TICAM1 (TRIF, TIR domain-containing adapter molecule 1) is a cytoplasmic signaling adaptor of the MyD88-independent branch of Toll-like receptor signaling. Its C-terminal TIR domain engages the TIR domain of endosomal TLR3 directly after double-stranded RNA recognition, and of TLR4 through the sorting adaptor TICAM2 (TRAM) after LPS-induced receptor internalization into endosomes. From this position TICAM1 recruits distinct effectors through separate motifs: TRAF6 through N-terminal TRAF6-binding motifs (NF-kappaB and MAPK activation via TAK1), TRAF3 and the kinase TBK1/IKBKE (via its N-terminal region), and RIPK1 and RIPK3 through a C-terminal RHIM region (NF-kappaB activation, caspase-8-dependent apoptosis or necroptosis). TBK1 phosphorylates Ser210 in the TICAM1 pLxIS motif, which then binds IRF3 and positions it for TBK1-mediated activation, driving IFN-beta and interferon-stimulated gene expression. TICAM1 is diffuse in the cytosol at rest and forms signaling speckles upon stimulation; its abundance and activity are controlled by ubiquitination (TRIM38, TRIM8), selective autophagy and inhibitory partners such as SARM1, and it is cleaved by several viral proteases as an immune-evasion strategy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002224 toll-like receptor signaling pathway | IDA PMID:12471095 Cutting edge: a novel Toll/IL-1 receptor domain-containing a... | ACCEPT | Summary: TICAM1 (TRIF) was identified as a TIR-domain adaptor that associates with TLR3 and mediates the MyD88-independent arm of TLR signaling. Reason: Direct evidence in the discovery paper: TRIF associates with TLR3, and dominant-negative TRIF blocks TLR3-driven NF-kappaB and IFN-beta promoter activation and TLR2/4/7-driven NF-kappaB activation. TICAM1 performs the adaptor step of the pathway, so participation is direct. The more specific TLR3, TLR4 and TRIF-dependent terms are also accepted. Supporting Evidence: PMID:12471095 TRIF associated with TLR3 and IFN regulatory factor 3. PMID:12471095 Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters. PMID:12471095 A dominant-negative form of TRIF inhibited TLR2-, TLR4-, and TLR7-dependent NF-kappaB activation. |
| GO:0002735 positive regulation of myeloid dendritic cell cytokine production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse-derived (Ticam1, Q80UF7) annotation for promoting cytokine production by myeloid dendritic cells. Consistent with TRIF driving TLR3/TLR4-induced cytokine output in dendritic cells, but this is a cell-type-specific downstream consequence of the adaptor function rather than a distinct activity. Reason: Transfer from the mouse orthologue is reasonable since the TLR3/TLR4-TRIF axis is conserved; however, the term describes an outcome in one cell type downstream of TRIF-dependent TLR signaling. Retained as non-core. Supporting Evidence: PMID:12471095 Furthermore, TRIF, but neither MyD88 nor TIRAP, activated the IFN-beta promoter. |
| GO:0002735 positive regulation of myeloid dendritic cell cytokine production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse-derived (Ticam1, Q80UF7) annotation for promoting cytokine production by myeloid dendritic cells. Consistent with TRIF driving TLR3/TLR4-induced cytokine output in dendritic cells, but this is a cell-type-specific downstream consequence of the adaptor function rather than a distinct activity. Reason: Transfer from the mouse orthologue is reasonable since the TLR3/TLR4-TRIF axis is conserved; however, the term describes an outcome in one cell type downstream of TRIF-dependent TLR signaling. Retained as non-core. Supporting Evidence: PMID:12471095 Furthermore, TRIF, but neither MyD88 nor TIRAP, activated the IFN-beta promoter. |
| GO:0005515 protein binding | IPI PMID:14982987 Toll-like receptor 3-mediated activation of NF-kappaB and IR... | MODIFY | Summary: IPI with TRAF6 (Q9Y4K3). The paper shows that TRIF recruits TRAF6-TAK1-TAB2 to TLR3 via a TRAF6-binding motif (PEEMSW 250-255), which is required for NF-kappaB but not IRF3 activation. Reason: Generic protein binding is uninformative. Here the paper directly supports the functional meaning of the interaction: TRIF bridges activated TLR3 to TRAF6 through a defined motif, i.e. signaling adaptor activity (GO:0035591). Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:14982987 We found that TLR3 recruits TRAF6 via adapter TRIF through a TRAF6-binding sequence in TRIF (PEEMSW, amino acids 250-255). PMID:14982987 In conclusion, TRIF recruits TRAF6-TAK1-TAB2 to TLR3 through its TRAF6-binding site, which is required for NF-ΞΊB but not IRF3 activation. |
| GO:0005515 protein binding | IPI PMID:15142865 A20 inhibits toll-like receptor 2- and 4-mediated interleuki... | REMOVE | Summary: IPI with TNFAIP3/A20 (P21580) from a paper on A20 as a negative regulator of TLR2/TLR4-induced IL-8 synthesis in airway epithelial cells. Reason: Generic protein binding is uninformative. The cached abstract does not describe the TRIF-A20 interaction or its functional meaning, and A20 acts on the pathway as a negative regulator rather than being a TICAM1 effector. Removal of this uninformative term does not dispute the reported interaction. |
| GO:0005515 protein binding | IPI PMID:15841462 Interaction between the HCV NS3 protein and the host TBK1 pr... | REMOVE | Summary: IPI with TBK1 (Q9UHD2) from a study of HCV NS3 binding to TBK1. Reason: Generic protein binding is uninformative; the TICAM1-TBK1 interaction is better captured by the accepted protein kinase binding (GO:0019901) and signaling adaptor activity rows. Removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:19416887 ISG56 is a negative-feedback regulator of virus-triggered si... | REMOVE | Summary: IPI with TBK1 (Q9UHD2) used as a control interaction in a study of ISG56 as a negative-feedback regulator. Reason: Generic protein binding is uninformative; the paper reports that ISG56 did not disrupt the TRIF-TBK1 interaction. The TBK1 association is captured by protein kinase binding and signaling adaptor activity. Removal does not dispute the interaction. Supporting Evidence: PMID:19416887 In similar experiments, ISG56 did not disrupt the MDA5βVISA and TRIFβTBK1 interactions. |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: IPI with TBK1 (Q9UHD2) from a large-scale innate immunity interaction network mapping study. Reason: Generic protein binding from a network screen is uninformative; the TBK1 association is captured by protein kinase binding and signaling adaptor activity. Removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:22948160 TRIM56 is an essential component of the TLR3 antiviral signa... | REMOVE | Summary: IPI with TRIM56 (Q9BRZ2). TRIM56 binds TRIF through its C-terminal region and promotes TLR3 signaling. Reason: Generic protein binding is uninformative. TRIM56 is a regulator that acts on TRIF; the interaction does not define a TICAM1 molecular function beyond the adaptor activity already captured. Removal does not dispute the interaction. Supporting Evidence: PMID:22948160 Conclusion: TRIM56 interacts with TRIF and promotes TLR3 signaling. |
| GO:0005515 protein binding | IPI PMID:25736436 WDFY1 mediates TLR3/4 signaling by recruiting TRIF. | MODIFY | Summary: IPI with TLR3 (O15455); WDFY1 enhances the TLR3-TRIF interaction. Reason: Generic protein binding is uninformative. In this paper TRIF is recruited to TLR3/TLR4 (assisted by WDFY1) and associates with the downstream effectors RIP1, TRAF6 and TBK1; interaction with TLR3 (receptor side) is part of the bridging function of TICAM1 between receptor and effectors, so the informative replacement is signaling adaptor activity (GO:0035591). Proposed replacements: signaling adaptor activity 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:25736436 WDFY1 mediates TLR3/4 signaling by recruiting TRIF. | MODIFY | Summary: IPI with RIPK1 (Q13546); RIP1 associates with TRIF downstream of TLR3/TLR4. Reason: Generic protein binding is uninformative. In this paper TRIF is recruited to TLR3/TLR4 (assisted by WDFY1) and associates with the downstream effectors RIP1, TRAF6 and TBK1; interaction with RIPK1 (effector side, via the RHIM region) is part of the bridging function of TICAM1 between receptor and effectors, so the informative replacement is signaling adaptor activity (GO:0035591). Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:25736436 TRIF contains multiple conserved domains that are responsible for further association with downstream molecules receptor-interacting protein 1 (RIP1), TRAF6, and TANK-binding kinase 1 (TBK1). |
| GO:0005515 protein binding | IPI PMID:25736436 WDFY1 mediates TLR3/4 signaling by recruiting TRIF. | MODIFY | Summary: IPI with TICAM2/TRAM (Q86XR7), the sorting adaptor that couples TRIF to TLR4. Reason: Generic protein binding is uninformative. In this paper TRIF is recruited to TLR3/TLR4 (assisted by WDFY1) and associates with the downstream effectors RIP1, TRAF6 and TBK1; interaction with TICAM2 (receptor-proximal bridging adaptor for TLR4) is part of the bridging function of TICAM1 between receptor and effectors, so the informative replacement is signaling adaptor activity (GO:0035591). Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:25736436 WDFY1 interacts with TLR3 and TLR4 and mediates the recruitment of TRIF to these receptors. PMID:25736436 Subsequently, TLR4 is internalized into early endosomes and triggers TRIF-dependent signaling |
| GO:0005515 protein binding | IPI PMID:25736436 WDFY1 mediates TLR3/4 signaling by recruiting TRIF. | MODIFY | Summary: IPI with TBK1 (Q9UHD2) in the WDFY1 study. Reason: Generic protein binding is uninformative. In this paper TRIF is recruited to TLR3/TLR4 (assisted by WDFY1) and associates with the downstream effectors RIP1, TRAF6 and TBK1; interaction with TBK1 (effector side) is part of the bridging function of TICAM1 between receptor and effectors, so the informative replacement is signaling adaptor activity (GO:0035591). Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:25736436 TRIF contains multiple conserved domains that are responsible for further association with downstream molecules receptor-interacting protein 1 (RIP1), TRAF6, and TANK-binding kinase 1 (TBK1). |
| GO:0005515 protein binding | IPI PMID:25736436 WDFY1 mediates TLR3/4 signaling by recruiting TRIF. | MODIFY | Summary: IPI with TRAF6 (Q9Y4K3) in the WDFY1 study. Reason: Generic protein binding is uninformative. In this paper TRIF is recruited to TLR3/TLR4 (assisted by WDFY1) and associates with the downstream effectors RIP1, TRAF6 and TBK1; interaction with TRAF6 (effector side) is part of the bridging function of TICAM1 between receptor and effectors, so the informative replacement is signaling adaptor activity (GO:0035591). Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:25736436 TRIF contains multiple conserved domains that are responsible for further association with downstream molecules receptor-interacting protein 1 (RIP1), TRAF6, and TANK-binding kinase 1 (TBK1). |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: IPI with CARM1 (Q86X55) from a proteome-scale binary interactome screen. Reason: Generic protein binding from a high-throughput screen with no functional follow-up for TICAM1; uninformative. Removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:36232715 PAUF Induces Migration of Human Pancreatic Cancer Cells Excl... | REMOVE | Summary: IPI with TLR4 (O00206) from a study showing PAUF activates TLR4 through MyD88 but not through TRIF. Reason: Generic protein binding is uninformative. The paper co-immunoprecipitated TRIF with TLR4 only as a readout (PAUF did not change it). TLR4 engagement by TRIF is better expressed through signaling adaptor activity and the TLR4 pathway terms. Removal does not dispute the interaction. Supporting Evidence: PMID:36232715 However, rPAUF did not affect the binding of TRIF to TLR4 (Figure 6B). |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Mitochondrial localization transferred from mouse Ticam1, where a DDX1-DDX21-DHX36-TRIF helicase complex in myeloid dendritic cells was reported to relocate to mitochondria after poly(I:C). Reason: The UniProt record carries this only as By similarity from a mouse study; there is no direct human evidence, and the main signaling sites of TICAM1 are the cytosol and endosomes. Not wrong but peripheral; retained as non-core. ORGANELLES check (2026-11-03): GO_REF:0000120 carries UniProt SL-0173 plus the Ensembl mouse orthologue; UniProt tags the human location only ECO:0000250 from mouse Ticam1, the same source as the ISS row. Mouse Ticam1 (Q80UF7) holds the term by a single IDA, PMID:21703541, in which tagged DDX1 and TRIF expressed in HEK293T cells showed increased mitochondrial staining after poly I:C, read by the authors as translocation of the helicase-TRIF complex; the paper reports no fractionation with an ER marker and no sub-mitochondrial assay. This is a stimulus-induced recruitment of a soluble TIR adaptor (TRAF3/BRAF precedent), so the organelle claim holds only as a non-core, condition-dependent pool; TICAM1 has no transit peptide or membrane anchor, and recruitment to the surface is not an outer-membrane location, so no sub-compartment is added. Supporting Evidence: file:human/TICAM1/TICAM1-uniprot.txt DDX21 and DHX36. Colocalizes in the mitochondria with DDX1 and PMID:21703541 there was increased expression of TRIF and DDX1 in the mitochondria after poly I:C activation |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mitochondrial localization transferred from mouse Ticam1, where a DDX1-DDX21-DHX36-TRIF helicase complex in myeloid dendritic cells was reported to relocate to mitochondria after poly(I:C). Reason: The UniProt record carries this only as By similarity from a mouse study; there is no direct human evidence, and the main signaling sites of TICAM1 are the cytosol and endosomes. Not wrong but peripheral; retained as non-core. ORGANELLES check (2026-11-03): the ISS WITH/FROM is mouse Ticam1, a true orthologue, so no source defect; GOA lists this ISS row twice (two dates), both covered by this entry. Mouse Ticam1 (Q80UF7) holds the term by a single IDA, PMID:21703541, in which tagged DDX1 and TRIF expressed in HEK293T cells showed increased mitochondrial staining after poly I:C, read by the authors as translocation of the helicase-TRIF complex; the paper reports no fractionation with an ER marker and no sub-mitochondrial assay. This is a stimulus-induced recruitment of a soluble TIR adaptor (TRAF3/BRAF precedent), so the organelle claim holds only as a non-core, condition-dependent pool; TICAM1 has no transit peptide or membrane anchor, and recruitment to the surface is not an outer-membrane location, so no sub-compartment is added. Supporting Evidence: file:human/TICAM1/TICAM1-uniprot.txt DDX21 and DHX36. Colocalizes in the mitochondria with DDX1 and PMID:21703541 there was increased expression of TRIF and DDX1 in the mitochondria after poly I:C activation |
| GO:0005768 endosome | IBA GO_REF:0000033 | ACCEPT | Summary: Endosome localization by phylogenetic inference (PAINT node shared with TICAM2). Reason: TICAM1 signals from endosomes downstream of endosomal TLR3 and internalized TLR4; supported by direct experimental data (see IDA rows). Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:25736436 Subsequently, TLR4 is internalized into early endosomes and triggers TRIF-dependent signaling |
| GO:0005768 endosome | IDA PMID:18222170 Roles for LPS-dependent interaction and relocation of TLR4 a... | ACCEPT | Summary: Endosome localization of TRIF signaling downstream of TLR4/TRAM relocation. Reason: The paper shows TRAM recruits TRIF to the membrane and TLR4-TRAM relocates to endosome/lysosome where TRIF signaling is activated. Curator read the full text; consistent with the wider literature. Supporting Evidence: PMID:18222170 Here, we show that TRAM recruits TRIF to the plasma membrane. PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. |
| GO:0005769 early endosome | IDA PMID:17982077 Spatiotemporal mobilization of Toll/IL-1 receptor domain-con... | ACCEPT | Summary: Early endosome: TICAM-1 transiently colocalizes with TLR3 (an endosomal receptor) after dsRNA stimulation before forming cytoplasmic speckles. Reason: Direct imaging evidence; the transient TLR3 co-localization places TICAM1 at the endosome where TLR3 signals. Full text not cached; defer to curator. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0005776 autophagosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Autophagosome localization from UniProt subcellular location (colocalization with UBQLN1). Reason: TICAM1 is delivered to autophagosomes for its own turnover (UBQLN1, and TAX1BP1/TRIM32-mediated selective autophagy per UniProt). This reflects regulation of TICAM1 levels, not a site of its function. Supporting Evidence: file:human/TICAM1/TICAM1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasmic vesicle, autophagosome |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: Cytosol (combined IEA). Reason: TICAM1 is a soluble cytoplasmic adaptor that is diffuse in the cytoplasm at rest and forms cytoplasmic speckles upon dsRNA stimulation. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | NAS PMID:36865541 Regulation of innate immune signaling by IRAK proteins. | ACCEPT | Summary: Cytosol (NAS, review on IRAK proteins). Reason: TICAM1 is a cytoplasmic adaptor; consistent with imaging evidence. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-166175 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-166245 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-166271 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-168915 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-168921 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-168929 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2201338 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2213017 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2559568 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2562541 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2562564 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2569057 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-450358 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5362486 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5362500 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5602712 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-936947 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-936951 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-936952 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-936985 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-937029 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-937075 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9823904 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9823906 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9823910 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9823932 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9823934 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9823939 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9824882 | ACCEPT | Summary: Cytosol location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome models TICAM1 on the cytoplasmic side of activated TLR complexes, where it recruits TRAF3, TRAF6, RIPK1 and TBK1. Consistent with experimental data showing a diffuse cytoplasmic distribution. Supporting Evidence: PMID:17982077 In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: Signal transduction, from InterPro TIR domain mapping. Reason: Correct but very general; TICAM1 is a TIR-domain signaling adaptor. The IEA does not introduce any receptor or enzyme term from the TIR domain. Supporting Evidence: PMID:12471095 TRIF associated with TLR3 and IFN regulatory factor 3. |
| GO:0007166 cell surface receptor signaling pathway | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Cell surface receptor signaling pathway (ARBA). Reason: GO:0002224 toll-like receptor signaling pathway is not classified under cell surface receptor signaling pathway (checked in OLS). TICAM1 signals mainly downstream of endosomal TLR3 and of TLR4 after internalization into endosomes, so the cell-surface framing is misleading; the TLR pathway terms capture the process correctly. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:36865541 Most TLRs employ MyD88 as signaling adaptor, with the exceptions being TLR3 that signals exclusively via TRIF and TLR4 that uses both TRIF and MyD88 (2). |
| GO:0010008 endosome membrane | IDA PMID:18222170 Roles for LPS-dependent interaction and relocation of TLR4 a... | ACCEPT | Summary: Endosome membrane: TRIF signaling from TLR4-TRAM complexes after relocation to endosome/lysosome. Reason: TICAM1 is a peripheral adaptor on the cytoplasmic face of endosomal TLR complexes; supported by direct evidence. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-168929 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-168930 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-177690 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-177692 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-177694 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-450259 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-5602624 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-847070 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013889 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013895 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013963 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013974 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013978 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013979 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013985 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013990 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9013992 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9014320 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9014342 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9014343 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9628444 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9828196 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9828200 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9828204 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9828205 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9828209 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9830706 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9830710 | ACCEPT | Summary: Endosome membrane location from Reactome TLR3/TLR4-TRIF pathway reactions. Reason: Reactome places the dsRNA:TLR3:TICAM1 and TLR4:TRAM:TICAM1 complexes at the endosome membrane; TICAM1 is recruited to the cytoplasmic face of these receptors. Consistent with experimental data. Supporting Evidence: PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. PMID:17982077 Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. |
| GO:0010508 positive regulation of autophagy | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of autophagy, transferred from mouse Ticam1. Reason: TLR4-induced autophagy in macrophages has been linked to the TRIF arm in mouse; this is a downstream consequence of TRIF-dependent signaling rather than a core TICAM1 function. No direct human evidence reviewed here. |
| GO:0010508 positive regulation of autophagy | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of autophagy, transferred from mouse Ticam1. Reason: TLR4-induced autophagy in macrophages has been linked to the TRIF arm in mouse; this is a downstream consequence of TRIF-dependent signaling rather than a core TICAM1 function. No direct human evidence reviewed here. |
| GO:0010628 positive regulation of gene expression | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of gene expression, transferred from mouse Ticam1. Reason: Correct in the broad sense (TICAM1 signaling drives IFNB1 and inflammatory gene expression) but uninformative; the specific terms (positive regulation of type I interferon production, canonical NF-kappaB) capture the function. Supporting Evidence: PMID:12471095 Furthermore, TRIF, but neither MyD88 nor TIRAP, activated the IFN-beta promoter. |
| GO:0010628 positive regulation of gene expression | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of gene expression, transferred from mouse Ticam1. Reason: Correct in the broad sense (TICAM1 signaling drives IFNB1 and inflammatory gene expression) but uninformative; the specific terms (positive regulation of type I interferon production, canonical NF-kappaB) capture the function. Supporting Evidence: PMID:12471095 Furthermore, TRIF, but neither MyD88 nor TIRAP, activated the IFN-beta promoter. |
| GO:0019901 protein kinase binding | IPI PMID:14530355 Toll/IL-1 receptor domain-containing adaptor inducing IFN-be... | ACCEPT | Summary: TICAM1 binds the kinase TBK1 through its N-terminal region; the association requires TBK1 kinase activity and TRIF phosphorylation. Reason: Informative and well supported. TBK1 binding is the basis of the IRF3 branch: TBK1 phosphorylates the TICAM1 pLxIS motif, which then recruits IRF3. Captured in core function as part of the adaptor activity. Supporting Evidence: PMID:14530355 also associated with the N-terminal region of TRIF PMID:14530355 Moreover, the association between TRIF and TBK1 appeared to require the kinase activity of TBK1, as well as phosphorylation of TRIF. PMID:25636800 We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. |
| GO:0031663 lipopolysaccharide-mediated signaling pathway | NAS PMID:35979366 Supramolecular organizing centers at the interface of inflam... | ACCEPT | Summary: LPS-mediated signaling pathway (NAS, review). Reason: TICAM1 mediates the MyD88-independent (TRAM-TRIF) arm of TLR4 signaling in response to LPS. The more specific GO:0035667 TRIF-dependent toll-like receptor 4 signaling pathway is also present. Supporting Evidence: PMID:35979366 TRIF can initiate various responses, including activation of transcription factors NF-ΞΊB, IRF3, and AP-1 through different pathways. PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. |
| GO:0032481 positive regulation of type I interferon production | IBA GO_REF:0000033 | ACCEPT | Summary: Positive regulation of type I interferon production (IBA). Reason: TICAM1 is the adaptor that links TLR3 and endosomal TLR4 to TBK1-IRF3 and IFN-beta induction; the phosphorylated pLxIS motif directly recruits IRF3. Core function. Supporting Evidence: PMID:12471095 Furthermore, TRIF, but neither MyD88 nor TIRAP, activated the IFN-beta promoter. PMID:25636800 We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. |
| GO:0032481 positive regulation of type I interferon production | IDA PMID:28049150 FOSL1 Inhibits Type I Interferon Responses to Malaria and Vi... | ACCEPT | Summary: Positive regulation of type I interferon production (IDA; FOSL1 study using TRIF-driven ISRE reporter). Reason: TICAM1 is the adaptor that links TLR3 and endosomal TLR4 to TBK1-IRF3 and IFN-beta induction; the phosphorylated pLxIS motif directly recruits IRF3. Core function. Supporting Evidence: PMID:28049150 These results suggest that FOSL1 acts on molecules downstream of STING/MAVS/TRIF but upstream of TBK1/IRF3/IKKi in IFN-I signaling. PMID:25636800 We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. |
| GO:0032481 positive regulation of type I interferon production | IEA GO_REF:0000117 | ACCEPT | Summary: Positive regulation of type I interferon production (ARBA). Reason: TICAM1 is the adaptor that links TLR3 and endosomal TLR4 to TBK1-IRF3 and IFN-beta induction; the phosphorylated pLxIS motif directly recruits IRF3. Core function. Supporting Evidence: PMID:12471095 Furthermore, TRIF, but neither MyD88 nor TIRAP, activated the IFN-beta promoter. |
| GO:0034138 toll-like receptor 3 signaling pathway | IDA PMID:12471095 Cutting edge: a novel Toll/IL-1 receptor domain-containing a... | ACCEPT | Summary: TLR3 signaling pathway: TICAM1 is the sole adaptor of TLR3. Reason: TRIF associates with TLR3 via TIR-TIR interaction and dominant-negative TRIF blocks TLR3-dependent NF-kappaB and IFN-beta promoter activation. Core function. Supporting Evidence: PMID:12471095 TRIF associated with TLR3 and IFN regulatory factor 3. PMID:12471095 Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters. PMID:12539043 We have identified an alternative adaptor, designated Toll-interleukin 1 receptor domain (TIR)-containing adaptor molecule (TICAM)-1, that can physically bind the TIR domain of TLR3 and activate the IFN-beta promoter in response to poly(I):poly(C). |
| GO:0034142 toll-like receptor 4 signaling pathway | IDA PMID:12471095 Cutting edge: a novel Toll/IL-1 receptor domain-containing a... | ACCEPT | Summary: TLR4 signaling pathway: TICAM1 mediates the MyD88-independent arm of TLR4 signaling. Reason: Dominant-negative TRIF inhibits TLR4-dependent NF-kappaB activation; TRIF is recruited to TLR4 via TICAM2/TRAM and signals from endosomes. Core function. Supporting Evidence: PMID:12471095 A dominant-negative form of TRIF inhibited TLR2-, TLR4-, and TLR7-dependent NF-kappaB activation. PMID:18222170 Here, we show that TRAM recruits TRIF to the plasma membrane. PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. |
| GO:0035591 signaling adaptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Signaling adaptor activity (IBA; PAINT node shared with TICAM2). Reason: TICAM1 bridges activated TLR3 (directly) and TLR4 (via TICAM2) to TRAF6, TRAF3, RIPK1 and TBK1, and its phosphorylated pLxIS motif recruits IRF3. This is exactly signaling adaptor activity; TICAM1 has no known catalytic activity. Core function. Supporting Evidence: PMID:14982987 In conclusion, TRIF recruits TRAF6-TAK1-TAB2 to TLR3 through its TRAF6-binding site, which is required for NF-ΞΊB but not IRF3 activation. PMID:25736436 TRIF contains multiple conserved domains that are responsible for further association with downstream molecules receptor-interacting protein 1 (RIP1), TRAF6, and TANK-binding kinase 1 (TBK1). PMID:27302953 The adaptor proteins STING, MAVS, and TRIF recruit IRF-3 through their phosphorylated p L x IS motifs. |
| GO:0035591 signaling adaptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: Signaling adaptor activity (IEA, Ensembl Compara from mouse). Reason: TICAM1 bridges activated TLR3 (directly) and TLR4 (via TICAM2) to TRAF6, TRAF3, RIPK1 and TBK1, and its phosphorylated pLxIS motif recruits IRF3. This is exactly signaling adaptor activity; TICAM1 has no known catalytic activity. Core function. Supporting Evidence: PMID:14982987 In conclusion, TRIF recruits TRAF6-TAK1-TAB2 to TLR3 through its TRAF6-binding site, which is required for NF-ΞΊB but not IRF3 activation. |
| GO:0035666 TRIF-dependent toll-like receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: TRIF-dependent toll-like receptor signaling pathway (IBA). Reason: The pathway is defined by TICAM1 itself (TRIF-dependent); TICAM1 performs the adaptor step. Core function. Supporting Evidence: PMID:12471095 TRIF associated with TLR3 and IFN regulatory factor 3. PMID:14982987 In conclusion, TRIF recruits TRAF6-TAK1-TAB2 to TLR3 through its TRAF6-binding site, which is required for NF-ΞΊB but not IRF3 activation. |
| GO:0035666 TRIF-dependent toll-like receptor signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: TRIF-dependent toll-like receptor signaling pathway (combined IEA). Reason: The pathway is defined by TICAM1 itself (TRIF-dependent); TICAM1 performs the adaptor step. Core function. Supporting Evidence: PMID:12471095 TRIF associated with TLR3 and IFN regulatory factor 3. |
| GO:0035666 TRIF-dependent toll-like receptor signaling pathway | IMP PMID:25636800 Phosphorylation of innate immune adaptor proteins MAVS, STIN... | ACCEPT | Summary: TRIF-dependent toll-like receptor signaling pathway (IMP; phosphorylation-site mutants of the pLxIS motif abolish IRF3 activation). Reason: The pathway is defined by TICAM1 itself (TRIF-dependent); TICAM1 performs the adaptor step. Core function. Mutation of the pLxIS motif abolishes TRIF-induced IRF3 activation. Supporting Evidence: PMID:25636800 We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. file:human/TICAM1/TICAM1-uniprot.txt TBK1 on the pLxIS motif leads to recruitment and subsequent activation |
| GO:0035666 TRIF-dependent toll-like receptor signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: TRIF-dependent toll-like receptor signaling pathway (ISS from mouse). Reason: The pathway is defined by TICAM1 itself (TRIF-dependent); TICAM1 performs the adaptor step. Core function. Supporting Evidence: PMID:12471095 TRIF associated with TLR3 and IFN regulatory factor 3. |
| GO:0035667 TRIF-dependent toll-like receptor 4 signaling pathway | NAS PMID:25385819 TRAM is required for TLR2 endosomal signaling to type I IFN ... | ACCEPT | Summary: TRIF-dependent toll-like receptor 4 signaling pathway (NAS). Reason: TLR4 signaling switches to TRAM and TRIF after internalization into endosomes; TICAM1 is the signaling adaptor of this arm. Core function. Supporting Evidence: PMID:25385819 TLR4 initially signals at the plasma membrane (via Mal and MyD88) and is then internalized into early endosomes, where signaling switches to utilizing TRAM and TRIF PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | HMP PMID:12761501 Large-scale identification and characterization of human gen... | ACCEPT | Summary: Positive regulation of canonical NF-kappaB signal transduction (HMP; large-scale cDNA overexpression screen for NF-kappaB activators). Reason: TICAM1 recruits TRAF6 (via N-terminal TRAF6-binding motifs) and RIPK1 (via its C-terminal RHIM region) to activate IKK and canonical NF-kappaB; mutation of the TRAF6-binding motif abolishes NF-kappaB but not IRF3 activation. The screen is overexpression-based, but the conclusion is confirmed by targeted studies. Supporting Evidence: PMID:12761501 For analysis of the NF-kappaB signaling pathway, we introduced each of the cDNAs into human embryonic kidney 293 cells and examined whether it activated the transcription of a luciferase reporter gene driven by a promoter containing the consensus NF-kappaB binding sites. PMID:14982987 In conclusion, TRIF recruits TRAF6-TAK1-TAB2 to TLR3 through its TRAF6-binding site, which is required for NF-ΞΊB but not IRF3 activation. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: Positive regulation of canonical NF-kappaB signal transduction (IBA). Reason: TICAM1 recruits TRAF6 (via N-terminal TRAF6-binding motifs) and RIPK1 (via its C-terminal RHIM region) to activate IKK and canonical NF-kappaB; mutation of the TRAF6-binding motif abolishes NF-kappaB but not IRF3 activation. Supporting Evidence: PMID:14982987 In conclusion, TRIF recruits TRAF6-TAK1-TAB2 to TLR3 through its TRAF6-binding site, which is required for NF-ΞΊB but not IRF3 activation. PMID:14739303 TRIF induced NF-kappaB activation through an IKKbeta- and tumor necrosis factor receptor-associated factor-6-dependent (but not TBK1- and IKKepsilon-dependent) pathway. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IEA GO_REF:0000120 | ACCEPT | Summary: Positive regulation of canonical NF-kappaB signal transduction (combined IEA). Reason: TICAM1 recruits TRAF6 (via N-terminal TRAF6-binding motifs) and RIPK1 (via its C-terminal RHIM region) to activate IKK and canonical NF-kappaB; mutation of the TRAF6-binding motif abolishes NF-kappaB but not IRF3 activation. Supporting Evidence: PMID:14739303 TRIF induced NF-kappaB activation through an IKKbeta- and tumor necrosis factor receptor-associated factor-6-dependent (but not TBK1- and IKKepsilon-dependent) pathway. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IMP PMID:14982987 Toll-like receptor 3-mediated activation of NF-kappaB and IR... | ACCEPT | Summary: Positive regulation of canonical NF-kappaB signal transduction (IMP; TRAF6-binding motif mutants). Reason: TICAM1 recruits TRAF6 (via N-terminal TRAF6-binding motifs) and RIPK1 (via its C-terminal RHIM region) to activate IKK and canonical NF-kappaB; mutation of the TRAF6-binding motif abolishes NF-kappaB but not IRF3 activation. Supporting Evidence: PMID:14982987 We found that TLR3 recruits TRAF6 via adapter TRIF through a TRAF6-binding sequence in TRIF (PEEMSW, amino acids 250-255). PMID:14982987 In conclusion, TRIF recruits TRAF6-TAK1-TAB2 to TLR3 through its TRAF6-binding site, which is required for NF-ΞΊB but not IRF3 activation. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | ISS GO_REF:0000024 | ACCEPT | Summary: Positive regulation of canonical NF-kappaB signal transduction (ISS from mouse). Reason: TICAM1 recruits TRAF6 (via N-terminal TRAF6-binding motifs) and RIPK1 (via its C-terminal RHIM region) to activate IKK and canonical NF-kappaB; mutation of the TRAF6-binding motif abolishes NF-kappaB but not IRF3 activation. Supporting Evidence: PMID:14739303 TRIF induced NF-kappaB activation through an IKKbeta- and tumor necrosis factor receptor-associated factor-6-dependent (but not TBK1- and IKKepsilon-dependent) pathway. |
| GO:0043330 response to exogenous dsRNA | IEA GO_REF:0000117 | ACCEPT | Summary: Response to exogenous dsRNA (ARBA). Reason: TICAM1 is required for the TLR3 response to extracellular/endosomal dsRNA (poly(I:C)), acting as the adaptor that transduces the signal. Correct, though the TLR3 signaling pathway term is the more precise description. Supporting Evidence: PMID:12539043 We have identified an alternative adaptor, designated Toll-interleukin 1 receptor domain (TIR)-containing adaptor molecule (TICAM)-1, that can physically bind the TIR domain of TLR3 and activate the IFN-beta promoter in response to poly(I):poly(C). |
| GO:0043330 response to exogenous dsRNA | IMP PMID:21266579 Raftlin is involved in the nucleocapture complex to induce p... | ACCEPT | Summary: Response to exogenous dsRNA (IMP, Raftlin study of poly(I:C) uptake and TLR3 activation). Reason: TICAM1 is required for the TLR3 response to extracellular/endosomal dsRNA (poly(I:C)), acting as the adaptor that transduces the signal. Correct, though the TLR3 signaling pathway term is the more precise description. The curator read the full text; the paper places TICAM-1 downstream of poly(I:C)-TLR3. Supporting Evidence: PMID:21266579 Toll-IL-1 receptor domain-containing adaptor molecule-1 (TICAM-1, also called TRIF) that activates the NF-ΞΊB, IRF-3, and AP-1 transcription factors, leading to IFN-Ξ² production PMID:12539043 We have identified an alternative adaptor, designated Toll-interleukin 1 receptor domain (TIR)-containing adaptor molecule (TICAM)-1, that can physically bind the TIR domain of TLR3 and activate the IFN-beta promoter in response to poly(I):poly(C). |
| GO:0043330 response to exogenous dsRNA | ISS GO_REF:0000024 | ACCEPT | Summary: Response to exogenous dsRNA (ISS from mouse). Reason: TICAM1 is required for the TLR3 response to extracellular/endosomal dsRNA (poly(I:C)), acting as the adaptor that transduces the signal. Correct, though the TLR3 signaling pathway term is the more precise description. Supporting Evidence: PMID:12539043 We have identified an alternative adaptor, designated Toll-interleukin 1 receptor domain (TIR)-containing adaptor molecule (TICAM)-1, that can physically bind the TIR domain of TLR3 and activate the IFN-beta promoter in response to poly(I):poly(C). |
| GO:0045087 innate immune response | IEA GO_REF:0000002 | ACCEPT | Summary: Innate immune response (InterPro). Reason: TICAM1 is an innate immune signaling adaptor; correct high-level term. Supporting Evidence: PMID:12471095 Furthermore, TRIF, but neither MyD88 nor TIRAP, activated the IFN-beta promoter. |
| GO:0045087 innate immune response | NAS PMID:35979366 Supramolecular organizing centers at the interface of inflam... | ACCEPT | Summary: Innate immune response (NAS, review). Reason: TICAM1 is an innate immune signaling adaptor; correct high-level term. Supporting Evidence: PMID:35979366 TRIF can initiate various responses, including activation of transcription factors NF-ΞΊB, IRF3, and AP-1 through different pathways. |
| GO:0060090 molecular adaptor activity | IDA PMID:12471095 Cutting edge: a novel Toll/IL-1 receptor domain-containing a... | MODIFY | Summary: Molecular adaptor activity (IDA, discovery paper). Reason: Molecular adaptor activity is correct but a generic parent; the more specific GO:0035591 signaling adaptor activity (a child of molecular adaptor activity, checked in OLS) describes TICAM1 bridging receptors to signaling effectors. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:12471095 TRIF associated with TLR3 and IFN regulatory factor 3. PMID:12471095 Furthermore, TRIF, but neither MyD88 nor TIRAP, activated the IFN-beta promoter. |
| GO:0060090 molecular adaptor activity | IEA GO_REF:0000117 | MODIFY | Summary: Molecular adaptor activity (ARBA). Reason: Molecular adaptor activity is correct but a generic parent; the more specific GO:0035591 signaling adaptor activity (a child of molecular adaptor activity, checked in OLS) describes TICAM1 bridging receptors to signaling effectors. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:12471095 TRIF associated with TLR3 and IFN regulatory factor 3. |
| GO:0071222 cellular response to lipopolysaccharide | IEA GO_REF:0000107 | ACCEPT | Summary: Cellular response to lipopolysaccharide, transferred from mouse Ticam1 (Trif-deficient mice lose the MyD88-independent LPS response). Reason: TICAM1 transduces the TRAM-dependent arm of TLR4 signaling in response to LPS; correct, with GO:0034142 and GO:0035667 as the more precise descriptions. Supporting Evidence: PMID:12471095 A dominant-negative form of TRIF inhibited TLR2-, TLR4-, and TLR7-dependent NF-kappaB activation. PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. |
| GO:0071222 cellular response to lipopolysaccharide | ISS GO_REF:0000024 | ACCEPT | Summary: Cellular response to lipopolysaccharide, transferred from mouse Ticam1 (Trif-deficient mice lose the MyD88-independent LPS response). Reason: TICAM1 transduces the TRAM-dependent arm of TLR4 signaling in response to LPS; correct, with GO:0034142 and GO:0035667 as the more precise descriptions. Supporting Evidence: PMID:12471095 A dominant-negative form of TRIF inhibited TLR2-, TLR4-, and TLR7-dependent NF-kappaB activation. PMID:18222170 These results suggest that TLR4 activates TRIF-signaling in endosome/lysosome after relocation from the cell surface. |
| GO:0140052 cellular response to oxidised low-density lipoprotein particle stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cellular response to oxidised LDL particle stimulus, transferred from mouse Ticam1. Reason: Oxidised LDL can engage TLR4-containing receptor complexes, and a TRIF requirement for this response in mouse is plausible; it is a ligand-specific consequence of TLR4-TRIF signaling rather than a distinct TICAM1 function. The mouse source paper was not reviewed here. |
| GO:0140052 cellular response to oxidised low-density lipoprotein particle stimulus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cellular response to oxidised LDL particle stimulus, transferred from mouse Ticam1. Reason: Oxidised LDL can engage TLR4-containing receptor complexes, and a TRIF requirement for this response in mouse is plausible; it is a ligand-specific consequence of TLR4-TRIF signaling rather than a distinct TICAM1 function. The mouse source paper was not reviewed here. |
| GO:1900017 positive regulation of cytokine production involved in inflammatory response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of cytokine production involved in inflammatory response, transferred from mouse Ticam1. Reason: TRIF-dependent TLR3/TLR4 signaling drives inflammatory cytokine production (TNF, IL-6) as well as type I IFN; this is a downstream outcome of the adaptor function and is retained as non-core. Supporting Evidence: PMID:35979366 TRIF can initiate various responses, including activation of transcription factors NF-ΞΊB, IRF3, and AP-1 through different pathways. |
| GO:1900017 positive regulation of cytokine production involved in inflammatory response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of cytokine production involved in inflammatory response, transferred from mouse Ticam1. Reason: TRIF-dependent TLR3/TLR4 signaling drives inflammatory cytokine production (TNF, IL-6) as well as type I IFN; this is a downstream outcome of the adaptor function and is retained as non-core. Supporting Evidence: PMID:35979366 TRIF can initiate various responses, including activation of transcription factors NF-ΞΊB, IRF3, and AP-1 through different pathways. |
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Download this section (compressed HTML)Q: Should TICAM1 carry a process term for RIPK1/RIPK3-dependent cell death (e.g. necroptotic signaling or extrinsic apoptotic signaling)? The RHIM-containing C-terminus induces RIPK1/FADD/caspase-8-dependent apoptosis on overexpression and Reactome models RIPK3:TRIF necroptosis, but no GOA row captures this, and human evidence beyond overexpression was not found in the cached literature.
Q: Is TLR5 signaling through TRIF (reported in intestinal epithelial cells, largely from mouse knockouts) robust enough to annotate TICAM1 to GO:0034146 toll-like receptor 5 signaling pathway, given that IRF3 activation was not observed in that setting?
Q: Is the mitochondrial localization of a DDX1-DDX21-DHX36-TICAM1 helicase complex (reported in mouse myeloid dendritic cells) reproducible in human cells, or should the mitochondrion annotations be retired?
Q: Does the TICAM1 N-terminal domain (IFIT-like fold) have an activity of its own, for example as a regulatory or autoinhibitory module, beyond its role in recruiting TRAF6 and TBK1?
Experiment: In TICAM1-knockout human macrophages or epithelial cells, reconstitute wild-type TICAM1, a RHIM-mutant, a TRAF6-motif mutant and a pLxIS (S210A) mutant, then stimulate with poly(I:C) and LPS and measure IRF3 phosphorylation, NF-kappaB activation, IFNB1 output and cell death (apoptosis vs necroptosis with caspase inhibition).
Hypothesis: The three effector-recruitment modules of TICAM1 are separable, and the RHIM module is required for TLR3/TLR4-induced cell death in human cells at endogenous expression levels.
Type: genetic complementation in knockout cells
Experiment: Live-cell imaging of endogenously tagged TICAM1 with TLR3, TICAM2 and organelle markers (EEA1, LAMP1, TOM20) after poly(I:C) or LPS stimulation in primary human dendritic cells.
Hypothesis: TICAM1 signaling speckles assemble at the cytoplasmic face of endosomes and not at mitochondria in human cells.
Type: live-cell imaging
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