabl... | KEEP AS NON CORE | Summary: Isolated TLR transmembrane domains, including that of TLR3, self-associate in bacterial membranes. Reason: An in vitro property of an isolated transmembrane peptide in a reporter system. It is consistent with the transmembrane helices contributing to the ligand-induced dimer, but it is not a demonstrated activity of the full-length receptor. Supporting Evidence: PMID:23155421 We saw agreement with this model as the TLR3 TMD showed a very high homotypic interaction potential. |
| GO:0042802 identical protein binding | IPI PMID:25217833 Toll-like receptor 3 transmembrane domain is able to perform... | KEEP AS NON CORE | Summary: NMR structures of the TLR3 transmembrane domain as dimers and trimers in micelles. Reason: An in vitro property of the isolated transmembrane helix in detergent. Kept as non-core; it does not establish the oligomeric state of the full-length receptor. Supporting Evidence: PMID:25217833 the ability of the TLR3 transmembrane domain to form dimers and trimers in detergent micelles was shown by solution NMR spectroscopy |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | ACCEPT | Summary: TLR ligands including poly(I:C) trigger IkappaBalpha phosphorylation and p65 nuclear translocation in melanocytes. Reason: Canonical NF-kappaB activation is one of the two principal outputs of TLR3-TRIF signalling, established in reporter assays and in primary cells. Supporting Evidence: PMID:19740627 Triggering of TLRs in melanocytes resulted in the up-regulation of phosphorylated IkappaBalpha and in the nucleus translocation of NF-kappaBp65 PMID:12054664 TLR3 recognized dsRNA to activate NF-kappaB and the IFN-beta promoter |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic canonical NF-kappaB term. Reason: Consistent with the experimental evidence. Supporting Evidence: PMID:12054664 TLR3 recognized dsRNA to activate NF-kappaB and the IFN-beta promoter |
| GO:0043330 response to exogenous dsRNA | IDA PMID:21266579 Raftlin is involved in the nucleocapture complex to induce p... | ACCEPT | Summary: Poly(I:C) uptake via Raftlin is required for TLR3-mediated IFN-beta induction. Reason: TLR3 is the endosomal receptor through which extracellular dsRNA (poly(I:C)) triggers responses; the annotation is correct in the upstream-or-within sense recorded. Supporting Evidence: PMID:21266579 When Raftlin was silenced, poly(I:C) failed to enter cells and induction of IFN-Ξ² production was inhibited. PMID:21266579 TLR3 signaling arises from an intracellular compartment in both cell types and requires endosomal maturation. |
| GO:0043330 response to exogenous dsRNA | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic response to exogenous dsRNA. Reason: Consistent with TLR3 being the receptor for extracellular and endocytosed dsRNA. Supporting Evidence: PMID:12054664 the mAb to TLR3 suppressed poly(I):poly(C)-mediated IFN-beta production by human fibroblasts naturally expressing TLR3 on their surface |
| GO:0043331 response to dsRNA | IBA GO_REF:0000033 | ACCEPT | Summary: Response to dsRNA, from the TLR3 clade node. Reason: Correct; TLR3 is the dsRNA-sensing receptor, and its own experimental data are among the node's sources. Supporting Evidence: PMID:12054664 TLR3 recognized dsRNA to activate NF-kappaB and the IFN-beta promoter |
| GO:0044389 ubiquitin-like protein ligase binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ubiquitin-like protein ligase binding, transferred from mouse Tlr3. Reason: TLR3 is a substrate of several E3 ubiquitin ligases (ZNRF1, TRIM3, RNF170) that control its sorting and degradation. Binding to its own E3 ligases is a feature of TLR3 turnover rather than an activity TLR3 performs, so kept as non-core. Supporting Evidence: PMID:37158982 c-Src kinase activated by TLR3 engagement phosphorylates ZNRF1 at tyrosine 103, which mediates K63-linked ubiquitination of TLR3 at lysine 813 and promotes TLR3 lysosomal trafficking and degradation |
| GO:0045087 innate immune response | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic innate immune response. Reason: Correct; TLR3 is an innate immune pattern recognition receptor. Supporting Evidence: PMID:17872438 TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1 PMID:16720699 only two, H539E and N541A, resulted in the loss of TLR3 activation and ligand binding functions |
| GO:0045087 innate immune response | TAS PMID:15356140 Microglia initiate central nervous system innate and adaptiv... | ACCEPT | Summary: Microglia respond to poly(I:C) among other TLR agonists. Reason: Correct for TLR3 as an innate immune receptor. The cited study is in mouse microglia and uses agonists rather than TLR3 perturbation; the term stands on other evidence. Supporting Evidence: PMID:15356140 stimulation of quiescent microglia with various TLR agonists, including LPS (TLR4), peptidoglycan (TLR2), polyinosinic-polycytidylic acid (TLR3), CpG DNA (TLR9) PMID:17872438 TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1 |
| GO:0045671 negative regulation of osteoclast differentiation | NAS PMID:12133979 Stimulation by toll-like receptors inhibits osteoclast diffe... | KEEP AS NON CORE | Summary: TLR agonists including poly(I:C) inhibit osteoclast differentiation of mouse precursors. Reason: A context-specific downstream consequence of TLR signalling in myeloid precursors, shown with agonists in mouse cells. Retained as non-core. Supporting Evidence: PMID:12133979 TLR stimulation of osteoclast precursors by these microbial products strongly inhibited their differentiation into multinucleated, mature osteoclasts |
| GO:0045766 positive regulation of angiogenesis | IEA GO_REF:0000107 | UNDECIDED | Summary: Positive regulation of angiogenesis, transferred from mouse Tlr3. Reason: The source mouse annotation could not be traced to a publication read for this review, and no cached evidence addresses TLR3 and angiogenesis. Unable to evaluate. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Positive regulation of RNA polymerase II transcription, transferred from mouse Tlr3. Reason: TLR3 is a membrane receptor several steps upstream of the transcription factors (IRF3, NF-kappaB, AP-1) that drive transcription. The process terms for its pathway and for interferon and cytokine production describe its role; a general transcription-regulation term is an over-propagation. Supporting Evidence: PMID:12054664 TLR3 recognized dsRNA to activate NF-kappaB and the IFN-beta promoter |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Positive regulation of RNA polymerase II transcription, by similarity to mouse Tlr3. Reason: As for the Ensembl Compara row: TLR3 acts far upstream of transcription. Supporting Evidence: PMID:12054664 TLR3 recognized dsRNA to activate NF-kappaB and the IFN-beta promoter |
| GO:0046330 positive regulation of JNK cascade | IDA PMID:27830702 Hyperglycaemia inhibits REG3A expression to exacerbate TLR3-... | KEEP AS NON CORE | Summary: TLR3 activates JNK2 in keratinocytes and skin wounds. Reason: Supported: JNK2 phosphorylation after skin wounding depends on Tlr3. A downstream MAPK output, kept as non-core relative to IRF3 and NF-kappaB activation. Supporting Evidence: PMID:27830702 Here we show that REG3A induces the negative regulator SHP-1 to inhibit TLR3-activated JNK2 phosphorylation, thus limiting TLR3 signalling. |
| GO:0046330 positive regulation of JNK cascade | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic positive regulation of JNK cascade. Reason: Downstream output, consistent with experimental data. Supporting Evidence: PMID:27830702 Here we show that REG3A induces the negative regulator SHP-1 to inhibit TLR3-activated JNK2 phosphorylation, thus limiting TLR3 signalling. |
| GO:0050729 positive regulation of inflammatory response | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | KEEP AS NON CORE | Summary: TLR ligands including poly(I:C) induce pro-inflammatory mediators in melanocytes. Reason: Pro-inflammatory cytokine production is a genuine output of TLR3 signalling but secondary to its antiviral role. Supporting Evidence: PMID:19740627 Stimulation of melanocytes with TLRs ligands resulted in the release of cytokines (IL-8 and IL-6) and the mRNA accumulation of chemokines (CCL2, CCL3 and CCL5) PMID:27830702 TLR3 is a key element in the initiation of inflammatory responses after skin injury |
| GO:0051607 defense response to virus | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic defense response to virus. Reason: Core process: TLR3 is required for antiviral immunity, notably control of HSV-1 in the human CNS. Supporting Evidence: PMID:17872438 TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1 |
| GO:0051607 defense response to virus | IEP PMID:32634389 Chikungunya virus infection induces differential inflammator... | ACCEPT | Summary: TLR expression changes in chikungunya-infected monocytes and macrophages. Reason: The IEP evidence (expression change on infection) is weak and the abstract does not single out TLR3, but the term is correct for TLR3 on strong human genetic evidence. Accepted on that basis. Supporting Evidence: PMID:32634389 CHIKV infection activates the TLR pathways in primary monocytes and MDMs PMID:17872438 TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1 |
| GO:0051607 defense response to virus | TAS PMID:15356140 Microglia initiate central nervous system innate and adaptiv... | ACCEPT | Summary: Defense response to virus, cited to a study of mouse microglia. Reason: Correct for TLR3 on human genetic and mechanistic evidence. Supporting Evidence: PMID:17872438 TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1 PMID:17872438 Human TLR3 appears to be redundant in host defense to most microbes but is vital for natural immunity to HSV-1 in the CNS |
| GO:0071260 cellular response to mechanical stimulus | IEP PMID:19593445 Expression of the Bcl-2 protein BAD promotes prostate cancer... | UNDECIDED | Summary: Cellular response to mechanical stimulus, cited to a paper on BAD in prostate cancer. Reason: The cached full text of this paper (BAD expression and prostate cancer growth) contains no mention of TLR3, Toll-like receptors or mechanical stimulation. The evidence could lie in supplementary data or the identifier may be wrong; this cannot be resolved from what is available. No other evidence links TLR3 to mechanical stimulus responses. |
| GO:0090594 inflammatory response to wounding | IDA PMID:27830702 Hyperglycaemia inhibits REG3A expression to exacerbate TLR3-... | KEEP AS NON CORE | Summary: TLR3 drives inflammation after skin injury; Tlr3-deficient wounds show less JNK2 activation. Reason: Supported by mouse knockout and human keratinocyte data: TLR3 senses dsRNA released from damaged cells and initiates wound inflammation. A genuine but context-specific role, kept as non-core. Supporting Evidence: PMID:27830702 TLR3 is a key element in the initiation of inflammatory responses after skin injury PMID:27830702 Here we show that REG3A induces the negative regulator SHP-1 to inhibit TLR3-activated JNK2 phosphorylation, thus limiting TLR3 signalling. |
| GO:0090594 inflammatory response to wounding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic inflammatory response to wounding. Reason: Consistent with experimental data; context-specific. Supporting Evidence: PMID:27830702 TLR3 is a key element in the initiation of inflammatory responses after skin injury |
| GO:0097527 necroptotic signaling pathway | IDA PMID:21737330 cIAPs block Ripoptosome formation, a RIP1/caspase-8 containi... | KEEP AS NON CORE | Summary: Loss of cIAPs promotes TLR3-induced RIPK1-RIPK3-dependent necroptosis. Reason: TLR3 initiates a TRIF-dependent death pathway that becomes necroptotic when cIAPs are lost or caspase-8 is blocked. A genuine but context-dependent output, kept as non-core. Supporting Evidence: PMID:21737330 We demonstrate that loss of cIAPs promotes TLR3-induced RIP1-RIP3-mediated necroptosis. |
| GO:0098586 cellular response to virus | IEA GO_REF:0000107 | ACCEPT | Summary: Cellular response to virus, transferred from mouse Tlr3. Reason: Correct; TLR3-dependent interferon induction in non-haematopoietic cells is a cell-intrinsic response to viral infection. Supporting Evidence: PMID:17872438 TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1 |
| GO:1900017 positive regulation of cytokine production involved in inflammatory response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cytokine production in inflammatory response, transferred from mouse Tlr3. Reason: Downstream output of TLR3 signalling. Supporting Evidence: PMID:27830702 TLR3 is a key element in the initiation of inflammatory responses after skin injury |
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Download this section (compressed HTML)Q: Should the Toll-like receptor family IBA for 'is active in plasma membrane' be restricted to the cell-surface TLR clade (TLR1/2/4/5/6/10), excluding the endosomal nucleic-acid-sensing TLRs (TLR3/7/8/9) whose signalling requires endosomal acidification?
Q: Is the IEP annotation of TLR3 to 'cellular response to mechanical stimulus' (PMID:19593445) supported by any data in that paper? The full text concerns BAD in prostate cancer and does not mention TLR3.
Q: Does cell-surface TLR3 on fibroblasts and epithelial cells signal at all, or is it only a pool en route to endosomes? The answer decides whether a NOT cell-surface annotation from melanocytes should stand at the gene level.
Q: Does TLR3 respond to endogenous dsRNA released from damaged cells in sterile injury (e.g. skin wounding), and if so, should a role in the inflammatory response to wounding be regarded as core rather than context-specific?
Q: Beyond the ligand-induced dimer, does TLR3 assemble laterally into higher-order multimers along long double-stranded RNA, and does that explain why robust cellular signalling needs longer duplexes than the 40-50 bp needed for a stable dimer? A 2023 cryo-electron microscopy study reporting this is summarised in the Falcon deep-research file but was not verified here against the primary paper, so the review still treats the dimer as the minimal signalling unit (PMID:18172197).
Q: Is there any contribution of MyD88 to human TLR3 signalling? The Falcon deep-research file summarises a 2025 report of TRIF-dependent MyD88 involvement in mouse macrophages. That primary paper was not available for verification here, so this review retains the MyD88-independent, TRIF-only model supported by PMID:12471095 and PMID:16286015.
Experiment: Knock the H539E and N541A dsRNA-binding-site mutations into the endogenous TLR3 locus of primary human fibroblasts and dendritic cells and measure poly(I:C)- and virus-induced IRF3 activation, type I/III interferon output and NF-kappaB activation, to confirm that direct dsRNA binding is rate-limiting at physiological expression.
Hypothesis: The dsRNA-binding site defined by overexpression mutagenesis is required for signalling at endogenous TLR3 levels.
Type: knock-in functional assay in primary cells
Experiment: Use compartment-restricted TLR3 constructs (surface-anchored vs endosome-restricted) in cells lacking endogenous TLR3 to test whether cell-surface TLR3 can signal, resolving whether the plasma-membrane annotations reflect a signalling pool or only a transit pool.
Hypothesis: TLR3 signalling requires the acidic endosomal compartment and surface TLR3 is signalling-incompetent.
Type: compartment-targeting rescue assay
Experiment: Compare TLR3-dependent transcriptional outputs (interferons, chemokines, IL-6, TNF) across matched cell types by RNA-seq after poly(I:C) with and without TLR3 knockout, to distinguish direct TLR3-driven outputs from indirect, cell-type-specific ones such as IFN-gamma and galectin-9 induction.
Hypothesis: Several cytokine-production annotations (IFN-gamma, IL-12, galectin-9) are indirect consequences of TLR3-driven type I interferon rather than direct TLR3 outputs.
Type: comparative transcriptomics with genetic perturbation
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