TLR9 (Toll-like receptor 9, CD289) is an endosomal pattern recognition receptor of the innate immune system that senses DNA containing unmethylated CpG dinucleotides, a feature enriched in bacterial and viral genomes. It is a single-pass type I membrane protein with a leucine-rich-repeat ectodomain and a cytoplasmic TIR domain. Newly made TLR9 is folded in the endoplasmic reticulum and trafficked with the chaperone UNC93B1 through the Golgi to endolysosomes, where proteolytic cleavage of the ectodomain generates the functional receptor. CpG DNA binding induces a 2:2 receptor-ligand dimer that recruits MyD88 through the TIR domain, assembling an IRAK4-IRAK1/2-TRAF6 complex that activates NF-kappaB and MAP kinases (pro-inflammatory cytokines) and, in plasmacytoid dendritic cells, IRF7 (type I interferon). TLR9 is expressed mainly in B cells and plasmacytoid dendritic cells, and also in epithelial and other cell types; it drives B cell proliferation and antibody secretion, and its intracellular localization limits responses to self DNA.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | EXP PMID:38169466 Cyclical palmitoylation regulates TLR9 signalling and system... | ACCEPT | Summary: TLR9 transits the Golgi on its way from the ER to endolysosomes; DHHC3 palmitoylates the TLR9 ectodomain in the Golgi. Reason: Experimental localization of TLR9 to the Golgi in the palmitoylation study. The Golgi is a transit compartment on the UNC93B1-dependent ER-to-endolysosome route rather than the signalling site, but the location is correct. Supporting Evidence: PMID:38169466 The palmitoylation cycle begins in the Golgi, where DHHC3 palmitoylates TLR9 and ends in lysosomes, where PPT1 depalmitoylates TLR9. PMID:38169466 Here we showed that Golgi-bound DHHC proteins could palmitoylate human TLR9 in vitro. |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to Golgi membrane. Reason: Consistent with the experimental Golgi localization (PMID:38169466); TLR9 passes through the Golgi en route to endolysosomes. Supporting Evidence: PMID:38169466 The palmitoylation cycle begins in the Golgi, where DHHC3 palmitoylates TLR9 and ends in lysosomes, where PPT1 depalmitoylates TLR9. |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-1678927 | ACCEPT | Summary: Reactome places full-length TLR9 in the Golgi membrane during UNC93B1-mediated trafficking to endolysosomes. Reason: Consistent with experimental data showing TLR9 in Golgi fractions during trafficking (PMID:38169466). Transit location, correct. Supporting Evidence: PMID:38169466 The palmitoylation cycle begins in the Golgi, where DHHC3 palmitoylates TLR9 and ends in lysosomes, where PPT1 depalmitoylates TLR9. |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-1678998 | ACCEPT | Summary: Reactome places full-length TLR9 in the Golgi membrane during UNC93B1-mediated trafficking to endolysosomes. Reason: Consistent with experimental data showing TLR9 in Golgi fractions during trafficking (PMID:38169466). Transit location, correct. Supporting Evidence: PMID:38169466 The palmitoylation cycle begins in the Golgi, where DHHC3 palmitoylates TLR9 and ends in lysosomes, where PPT1 depalmitoylates TLR9. |
| GO:0001774 microglial cell activation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer from rat Tlr9 of microglial cell activation. Reason: CpG DNA acting through TLR9 activates microglia (reported in mouse microglia, PMID:15356140), so the outcome is plausible for human TLR9, but it is a cell-type-specific consequence of TLR9 signalling rather than the receptor's core function. Supporting Evidence: PMID:15356140 stimulation of quiescent microglia with various TLR agonists, including LPS (TLR4), peptidoglycan (TLR2), polyinosinic-polycytidylic acid (TLR3), CpG DNA (TLR9) |
| GO:0001819 positive regulation of cytokine production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of positive regulation of cytokine production from mouse Tlr9. Reason: TLR9 stimulation leads to cytokine production in many human cell types (e.g. PMID:19740627, PMID:24409285). This is a downstream outcome of TLR9 signalling; it is correct but general and not the receptor's core activity. 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:24409285 CpG-ODN (CpG β oligodeoxynucleotide) and Poly(I:C)LL respectively, induced the activation of pro-inflammatory cytokines, IL-6, IL-8 and GM-CSF production via NF-ΞΊB signaling. |
| GO:0002218 activation of innate immune response | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of activation of innate immune response from mouse Tlr9. Reason: TLR9 is the receptor that initiates the innate immune response to CpG DNA; TLR9-deficient mice do not respond to CpG DNA (PMID:11130078). Correct. Supporting Evidence: PMID:11130078 Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. |
| GO:0002224 toll-like receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA placing toll-like receptor signaling pathway at the TLR7/8/9 clade node. Reason: The generic TLR signalling term is the appropriate level for a node covering TLR7, TLR8 and TLR9; human TLR9 is inside that clade and has direct evidence for signalling through MyD88 after ligand recognition (PMID:14716310). The more specific GO:0034162 is also annotated. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. |
| GO:0002224 toll-like receptor signaling pathway | IDA PMID:17128265 Maintenance of colonic homeostasis by distinctive apical TLR... | ACCEPT | Summary: IDA from polarized intestinal epithelial cells stimulated with CpG DNA through apical or basolateral surfaces. Reason: TLR9 is the receptor of a toll-like receptor signalling pathway and the paper shows TLR9-dependent NF-kappaB responses. Correct; the receptor-specific child term toll-like receptor 9 signaling pathway (GO:0034162) is also annotated and is the more informative term. Supporting Evidence: PMID:17128265 TLR9 activation through apical and basolateral surface domains have distinct transcriptional responses, evident by NF-kappaB activation and cDNA microarray analysis. |
| GO:0002224 toll-like receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from rat of toll-like receptor signaling pathway. Reason: Correct; ligand specificity for CpG DNA is conserved between rodent and human TLR9 (with species differences in optimal motif, PMID:11564765). The more specific GO:0034162 is also annotated. Supporting Evidence: PMID:11564765 Cells that are not responsive to CpG DNA become responsive when transfected with hTLR9. PMID:11564765 Cells expressing hTLR9 are stimulated by CpG motifs that are active in primates but not rodents |
| GO:0002639 positive regulation of immunoglobulin production | IDA PMID:23857366 FCRL3 promotes TLR9-induced B-cell activation and suppresses... | KEEP AS NON CORE | Summary: CpG DNA (TLR9 agonist) drives human blood B cells to differentiate into antibody-secreting cells. Reason: TLR9 engagement by CpG induces IgM/IgG/IgA secretion by human B cells; this is a B-cell-specific downstream consequence of TLR9 signalling rather than the receptor's core function. Supporting Evidence: PMID:23857366 As previously established [34], CpG could induce blood B lymphocytes to differentiate into antibody-secreting cells as indicated by the detection of the IgM, IgG, and IgA isotypes in supernatants by ELISA after 5 days of culture |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of MyD88-dependent toll-like receptor signaling pathway from mouse Tlr9. Reason: TLR9 signals through MyD88: MyD88 accumulates at CpG DNA-containing compartments with TLR9, and only the processed receptor recruits MyD88 (PMID:14716310, PMID:18820679). Correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0005149 interleukin-1 receptor binding | IPI PMID:12925853 SIGIRR, a negative regulator of Toll-like receptor-interleuk... | KEEP AS NON CORE | Summary: IPI with SIGIRR (IL1R8; UniProtKB:Q6IA17), a TIR-domain negative regulator of TLR/IL-1R signalling. Reason: SIGIRR is a member of the IL-1 receptor family and was reported to associate with TLR-IL-1R signalling components in a ligand-dependent way. The cached record is abstract-only, so the TLR9-specific assay cannot be checked; the interaction reflects negative regulation of TLR9 signalling by SIGIRR rather than a function of TLR9 itself, so it is retained as non-core. Supporting Evidence: PMID:12925853 biochemical analysis indicated that SIGIRR binds to the TLR-IL-1R signaling components in a ligand-dependent way. |
| GO:0005576 extracellular region | NAS PMID:11130078 A Toll-like receptor recognizes bacterial DNA. | REMOVE | Summary: NAS asserting TLR9 is located in the extracellular region, citing the TLR9 knockout paper. Reason: TLR9 is a single-pass type I membrane protein resident in the ER, Golgi and endolysosomal membranes; its ectodomain faces the lumen of these compartments, not the extracellular space. The cited paper is a knockout/function paper and contains no evidence for a secreted form. No experimental support; the ectodomain is not released. Supporting Evidence: PMID:14716310 We have found that TLR9 is localized to the endoplasmic reticulum (ER) of dendritic cells (DCs) and macrophages. PMID:18820679 The ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. |
| GO:0005737 cytoplasm | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | KEEP AS NON CORE | Summary: IDA in cultured human melanocytes (immunofluorescence/flow cytometry) placing TLR9 in the cytoplasm. Reason: True in a broad sense - TLR9 is intracellular - but cytoplasm is uninformative relative to the membrane compartments (ER, endolysosome) where TLR9 actually resides. Supporting Evidence: PMID:19740627 Ample amounts of TLRs 2-4, 7 and 9 were confirmed at protein level. |
| GO:0005764 lysosome | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA placing TLR9 in lysosomes. Reason: TLR9 is recruited to a tubular lysosomal compartment with CpG DNA and is cleaved in the endolysosome (PMID:14716310, PMID:18820679). Supporting Evidence: PMID:14716310 CpG DNA moves into early endosomes and is subsequently transported to a tubular lysosomal compartment. PMID:18820679 The ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. |
| GO:0005764 lysosome | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Tlr9 to lysosome. Reason: Consistent with direct evidence of TLR9 in lysosomal/endolysosomal compartments (PMID:14716310, PMID:18820679). Supporting Evidence: PMID:14716310 CpG DNA moves into early endosomes and is subsequently transported to a tubular lysosomal compartment. |
| GO:0005768 endosome | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of endosome from mouse. Reason: TLR9 is recruited to CpG-containing endosomes (PMID:14716310). Supporting Evidence: PMID:14716310 CpG DNA moves into early endosomes and is subsequently transported to a tubular lysosomal compartment. PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. |
| GO:0005768 endosome | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Tlr9 to endosome. Reason: TLR9 is recruited to CpG-containing endosomes (PMID:14716310). Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. |
| GO:0005783 endoplasmic reticulum | IDA PMID:14716310 TLR9 signals after translocating from the ER to CpG DNA in t... | ACCEPT | Summary: IDA localizing TLR9 to the ER of dendritic cells and macrophages. Reason: Directly shown (PMID:14716310). The ER is the resting location from which TLR9 exits with UNC93B1; signalling itself occurs in endolysosomes, so the ER is a correct location but not the site of activity. Supporting Evidence: PMID:14716310 We have found that TLR9 is localized to the endoplasmic reticulum (ER) of dendritic cells (DCs) and macrophages. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of endoplasmic reticulum from mouse. Reason: Consistent with direct evidence (PMID:14716310). Supporting Evidence: PMID:14716310 We have found that TLR9 is localized to the endoplasmic reticulum (ER) of dendritic cells (DCs) and macrophages. |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Tlr9 to endoplasmic reticulum. Reason: Consistent with direct evidence (PMID:14716310). Supporting Evidence: PMID:14716310 We have found that TLR9 is localized to the endoplasmic reticulum (ER) of dendritic cells (DCs) and macrophages. |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:14716310 TLR9 signals after translocating from the ER to CpG DNA in t... | ACCEPT | Summary: EXP placing TLR9 in the ER membrane. Reason: TLR9 is a type I transmembrane protein localized to the ER at rest (PMID:14716310). Supporting Evidence: PMID:14716310 We have found that TLR9 is localized to the endoplasmic reticulum (ER) of dendritic cells (DCs) and macrophages. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to ER membrane. Reason: Consistent with direct evidence (PMID:14716310). Supporting Evidence: PMID:14716310 We have found that TLR9 is localized to the endoplasmic reticulum (ER) of dendritic cells (DCs) and macrophages. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1678921 | ACCEPT | Summary: Reactome reaction placing TLR9 in the ER membrane (folding by gp96/CNPY3, UNC93B1 binding, export). Reason: Consistent with experimental ER localization of TLR9 (PMID:14716310). Supporting Evidence: PMID:14716310 We have found that TLR9 is localized to the endoplasmic reticulum (ER) of dendritic cells (DCs) and macrophages. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1678923 | ACCEPT | Summary: Reactome reaction placing TLR9 in the ER membrane (folding by gp96/CNPY3, UNC93B1 binding, export). Reason: Consistent with experimental ER localization of TLR9 (PMID:14716310). Supporting Evidence: PMID:14716310 We have found that TLR9 is localized to the endoplasmic reticulum (ER) of dendritic cells (DCs) and macrophages. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1678944 | ACCEPT | Summary: Reactome reaction placing TLR9 in the ER membrane (folding by gp96/CNPY3, UNC93B1 binding, export). Reason: Consistent with experimental ER localization of TLR9 (PMID:14716310). Supporting Evidence: PMID:14716310 We have found that TLR9 is localized to the endoplasmic reticulum (ER) of dendritic cells (DCs) and macrophages. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1678998 | ACCEPT | Summary: Reactome reaction placing TLR9 in the ER membrane (folding by gp96/CNPY3, UNC93B1 binding, export). Reason: Consistent with experimental ER localization of TLR9 (PMID:14716310). Supporting Evidence: PMID:14716310 We have found that TLR9 is localized to the endoplasmic reticulum (ER) of dendritic cells (DCs) and macrophages. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT IBA for plasma membrane at the TLR7/8/9 clade node; human TLR9 is among the descendant evidences. Reason: TLR9 has been observed at the cell surface in several human cell types (polarized intestinal epithelium, PMID:17128265; melanocytes, PMID:19740627), so the location is defensible. It is not the compartment where TLR9 normally signals: TLR9 is ER-resident at rest, signals after ectodomain cleavage in endolysosomes, and forcing it to the cell surface renders it non-functional (PMID:18820679). Retained as a non-core location. Supporting Evidence: PMID:17128265 TLR9 activation through apical and basolateral surface domains have distinct transcriptional responses, evident by NF-kappaB activation and cDNA microarray analysis. PMID:18820679 Furthermore, conditions that prevent receptor proteolysis, including forced TLR9 surface localization, render the receptor non-functional. |
| GO:0005886 plasma membrane | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | KEEP AS NON CORE | Summary: IDA in cultured human melanocytes reporting TLR9 at the cell surface. Reason: Cell-type-specific observation; TLR9 is predominantly intracellular and its canonical signalling requires endolysosomal processing (PMID:18820679). Retained as a non-core location. Supporting Evidence: PMID:19740627 Ample amounts of TLRs 2-4, 7 and 9 were confirmed at protein level. |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of plasma membrane from mouse. Reason: Surface TLR9 is reported in some cell types (e.g. intestinal epithelium, PMID:17128265) but is not where the receptor normally signals (PMID:18820679). Non-core. Supporting Evidence: PMID:17128265 TLR9 activation through apical and basolateral surface domains have distinct transcriptional responses, evident by NF-kappaB activation and cDNA microarray analysis. PMID:18820679 Furthermore, conditions that prevent receptor proteolysis, including forced TLR9 surface localization, render the receptor non-functional. |
| GO:0006952 defense response | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA assignment of defense response. Reason: True but very general; TLR9 initiates innate defence against DNA-bearing microbes. The specific pathway and defence terms carry the information. Supporting Evidence: PMID:11130078 Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. |
| GO:0006955 immune response | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA assignment of immune response. Reason: True but very general; covered more precisely by innate immune response and the TLR9 signalling pathway. Supporting Evidence: PMID:11130078 Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro TIR domain mapping to signal transduction. Reason: Correct but uninformative; TLR9 is a signalling receptor whose TIR domain recruits MyD88. The specific TLR9 signalling pathway term is preferred. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. |
| GO:0007249 canonical NF-kappaB signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for canonical NF-kappaB signal transduction at the TLR7/8/9 node. Reason: TLR9 ligation triggers IkappaBalpha degradation and NF-kappaB activation via MyD88/IRAK/TRAF6 (PMID:17128265, PMID:17932028); the receptor initiates this cascade. Human TLR9 is within the clade; no evidence of divergence. Supporting Evidence: PMID:17128265 Whereas basolateral TLR9 signals IkappaBalpha degradation and activation of the NF-kappaB pathway, apical TLR9 stimulation invokes a unique response PMID:17932028 Here we report the endogenous interaction between Brutons's tyrosine kinase (Btk) and human TLR8 and TLR9 in the monocytic cell line THP1. |
| GO:0007249 canonical NF-kappaB signal transduction | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of canonical NF-kappaB signal transduction from mouse. Reason: As for the IBA row; TLR9 activation leads to NF-kappaB activation in human cells (PMID:17128265, PMID:19740627). Supporting Evidence: PMID:17128265 Whereas basolateral TLR9 signals IkappaBalpha degradation and activation of the NF-kappaB pathway, apical TLR9 stimulation invokes a unique response PMID:19740627 Triggering of TLRs in melanocytes resulted in the up-regulation of phosphorylated IkappaBalpha and in the nucleus translocation of NF-kappaBp65. |
| GO:0008584 male gonad development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer of male gonad development from rat Tlr9. Reason: No evidence that TLR9 contributes to gonad development; the rat source is likely an expression-based observation. TLR9 knockout mice are fertile and the literature on TLR9 function concerns nucleic-acid sensing (PMID:11130078). Over-annotation propagated electronically. Supporting Evidence: PMID:11130078 Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-109699 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-1679098 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-1679589 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-187895 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-188002 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9679045 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975098 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975100 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975106 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975111 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975115 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975118 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975125 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975134 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975156 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975160 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975170 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975175 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975180 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975188 | ACCEPT | Summary: Reactome reaction placing TLR9 (full length or processed C-terminal fragment) in the endosome membrane during ligand binding and myddosome assembly. Reason: TLR9 binds CpG DNA and recruits MyD88 in endosomal/endolysosomal membranes (PMID:14716310, PMID:18820679). Correct, although endolysosome membrane (GO:0036020) is the more precise compartment. Reactome R-HSA-109699 (PI3K phosphorylates PIP2) is a generic reaction in which TLR9 is one of many possible activators; the location assertion is still correct. Supporting Evidence: PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. PMID:18820679 only the processed form recruits MyD88 on activation, indicating that this truncated receptor, rather than the full-length form, is functional. |
| GO:0010508 positive regulation of autophagy | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of positive regulation of autophagy from rat. Reason: CpG/TLR9 stimulation has been linked to autophagy induction in some cell types, but this is a context-dependent downstream effect not established for human TLR9 in the cached literature. Retained as non-core. |
| GO:0010628 positive regulation of gene expression | IDA PMID:24409285 TLR9 and RIG-I signaling in human endocervical epithelial ce... | KEEP AS NON CORE | Summary: IDA: CpG-ODN stimulation of endocervical epithelial cells increases cytokine gene expression. Reason: Correct but very general; the specific cytokine terms (IL-6, IL-8, GM-CSF) from the same paper capture what was measured. Downstream outcome, non-core. Supporting Evidence: PMID:24409285 CpG-ODN (CpG β oligodeoxynucleotide) and Poly(I:C)LL respectively, induced the activation of pro-inflammatory cytokines, IL-6, IL-8 and GM-CSF production via NF-ΞΊB signaling. |
| GO:0016323 basolateral plasma membrane | IDA PMID:17128265 Maintenance of colonic homeostasis by distinctive apical TLR... | KEEP AS NON CORE | Summary: IDA: TLR9 in the basolateral surface of polarized intestinal epithelial cells. Reason: Polarized IECs respond to CpG through apical and basolateral surface domains. This is a cell-type-specific surface localization, not TLR9's general site of activity (PMID:18820679). Supporting Evidence: PMID:17128265 TLR9 activation through apical and basolateral surface domains have distinct transcriptional responses, evident by NF-kappaB activation and cDNA microarray analysis. |
| GO:0016324 apical plasma membrane | IDA PMID:17128265 Maintenance of colonic homeostasis by distinctive apical TLR... | KEEP AS NON CORE | Summary: IDA: TLR9 in the apical surface of polarized intestinal epithelial cells. Reason: As for the basolateral row: specific to polarized IECs, where apical TLR9 signalling confers tolerance. Supporting Evidence: PMID:17128265 TLR9 activation through apical and basolateral surface domains have distinct transcriptional responses, evident by NF-kappaB activation and cDNA microarray analysis. PMID:17128265 Whereas basolateral TLR9 signals IkappaBalpha degradation and activation of the NF-kappaB pathway, apical TLR9 stimulation invokes a unique response |
| GO:0030277 maintenance of gastrointestinal epithelium | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of maintenance of gastrointestinal epithelium from mouse Tlr9. Reason: TLR9-deficient mice are highly susceptible to experimental colitis and IECs have a lower NF-kappaB activation threshold (PMID:17128265). Tissue-level homeostatic role; non-core. Supporting Evidence: PMID:17128265 IECs in TLR9-deficient mice, when compared with wild-type and TLR2-deficient mice, display a lower NF-kappaB activation threshold and these mice are highly susceptible to experimental colitis. |
| GO:0030277 maintenance of gastrointestinal epithelium | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Tlr9 for maintenance of gastrointestinal epithelium. Reason: As for the IEA row (PMID:17128265). Non-core. Supporting Evidence: PMID:17128265 IECs in TLR9-deficient mice, when compared with wild-type and TLR2-deficient mice, display a lower NF-kappaB activation threshold and these mice are highly susceptible to experimental colitis. |
| GO:0030890 positive regulation of B cell proliferation | IDA PMID:23857366 FCRL3 promotes TLR9-induced B-cell activation and suppresses... | KEEP AS NON CORE | Summary: IDA: CpG (TLR9 agonist) promotes human B cell proliferation. Reason: B-cell-specific outcome of TLR9 signalling; correct and retained as non-core. Supporting Evidence: PMID:23857366 FCRL3 ligation augmented CpG oligodeoxynucleotide TLR9-mediated B-cell proliferation, activation, and survival, but surprisingly, abrogated plasma cell differentiation and antibody production. |
| GO:0031901 early endosome membrane | IDA PMID:14716310 TLR9 signals after translocating from the ER to CpG DNA in t... | ACCEPT | Summary: IDA: TLR9 and CpG DNA colocalize in early endosomes after stimulation. Reason: Directly shown (PMID:14716310). Supporting Evidence: PMID:14716310 CpG DNA moves into early endosomes and is subsequently transported to a tubular lysosomal compartment. PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. |
| GO:0031901 early endosome membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to early endosome membrane. Reason: Consistent with PMID:14716310. Supporting Evidence: PMID:14716310 CpG DNA moves into early endosomes and is subsequently transported to a tubular lysosomal compartment. |
| GO:0032009 early phagosome | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of early phagosome from mouse. Reason: TLR9 is recruited to phagosomes containing DNA-bearing microbes; human B cells detect gonococci within the phagolysosome in a TLR9-dependent way (PMID:22427638). Non-core location. Supporting Evidence: PMID:22427638 TLR9-inhibitory CpGs blocked B cell responses, indicating that intracellular bacterial degradation allows for innate immune detection within the phagolysosome. |
| GO:0032009 early phagosome | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Tlr9 for early phagosome. Reason: As for the IEA row. Non-core. Supporting Evidence: PMID:22427638 TLR9-inhibitory CpGs blocked B cell responses, indicating that intracellular bacterial degradation allows for innate immune detection within the phagolysosome. |
| GO:0032490 detection of molecule of bacterial origin | IDA PMID:17128265 Maintenance of colonic homeostasis by distinctive apical TLR... | ACCEPT | Summary: IDA: intestinal epithelial cells detect CpG DNA (a bacterial DNA motif) through TLR9. Reason: TLR9 is the receptor that distinguishes unmethylated CpG-containing bacterial DNA from self DNA (PMID:11130078) and binds CpG DNA directly (PMID:14716310). Detection of molecule of bacterial origin describes the receptor's recognition role. Supporting Evidence: PMID:17128265 TLR9 activation through apical and basolateral surface domains have distinct transcriptional responses, evident by NF-kappaB activation and cDNA microarray analysis. PMID:11130078 Thus, vertebrate immune systems appear to have evolved a specific Toll-like receptor that distinguishes bacterial DNA from self-DNA. PMID:14716310 We show that CpG DNA binds directly to TLR9 in ligand-binding studies. |
| GO:0032722 positive regulation of chemokine production | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | KEEP AS NON CORE | Summary: IDA: TLR ligand stimulation of melanocytes increases chemokine mRNA (CCL2, CCL3, CCL5). Reason: Downstream outcome in a specific cell type; 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:0032725 positive regulation of granulocyte macrophage colony-stimulating factor production | IDA PMID:24409285 TLR9 and RIG-I signaling in human endocervical epithelial ce... | KEEP AS NON CORE | Summary: IDA: CpG-ODN stimulation of endocervical epithelial cells increases GM-CSF. Reason: Downstream outcome in a specific cell type; non-core. Supporting Evidence: PMID:24409285 CpG-ODN (CpG β oligodeoxynucleotide) and Poly(I:C)LL respectively, induced the activation of pro-inflammatory cytokines, IL-6, IL-8 and GM-CSF production via NF-ΞΊB signaling. |
| 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: IDA: TLR9 agonist CpG-C induces IFN-alpha in human blood cells, dependent on IRAK-4. Reason: Type I IFN (notably IFN-alpha from plasmacytoid dendritic cells) is the signature output of TLR9 signalling in humans. Supporting Evidence: PMID:16286015 We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. PMID:16286015 The TLR-7, -8, and -9 agonists tested strongly induced IFN-Ξ±/Ξ² and -Ξ», to levels similar to those for the two viruses tested. |
| GO:0032727 positive regulation of interferon-alpha production | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA assignment of positive regulation of interferon-alpha production. Reason: Consistent with experimental evidence (PMID:16286015). Supporting Evidence: PMID:16286015 We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. |
| 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: IDA: TLR9 agonist induces IFN-beta in human blood cells. Reason: Directly shown (PMID:16286015). Supporting Evidence: PMID:16286015 We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. PMID:16286015 The TLR-7, -8, and -9 agonists tested strongly induced IFN-Ξ±/Ξ² and -Ξ», to levels similar to those for the two viruses tested. |
| GO:0032728 positive regulation of interferon-beta production | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA for positive regulation of interferon-beta production. Reason: Consistent with experimental evidence (PMID:16286015). Supporting Evidence: PMID:16286015 We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. |
| GO:0032728 positive regulation of interferon-beta production | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Tlr9 for positive regulation of interferon-beta production. Reason: Consistent with human experimental evidence (PMID:16286015). Supporting Evidence: PMID:16286015 We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. |
| GO:0032729 positive regulation of type II interferon production | IDA PMID:16286015 Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/be... | MODIFY | Summary: IDA from the IRAK-4 deficiency study, annotated as positive regulation of type II interferon production. Reason: The paper measured IFN-alpha/beta (type I) and IFN-lambda (type III) after TLR-7/8/9 agonist stimulation; IFN-gamma (type II) responses to TLR9 agonist are not reported in the results. The finding matches positive regulation of type III interferon production (GO:0034346) rather than type II. Proposed replacements: positive regulation of type III interferon production Supporting Evidence: PMID:16286015 We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. PMID:16286015 The TLR-7, -8, and -9 agonists tested strongly induced IFN-Ξ±/Ξ² and -Ξ», to levels similar to those for the two viruses tested. |
| GO:0032729 positive regulation of type II interferon production | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA assignment of positive regulation of type II interferon production. Reason: IFN-gamma production after CpG stimulation arises largely indirectly (e.g. NK or T cells responding to cytokines from TLR9-expressing cells). No direct evidence in the cached literature for TLR9 driving IFN-gamma; over-annotation. |
| GO:0032733 positive regulation of interleukin-10 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of positive regulation of IL-10 production from mouse Tlr9. Reason: IL-10 production is a downstream outcome of TLR9 signalling in myeloid cells (CpG responses are abolished in TLR9-deficient mice, PMID:11130078). Correct but non-core. Supporting Evidence: PMID:11130078 Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. |
| GO:0032733 positive regulation of interleukin-10 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Tlr9 for positive regulation of IL-10 production. Reason: As for the IEA row: downstream output of TLR9 signalling. Non-core. Supporting Evidence: PMID:11130078 Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. |
| GO:0032735 positive regulation of interleukin-12 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of positive regulation of IL-12 production from mouse Tlr9. Reason: IL-12 production is a downstream outcome of TLR9 signalling in myeloid cells (CpG responses are abolished in TLR9-deficient mice, PMID:11130078). Correct but non-core. Supporting Evidence: PMID:11130078 Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. |
| GO:0032735 positive regulation of interleukin-12 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Tlr9 for positive regulation of IL-12 production. Reason: As for the IEA row: downstream output of TLR9 signalling. Non-core. Supporting Evidence: PMID:11130078 Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. |
| GO:0032741 positive regulation of interleukin-18 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of positive regulation of IL-18 production from mouse Tlr9. Reason: IL-18 production is a downstream outcome of TLR9 signalling in myeloid cells (CpG responses are abolished in TLR9-deficient mice, PMID:11130078). Correct but non-core. Supporting Evidence: PMID:11130078 Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. |
| GO:0032741 positive regulation of interleukin-18 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Tlr9 for positive regulation of IL-18 production. Reason: As for the IEA row: downstream output of TLR9 signalling. Non-core. Supporting Evidence: PMID:11130078 Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. |
| GO:0032755 positive regulation of interleukin-6 production | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT IBA for positive regulation of interleukin-6 production at the TLR7/8/9 node. Reason: IL-6 induction by CpG is TLR9-dependent in human cells (PMID:17932028, PMID:19740627). This is a downstream output common to the clade; accepted but non-core. Supporting Evidence: PMID:17932028 peripheral blood mononuclear cells from patients with X-linked agammaglobulinaemia (XLA) that have dysfunctional Btk are impaired in the induction of interleukin-6 by CpGB-DNA. 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 | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | KEEP AS NON CORE | Summary: IDA: TLR9 agonist induces IL-6 in human melanocytes. Reason: Downstream outcome; 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:0032755 positive regulation of interleukin-6 production | IDA PMID:24409285 TLR9 and RIG-I signaling in human endocervical epithelial ce... | KEEP AS NON CORE | Summary: IDA: CpG-ODN induces IL-6 in endocervical epithelial cells. Reason: Downstream outcome; non-core. Supporting Evidence: PMID:24409285 CpG-ODN (CpG β oligodeoxynucleotide) and Poly(I:C)LL respectively, induced the activation of pro-inflammatory cytokines, IL-6, IL-8 and GM-CSF production via NF-ΞΊB signaling. |
| GO:0032755 positive regulation of interleukin-6 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of positive regulation of IL-6 production. Reason: Downstream outcome; non-core. Supporting Evidence: PMID:17932028 peripheral blood mononuclear cells from patients with X-linked agammaglobulinaemia (XLA) that have dysfunctional Btk are impaired in the induction of interleukin-6 by CpGB-DNA. |
| GO:0032757 positive regulation of interleukin-8 production | IDA PMID:17128265 Maintenance of colonic homeostasis by distinctive apical TLR... | KEEP AS NON CORE | Summary: IDA (acts upstream of): TLR9 stimulation in intestinal epithelial cells and IL-8. Reason: Downstream outcome in IECs; non-core. Supporting Evidence: PMID:17128265 TLR9 activation through apical and basolateral surface domains have distinct transcriptional responses, evident by NF-kappaB activation and cDNA microarray analysis. |
| GO:0032757 positive regulation of interleukin-8 production | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | KEEP AS NON CORE | Summary: IDA: TLR9 agonist induces IL-8 in melanocytes. Reason: Downstream outcome; 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:0032757 positive regulation of interleukin-8 production | IDA PMID:24409285 TLR9 and RIG-I signaling in human endocervical epithelial ce... | KEEP AS NON CORE | Summary: IDA: CpG-ODN induces IL-8 in endocervical epithelial cells. Reason: Downstream outcome; non-core. Supporting Evidence: PMID:24409285 CpG-ODN (CpG β oligodeoxynucleotide) and Poly(I:C)LL respectively, induced the activation of pro-inflammatory cytokines, IL-6, IL-8 and GM-CSF production via NF-ΞΊB signaling. |
| GO:0032757 positive regulation of interleukin-8 production | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA assignment of positive regulation of IL-8 production. Reason: Consistent with experimental data (PMID:19740627, PMID:24409285). 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: Ensembl Compara transfer of positive regulation of TNF production from mouse Tlr9. Reason: TNF production is a downstream outcome of TLR9 signalling in myeloid cells (CpG responses are abolished in TLR9-deficient mice, PMID:11130078). Correct but non-core. Supporting Evidence: PMID:11130078 Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. |
| GO:0032760 positive regulation of tumor necrosis factor production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Tlr9 for positive regulation of TNF production. Reason: As for the IEA row: downstream output of TLR9 signalling. Non-core. Supporting Evidence: PMID:11130078 Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. |
| GO:0034162 toll-like receptor 9 signaling pathway | IDA PMID:23857366 FCRL3 promotes TLR9-induced B-cell activation and suppresses... | ACCEPT | Summary: IDA: CpG-driven TLR9 signalling in human B cells. Reason: TLR9 is the receptor of the TLR9 signalling pathway. The core pathway term for this gene. Supporting Evidence: PMID:23857366 FCRL3 ligation augmented CpG oligodeoxynucleotide TLR9-mediated B-cell proliferation, activation, and survival, but surprisingly, abrogated plasma cell differentiation and antibody production. |
| GO:0034162 toll-like receptor 9 signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of toll-like receptor 9 signaling pathway from mouse. Reason: Ligand specificity for CpG DNA is conserved between mouse and human TLR9 (PMID:11564765, PMID:11130078). Core. Supporting Evidence: PMID:11130078 Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. PMID:11564765 Cells that are not responsive to CpG DNA become responsive when transfected with hTLR9. |
| GO:0034165 positive regulation of toll-like receptor 9 signaling pathway | IEA GO_REF:0000107 | MODIFY | Summary: Positive regulation of toll-like receptor 9 signaling pathway (IEA), transferred from mouse Tlr9; the receptor is a component of the pathway, which is the supported term. Reason: The row is transferred from mouse Tlr9, annotated from a mutant phenotype, and what loss of the receptor shows is that TLR9 is required for signalling through its own pathway. A receptor is a component of the pathway it initiates rather than an outside regulator of it, so the supported statement is the toll-like receptor 9 signaling pathway itself, which TLR9 already carries. That the replacement is already annotated is a reason to redirect the row to it, not to remove it. Proposed replacements: toll-like receptor 9 signaling pathway Supporting Evidence: PMID:38169466 The palmitoylation cycle begins in the Golgi, where DHHC3 palmitoylates TLR9 and ends in lysosomes, where PPT1 depalmitoylates TLR9. |
| GO:0035197 siRNA binding | IMP PMID:15723075 Sequence-specific potent induction of IFN-alpha by short int... | UNDECIDED | Summary: IMP for siRNA binding citing a study of siRNA-induced IFN-alpha in plasmacytoid dendritic cells. Reason: The cached record is abstract-only. The abstract attributes siRNA recognition to TLR7 and reports loss of the response in TLR7-deficient mice; TLR9 is mentioned only through its ligand CpG as a comparator. TLR9 is a DNA sensor and there is no evidence in the cached literature that it binds siRNA, and an IMP is weak evidence for a binding activity. The annotation looks unsupported but the full text was not available to check what was assayed, so it is left undecided. Supporting Evidence: PMID:15723075 Immunostimulation by siRNA was absent in TLR7-deficient mice. |
| GO:0036019 endolysosome | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of endolysosome from mouse. Reason: TLR9 is cleaved and signals in the endolysosome (PMID:18820679, PMID:18931679). Supporting Evidence: PMID:18820679 The ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. PMID:18931679 Here we show that TLR9 proteolytic cleavage is a prerequisite for TLR9 signaling. |
| GO:0036019 endolysosome | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Tlr9 for endolysosome. Reason: As above. Supporting Evidence: PMID:18820679 The ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. |
| GO:0036020 endolysosome membrane | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA assignment of endolysosome membrane. Reason: TLR9 is a transmembrane receptor processed and activated in endolysosomes (PMID:18820679). Core location. Supporting Evidence: PMID:18820679 The ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-1678920 | ACCEPT | Summary: Reactome reaction placing TLR9 in the endolysosome membrane (UNC93B1 delivery, ectodomain processing). Reason: Consistent with experimental evidence that TLR9 ectodomain cleavage and ligand recognition occur in endolysosomes (PMID:18820679, PMID:18931679). Supporting Evidence: PMID:18820679 The ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. PMID:18931679 Here we show that TLR9 proteolytic cleavage is a prerequisite for TLR9 signaling. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-1678927 | ACCEPT | Summary: Reactome reaction placing TLR9 in the endolysosome membrane (UNC93B1 delivery, ectodomain processing). Reason: Consistent with experimental evidence that TLR9 ectodomain cleavage and ligand recognition occur in endolysosomes (PMID:18820679, PMID:18931679). Supporting Evidence: PMID:18820679 The ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. PMID:18931679 Here we show that TLR9 proteolytic cleavage is a prerequisite for TLR9 signaling. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-1678981 | ACCEPT | Summary: Reactome reaction placing TLR9 in the endolysosome membrane (UNC93B1 delivery, ectodomain processing). Reason: Consistent with experimental evidence that TLR9 ectodomain cleavage and ligand recognition occur in endolysosomes (PMID:18820679, PMID:18931679). Supporting Evidence: PMID:18820679 The ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. PMID:18931679 Here we show that TLR9 proteolytic cleavage is a prerequisite for TLR9 signaling. |
| GO:0038187 pattern recognition receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for pattern recognition receptor activity at the TLR7/8/9 node. Reason: TLR9 directly binds microbial CpG DNA and initiates signalling (PMID:14716310, PMID:25686612); the clade members recognise microbial nucleic acids. There is no TLR-specific MF term, and pattern recognition receptor activity is the appropriate MF. Supporting Evidence: PMID:14716310 We show that CpG DNA binds directly to TLR9 in ligand-binding studies. PMID:25686612 Agonistic-CpG-DNA-bound TLR9 formed a symmetric TLR9-CpG-DNA complex with 2:2 stoichiometry, whereas iDNA-bound TLR9 was a monomer. |
| GO:0038187 pattern recognition receptor activity | IDA PMID:14716310 TLR9 signals after translocating from the ER to CpG DNA in t... | ACCEPT | Summary: IDA: CpG DNA binds directly to TLR9, which then signals from CpG-containing compartments. Reason: Direct ligand binding plus signalling establishes the receptor activity. Supporting Evidence: PMID:14716310 We show that CpG DNA binds directly to TLR9 in ligand-binding studies. PMID:14716310 TLR9 redistributes from the ER to CpG DNA-containing structures, which also accumulate MyD88. |
| GO:0038187 pattern recognition receptor activity | IDA PMID:17128265 Maintenance of colonic homeostasis by distinctive apical TLR... | ACCEPT | Summary: IDA: TLR9 on intestinal epithelial cells responds to CpG DNA. Reason: Supports receptor function of TLR9 for microbial CpG DNA in human IECs; consistent with direct binding data (PMID:14716310). Supporting Evidence: PMID:17128265 TLR9 activation through apical and basolateral surface domains have distinct transcriptional responses, evident by NF-kappaB activation and cDNA microarray analysis. PMID:14716310 We show that CpG DNA binds directly to TLR9 in ligand-binding studies. |
| GO:0042742 defense response to bacterium | NAS PMID:11130078 A Toll-like receptor recognizes bacterial DNA. | KEEP AS NON CORE | Summary: NAS citing the TLR9 knockout paper for defense response to bacterium. Reason: TLR9 recognizes bacterial CpG DNA (PMID:11130078), and TLR9-dependent detection of bacteria is shown in human B cells (PMID:22427638). Correct but a broad organismal outcome; non-core. Supporting Evidence: PMID:11130078 Thus, vertebrate immune systems appear to have evolved a specific Toll-like receptor that distinguishes bacterial DNA from self-DNA. PMID:22427638 TLR9-inhibitory CpGs blocked B cell responses, indicating that intracellular bacterial degradation allows for innate immune detection within the phagolysosome. |
| GO:0042803 protein homodimerization activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from horse TLR9 (Q2EEY0) for protein homodimerization activity. Reason: Crystal structures show CpG DNA induces a 2:2 TLR9:DNA dimer, and dimerization is required for activation; inhibitory DNA leaves TLR9 monomeric (PMID:25686612). Part of the receptor mechanism. Supporting Evidence: PMID:25686612 Agonistic-CpG-DNA-bound TLR9 formed a symmetric TLR9-CpG-DNA complex with 2:2 stoichiometry, whereas iDNA-bound TLR9 was a monomer. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IDA PMID:17128265 Maintenance of colonic homeostasis by distinctive apical TLR... | ACCEPT | Summary: IDA: basolateral TLR9 stimulation of IECs activates NF-kappaB. Reason: TLR9 ligation activates NF-kappaB (PMID:17128265). Supporting Evidence: PMID:17128265 Whereas basolateral TLR9 signals IkappaBalpha degradation and activation of the NF-kappaB pathway, apical TLR9 stimulation invokes a unique response |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | ACCEPT | Summary: IDA: TLR9 ligand triggers IkappaBalpha phosphorylation and NF-kappaB p65 nuclear translocation in melanocytes. Reason: Consistent with TLR9 signalling to NF-kappaB. 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. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA assignment of positive regulation of canonical NF-kappaB signal transduction. Reason: Consistent with experimental evidence (PMID:17128265, PMID:17932028). Supporting Evidence: PMID:17128265 Whereas basolateral TLR9 signals IkappaBalpha degradation and activation of the NF-kappaB pathway, apical TLR9 stimulation invokes a unique response PMID:17932028 Here we report the endogenous interaction between Brutons's tyrosine kinase (Btk) and human TLR8 and TLR9 in the monocytic cell line THP1. |
| GO:0043410 positive regulation of MAPK cascade | IDA PMID:23857366 FCRL3 promotes TLR9-induced B-cell activation and suppresses... | KEEP AS NON CORE | Summary: IDA: CpG stimulation of human B cells activates MAPK cascades. Reason: The paper shows CpG-triggered MAPK activation (augmented by FCRL3). Downstream signalling branch; non-core. Supporting Evidence: PMID:23857366 Although FCRL3 amplified the NF-ΞΊB and mitogen-activated protein kinase signaling cascades, it halted CpG triggered BLIMP1 induction in an ERK-dependent fashion. |
| GO:0045087 innate immune response | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of innate immune response from mouse. Reason: TLR9 is an innate immune receptor for CpG DNA (PMID:11130078). Supporting Evidence: PMID:11130078 Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. |
| GO:0045087 innate immune response | TAS PMID:15356140 Microglia initiate central nervous system innate and adaptiv... | ACCEPT | Summary: TAS citing mouse microglia responses to TLR agonists including CpG DNA. Reason: TLR9 is an innate immune receptor; the cited paper shows CpG (TLR9 agonist) activates innate responses in microglia. Correct. Supporting Evidence: PMID:15356140 stimulation of quiescent microglia with various TLR agonists, including LPS (TLR4), peptidoglycan (TLR2), polyinosinic-polycytidylic acid (TLR3), CpG DNA (TLR9) |
| GO:0045322 unmethylated CpG binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of unmethylated CpG binding from rat. Reason: TLR9 binds CpG DNA directly (PMID:14716310) and forms a 2:2 complex with agonistic CpG DNA (PMID:25686612). Core MF. Supporting Evidence: PMID:14716310 We show that CpG DNA binds directly to TLR9 in ligand-binding studies. PMID:25686612 Agonistic-CpG-DNA-bound TLR9 formed a symmetric TLR9-CpG-DNA complex with 2:2 stoichiometry, whereas iDNA-bound TLR9 was a monomer. file:human/TLR9/TLR9-deep-research-falcon.md TLR9 functions as an intracellular pattern-recognition receptor and DNA sensor that detects unmethylated cytosine-phosphate-guanosine (CpG) dinucleotide motifs |
| GO:0045322 unmethylated CpG binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from horse TLR9 (Q2EEY0) for unmethylated CpG binding. Reason: Supported by direct binding of CpG DNA to TLR9 (PMID:14716310) and the structures of TLR9-CpG complexes (PMID:25686612). Core MF. Supporting Evidence: PMID:14716310 We show that CpG DNA binds directly to TLR9 in ligand-binding studies. PMID:25686612 Agonistic-CpG-DNA-bound TLR9 formed a symmetric TLR9-CpG-DNA complex with 2:2 stoichiometry, whereas iDNA-bound TLR9 was a monomer. |
| GO:0045335 phagocytic vesicle | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined IEA for phagocytic vesicle. Reason: TLR9 detects bacteria within phagolysosomes (PMID:22427638). Non-core location. Supporting Evidence: PMID:22427638 TLR9-inhibitory CpGs blocked B cell responses, indicating that intracellular bacterial degradation allows for innate immune detection within the phagolysosome. |
| GO:0045577 regulation of B cell differentiation | IDA PMID:23857366 FCRL3 promotes TLR9-induced B-cell activation and suppresses... | KEEP AS NON CORE | Summary: IDA: CpG-driven B cell differentiation to antibody-secreting cells. Reason: B-cell-specific downstream outcome of TLR9 signalling; non-core. Supporting Evidence: PMID:23857366 As previously established [34], CpG could induce blood B lymphocytes to differentiate into antibody-secreting cells as indicated by the detection of the IgM, IgG, and IgA isotypes in supernatants by ELISA after 5 days of culture |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer of positive regulation of transcription by RNA polymerase II. Reason: TLR9 signalling ultimately activates transcription factors (NF-kappaB, IRF7), but the receptor is several steps removed from transcription. This is an indirect effect and an over-annotation for a membrane receptor. |
| GO:0046330 positive regulation of JNK cascade | IDA PMID:17128265 Maintenance of colonic homeostasis by distinctive apical TLR... | KEEP AS NON CORE | Summary: IDA: TLR9 stimulation of intestinal epithelial cells activates JNK. Reason: Downstream signalling branch; non-core. Supporting Evidence: PMID:17128265 TLR9 activation through apical and basolateral surface domains have distinct transcriptional responses, evident by NF-kappaB activation and cDNA microarray analysis. |
| GO:0050727 regulation of inflammatory response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of regulation of inflammatory response. Reason: TLR9 signalling drives inflammatory responses and apical TLR9 signalling in IECs dampens them (PMID:17128265). Downstream; non-core. Supporting Evidence: PMID:17128265 IECs in TLR9-deficient mice, when compared with wild-type and TLR2-deficient mice, display a lower NF-kappaB activation threshold and these mice are highly susceptible to experimental colitis. |
| GO:0050729 positive regulation of inflammatory response | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | KEEP AS NON CORE | Summary: IDA: TLR9 agonist induces pro-inflammatory cytokines in melanocytes. Reason: Downstream outcome; 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:0050829 defense response to Gram-negative bacterium | IMP PMID:22427638 Vigorous response of human innate functioning IgM memory B c... | KEEP AS NON CORE | Summary: IMP: TLR9-inhibitory CpG blocks human B cell responses to Neisseria gonorrhoeae. Reason: Supports TLR9-dependent detection of a Gram-negative bacterium by B cells. Organismal-level outcome; non-core. Supporting Evidence: PMID:22427638 TLR9-inhibitory CpGs blocked B cell responses, indicating that intracellular bacterial degradation allows for innate immune detection within the phagolysosome. |
| GO:0050871 positive regulation of B cell activation | IDA PMID:23857366 FCRL3 promotes TLR9-induced B-cell activation and suppresses... | KEEP AS NON CORE | Summary: IDA: CpG (TLR9 agonist) activates human B cells. Reason: B-cell-specific outcome; non-core. Supporting Evidence: PMID:23857366 FCRL3 ligation augmented CpG oligodeoxynucleotide TLR9-mediated B-cell proliferation, activation, and survival, but surprisingly, abrogated plasma cell differentiation and antibody production. |
| GO:0051607 defense response to virus | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for defense response to virus at the TLR7/8/9 node. Reason: The TLR7/8/9 clade senses viral nucleic acids and drives type I IFN; TLR9 recognizes DNA viruses. In humans TLR7/8/9-dependent IFN induction is redundant for protective immunity to most viruses (PMID:16286015), but the function is inherited and consistent with the clade. Supporting Evidence: PMID:16286015 We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. PMID:16286015 paradoxically redundant for protective immunity to most viruses in humans. |
| GO:0051607 defense response to virus | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of defense response to virus from rat. Reason: As for the IBA row. Supporting Evidence: PMID:16286015 We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. |
| GO:0051707 response to other organism | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA assignment of response to other organism. Reason: True but very general; non-core. Supporting Evidence: PMID:11130078 Thus, vertebrate immune systems appear to have evolved a specific Toll-like receptor that distinguishes bacterial DNA from self-DNA. |
| GO:0071222 cellular response to lipopolysaccharide | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer of cellular response to lipopolysaccharide from rat Tlr9. Reason: LPS is recognized by TLR4, not TLR9; TLR9 recognizes unmethylated CpG DNA (PMID:11130078). The rat source is likely an expression change; asserting an LPS response for TLR9 invites confusion with ligand specificity. Supporting Evidence: PMID:11130078 Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. |
| GO:0071248 cellular response to metal ion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer of cellular response to metal ion from rat Tlr9. Reason: No evidence that TLR9 has a role in responding to metal ions; the rat source is likely an expression observation. Over-annotation. |
| GO:0140894 endolysosomal toll-like receptor signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA assignment of endolysosomal toll-like receptor signaling pathway. Reason: TLR9 signals from endolysosomes after cleavage (PMID:18820679). GO:0034162 (TLR9 signaling pathway) is a child of this term and is the preferred, more specific annotation. Supporting Evidence: PMID:18820679 The ectodomains of TLR9 and TLR7 are cleaved in the endolysosome, such that no full-length protein is detectable in the compartment where ligand is recognized. PMID:18931679 Here we show that TLR9 proteolytic cleavage is a prerequisite for TLR9 signaling. |
| GO:1900227 positive regulation of NLRP3 inflammasome complex assembly | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer from mouse of positive regulation of NLRP3 inflammasome complex assembly. Reason: UniProt reports (by similarity to mouse) that TLR9 acts via ADCY7 to produce c-di-AMP and activate the NLRP3 inflammasome. Not tested for human TLR9 in the cached literature; non-core. |
| GO:1900227 positive regulation of NLRP3 inflammasome complex assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Tlr9 for positive regulation of NLRP3 inflammasome complex assembly. Reason: As for the IEA row; non-core. |
| GO:1901895 negative regulation of ATPase-coupled calcium transmembrane transporter activity | IDA PMID:24610369 Toll-like receptor 9 protects non-immune cells from stress b... | KEEP AS NON CORE | Summary: IDA: TLR9 stimulation reduces SERCA2 activity in cardiomyocytes (alternative, MyD88-independent TLR9 signalling). Reason: The work was carried out largely in rodent cardiomyocytes; TLR9 associates with SERCA2 and reduces its activity, lowering mitochondrial ATP. A non-immune, cell-type-specific function; retained as non-core. Supporting Evidence: PMID:24610369 TLR9 stimulation reduces SERCA2 activity, modulating Ca(2+) handling between the SR/ER and mitochondria |
| GO:1905300 positive regulation of intestinal epithelial cell development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of positive regulation of intestinal epithelial cell development from mouse. Reason: Related to the TLR9 role in colonic epithelial homeostasis (PMID:17128265); non-core. Supporting Evidence: PMID:17128265 IECs in TLR9-deficient mice, when compared with wild-type and TLR2-deficient mice, display a lower NF-kappaB activation threshold and these mice are highly susceptible to experimental colitis. |
| GO:1905300 positive regulation of intestinal epithelial cell development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Tlr9 for positive regulation of intestinal epithelial cell development. Reason: As for the IEA row; non-core. Supporting Evidence: PMID:17128265 IECs in TLR9-deficient mice, when compared with wild-type and TLR2-deficient mice, display a lower NF-kappaB activation threshold and these mice are highly susceptible to experimental colitis. |
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Download this section (compressed HTML)Q: Should siRNA binding (GO:0035197, IMP, PMID:15723075) remain on TLR9? The abstract attributes siRNA recognition to TLR7; what in the full text supports a TLR9 assignment?
Q: The IDA for positive regulation of type II interferon production (PMID:16286015) appears to reflect IFN-lambda (type III) data; can the curator confirm and move it to GO:0034346?
Q: Surface TLR9 is reported on intestinal epithelium and melanocytes, yet forced surface TLR9 is non-functional in macrophages (PMID:18820679). Does surface TLR9 in these cells signal on its own, and is the ectodomain processed there?
Q: Is the MyD88-independent TLR9-SERCA2 pathway described in rodent cardiomyocytes (PMID:24610369) operative in human cells?
Experiment: Direct binding assays of purified human TLR9 ectodomain with siRNA versus CpG DNA to test whether the siRNA binding annotation has any basis.
Experiment: Measure IFN-gamma versus IFN-lambda in purified human pDC and B cell cultures from TLR9-deficient or knockdown cells after CpG stimulation to separate direct from bystander interferon outputs.
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