TLR7 (Toll-like receptor 7) is an endolysosomal pattern recognition receptor of the innate immune system that detects RNA degradation products, chiefly those of viral single-stranded RNA genomes. It is a single-pass type I membrane glycoprotein: a large leucine-rich-repeat ectodomain faces the lumen of the compartment, a single transmembrane helix crosses the membrane, and a cytoplasmic TIR domain carries the signal. Unlike a simple ssRNA sensor, TLR7 is a dual receptor with two spatially distinct ligand-binding sites on its horseshoe-shaped ectodomain. The first site, at the dimerisation interface and conserved with TLR8, binds a guanosine moiety - guanosine itself, deoxyguanosine, synthetic guanosine analogues and imidazoquinolines such as imiquimod and R-848, and physiologically the guanosine 2',3'-cyclic monophosphate released from RNA. The second site, on the concave surface and unique to TLR7, binds short uridine-containing single-stranded RNA fragments, which raise the affinity of the first site. Both ligands are made in situ by sequential RNA catabolism: the lysosomal endonuclease RNase T2 cuts RNA between purine and uridine residues, and the exonucleases PLD3 and PLD4 release the terminal 2',3'-cyclic GMP and generate the pyrimidine-rich fragments. Occupancy of both sites locks TLR7 into an activated m-shaped homodimer that brings the two TIR domains together, recruiting MyD88 and assembling the myddosome with IRAK4, IRAK1/IRAK2 and TRAF6; this activates canonical NF-kappaB and MAP kinases, driving IL-6, IL-8, TNF and chemokine production, and activates IRF7, driving type I interferon. Newly made TLR7 folds in the endoplasmic reticulum membrane and is delivered to endosomes and lysosomes by the chaperone UNC93B1, which engages its transmembrane and juxtamembrane regions; signalling requires endosomal acidification, and this intracellular confinement is what restrains responses to self RNA. TLR7 is expressed most strongly in plasmacytoid dendritic cells and B cells, and also in monocytes and various epithelial and pigment cells. Loss-of-function variants cause an X-linked immunodeficiency presenting as severe COVID-19 with impaired interferon responses, while gain-of-function variants that increase guanosine sensing cause X-linked systemic lupus erythematosus, driving survival of B-cell-receptor-activated B cells and accumulation of CD11c-positive age-associated B cells in a MyD88-dependent manner.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-1678927 | KEEP AS NON CORE | Summary: Reactome places endosomal TLRs in the Golgi membrane as a transit step on the UNC93B1-dependent route from the ER to endolysosomes. Reason: Plausible as a transit compartment rather than a signalling site, but there is no direct evidence for human TLR7 in the Golgi, and in the paralogue TLR8 Golgi markers explicitly failed to colocalise with the receptor. Retained as non-core. Supporting Evidence: PMID:22164301 Late endosome (MPR), lysosome (LAMP-1), and Golgi (p115) markers did not colocalize with TLR8 PMID:33432245 Although chaperone Unc-93 homolog B1, TLR signaling regulator (UNC93B1) is indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome, mechanisms of UNC93B1-mediated TLR regulation remain largely unknown. |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-1678998 | KEEP AS NON CORE | Summary: Reactome places endosomal TLRs in the Golgi membrane as a transit step on the UNC93B1-dependent route from the ER to endolysosomes. Reason: Plausible as a transit compartment rather than a signalling site, but there is no direct evidence for human TLR7 in the Golgi, and in the paralogue TLR8 Golgi markers explicitly failed to colocalise with the receptor. Retained as non-core. Supporting Evidence: PMID:22164301 Late endosome (MPR), lysosome (LAMP-1), and Golgi (p115) markers did not colocalize with TLR8 PMID:33432245 Although chaperone Unc-93 homolog B1, TLR signaling regulator (UNC93B1) is indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome, mechanisms of UNC93B1-mediated TLR regulation remain largely unknown. |
| GO:0000165 MAPK cascade | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer from mouse Tlr7 of MAPK cascade. Reason: Correct but downstream and generic: the myddosome assembled on ligand-bound TLR7 activates MAP kinases as well as NF-kappaB and IRF7. The receptor-specific pathway term GO:0034154 carries the informative content. Non-core. Supporting Evidence: PMID:35477763 Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. |
| 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 right level for a node covering TLR7, TLR8 and TLR9, and human TLR7 is inside that clade with direct evidence for ligand-induced dimerisation and MyD88-dependent signalling. The more specific GO:0034154 is also annotated. Supporting Evidence: PMID:27742543 Our structural, biochemical, and mutagenesis studies indicated that TLR7 is a dual receptor for guanosine and uridine-containing ssRNA. PMID:35477763 Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. |
| GO:0003725 double-stranded RNA binding | IDA PMID:16111635 Suppression of RNA recognition by Toll-like receptors: the i... | MODIFY | Summary: IDA for double-stranded RNA binding from the nucleoside-modification study, which reports that RNA signals through TLR3, TLR7 and TLR8. Reason: The essence is right - TLR7 recognises RNA - but the RNA species is wrong. Double-stranded RNA is the TLR3 ligand; the crystal structures show that TLR7's second site binds single-stranded, uridine-containing RNA, and its first site binds guanosine or 2',3'-cGMP released from RNA by RNase T2 and the PLD exonucleases. Single-stranded RNA binding (GO:0003727) is the supported term and is already annotated from other evidence. Proposed replacements: single-stranded RNA binding Supporting Evidence: PMID:16111635 We show that RNA signals through human TLR3, TLR7, and TLR8, but incorporation of modified nucleosides m5C, m6A, m5U, s2U, or pseudouridine ablates activity. PMID:27742543 The first site preferentially recognized guanosine and the second site specifically bound to uridine moieties in ssRNA. PMID:38697119 PLD exonuclease activity further released the terminal 2',3'-cyclic guanosine monophosphate (2',3'-cGMP) to engage pocket 1 and was also needed to generate RNA fragments for pocket 2. |
| GO:0003727 single-stranded RNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from mouse Tlr7 of single-stranded RNA binding. Reason: Correct and conserved: ssRNA recognition is the shared function of mouse and human TLR7, and the human structures define the uridine-binding second site directly. Supporting Evidence: PMID:27742543 The first site preferentially recognized guanosine and the second site specifically bound to uridine moieties in ssRNA. PMID:14976261 Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. |
| GO:0003727 single-stranded RNA binding | IMP PMID:35477763 TLR7 gain-of-function genetic variation causes human lupus. | ACCEPT | Summary: IMP from the lupus gain-of-function study, in which the TLR7 Y264H variant alters ligand sensing. Reason: Core molecular function. TLR7 binds single-stranded uridine-containing RNA at its second site, with guanosine or 2',3'-cGMP at the first; the Y264H variant lies in the first site and selectively increases sensing of those ligands. Supporting Evidence: PMID:35477763 The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10-12, and was sufficient to cause lupus when introduced into mice. PMID:27742543 The first site preferentially recognized guanosine and the second site specifically bound to uridine moieties in ssRNA. |
| GO:0003727 single-stranded RNA binding | ISS GO_REF:0000024 | ACCEPT | Summary: Curator transfer of single-stranded RNA binding from mouse Tlr7. Reason: Correct; ssRNA sensing is conserved and is established directly for human TLR7 by the crystal structures. Supporting Evidence: PMID:27742543 The first site preferentially recognized guanosine and the second site specifically bound to uridine moieties in ssRNA. |
| GO:0005515 protein binding | IPI PMID:33432245 Cryo-EM structures of Toll-like receptors in complex with UN... | REMOVE | Summary: IPI recording the TLR7-UNC93B1 interaction seen in the cryo-EM structure. Reason: Generic protein binding is uninformative. TLR7 is the client of UNC93B1, and the relevant biology - UNC93B1-dependent exit from the ER to the endosome - is a trafficking and localisation matter rather than a molecular function of TLR7. Removal does not dispute the interaction, which the structure establishes. Supporting Evidence: PMID:33432245 Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions PMID:33432245 Although chaperone Unc-93 homolog B1, TLR signaling regulator (UNC93B1) is indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome, mechanisms of UNC93B1-mediated TLR regulation remain largely unknown. |
| GO:0005737 cytoplasm | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | KEEP AS NON CORE | Summary: IDA in cultured human melanocytes reporting TLR7 immunoreactivity in the cytoplasm. Reason: Not wrong - TLR7's resting and signalling compartments (ER, endosome, lysosome) are all cytoplasmic - but uninformative. The specific membrane compartments carry the content. Supporting Evidence: PMID:19740627 Human melanocytes constitutively expressed TLRs 1-4, 6, 7 and 9 mRNA. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0005764 lysosome | IEA GO_REF:0000120 | ACCEPT | Summary: UniProt combined electronic annotation of lysosome, from mouse Tlr7 and the Swiss-Prot subcellular-location vocabulary. Reason: Correct. TLR7 relocates from the ER to endosomes and lysosomes on stimulation, and its activation requires endosomal acidification. Supporting Evidence: PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. |
| GO:0005764 lysosome | ISS GO_REF:0000024 | ACCEPT | Summary: Curator transfer of lysosome from mouse Tlr7. Reason: Correct and conserved; human TLR7 resides in the endolysosome and the ER. Supporting Evidence: PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0005765 lysosomal membrane | IDA PMID:12738885 Molecular basis for the immunostimulatory activity of guanin... | ACCEPT | Summary: IDA placing TLR7 activity at the lysosomal membrane, from the guanosine-analogue study in which chloroquine blocks signalling. Reason: Core location. Guanosine analogues activate cells exclusively through TLR7, and the requirement for endosomal maturation places the activated receptor in an acidified endolysosomal membrane. Supporting Evidence: PMID:12738885 Genetic complementation studies in human embryonic kidney 293 cells confirmed that the guanosine analogs activate cells exclusively via TLR7. PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. |
| GO:0005768 endosome | IEA GO_REF:0000120 | ACCEPT | Summary: UniProt combined electronic annotation of endosome. Reason: Correct; the endosome/endolysosome is where TLR7 encounters its ligands. Supporting Evidence: PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0005768 endosome | ISS GO_REF:0000024 | ACCEPT | Summary: Curator transfer of endosome from mouse Tlr7. Reason: Correct and conserved. Supporting Evidence: PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from mouse Tlr7 of endoplasmic reticulum. Reason: Correct: TLR7 is ER-resident at rest and is delivered from the ER by UNC93B1. Supporting Evidence: PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. PMID:33432245 Although chaperone Unc-93 homolog B1, TLR signaling regulator (UNC93B1) is indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome, mechanisms of UNC93B1-mediated TLR regulation remain largely unknown. |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | ACCEPT | Summary: Curator transfer of endoplasmic reticulum from mouse Tlr7. Reason: Correct and conserved. Supporting Evidence: PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to endoplasmic reticulum membrane. Reason: Correct. TLR7 is a single-pass type I membrane protein whose resting pool is in the ER membrane, where UNC93B1 engages its transmembrane and juxtamembrane regions. Supporting Evidence: PMID:33432245 Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Curator transfer of endoplasmic reticulum membrane from mouse Tlr7. Reason: Correct and conserved. Supporting Evidence: PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1678921 | ACCEPT | Summary: Reactome reactions placing full-length TLR7 in the ER membrane during chaperone-assisted folding and UNC93B1 binding. Reason: Consistent with the structural evidence that UNC93B1 engages TLR7 in the ER membrane before delivery to the endosome. Supporting Evidence: PMID:33432245 Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions PMID:33432245 Although chaperone Unc-93 homolog B1, TLR signaling regulator (UNC93B1) is indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome, mechanisms of UNC93B1-mediated TLR regulation remain largely unknown. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1678923 | ACCEPT | Summary: Reactome reactions placing full-length TLR7 in the ER membrane during chaperone-assisted folding and UNC93B1 binding. Reason: Consistent with the structural evidence that UNC93B1 engages TLR7 in the ER membrane before delivery to the endosome. Supporting Evidence: PMID:33432245 Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions PMID:33432245 Although chaperone Unc-93 homolog B1, TLR signaling regulator (UNC93B1) is indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome, mechanisms of UNC93B1-mediated TLR regulation remain largely unknown. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1678944 | ACCEPT | Summary: Reactome reactions placing full-length TLR7 in the ER membrane during chaperone-assisted folding and UNC93B1 binding. Reason: Consistent with the structural evidence that UNC93B1 engages TLR7 in the ER membrane before delivery to the endosome. Supporting Evidence: PMID:33432245 Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions PMID:33432245 Although chaperone Unc-93 homolog B1, TLR signaling regulator (UNC93B1) is indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome, mechanisms of UNC93B1-mediated TLR regulation remain largely unknown. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1678998 | ACCEPT | Summary: Reactome reactions placing full-length TLR7 in the ER membrane during chaperone-assisted folding and UNC93B1 binding. Reason: Consistent with the structural evidence that UNC93B1 engages TLR7 in the ER membrane before delivery to the endosome. Supporting Evidence: PMID:33432245 Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions PMID:33432245 Although chaperone Unc-93 homolog B1, TLR signaling regulator (UNC93B1) is indispensable for the trafficking of TLRs from the endoplasmic reticulum to the endosome, mechanisms of UNC93B1-mediated TLR regulation remain largely unknown. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT IBA asserting that TLR7 is active in the plasma membrane, at the TLR7/8/9 clade node. Reason: Surface TLR7 is reported in some human cell types, so the location is defensible, but it is not where TLR7 acts: the receptor is ER-resident at rest, is delivered to endolysosomes by UNC93B1, and requires endosomal acidification to signal. Intracellular confinement is what keeps TLR7 from responding to extracellular self RNA. Retained as non-core rather than accepted, and whether is_active_in plasma membrane should stand at this node is raised as a question. Supporting Evidence: PMID:19740627 Human melanocytes constitutively expressed TLRs 1-4, 6, 7 and 9 mRNA. PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| 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, where TLR7 protein was detected by flow cytometry and immunofluorescence. Reason: A cell-type-specific surface observation. TLR7's canonical signalling compartment is the acidified endolysosome, so this is retained as a non-core location. Supporting Evidence: PMID:19740627 Human melanocytes constitutively expressed TLRs 1-4, 6, 7 and 9 mRNA. PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. |
| GO:0006952 defense response | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA assignment of defense response. Reason: True but very general; TLR7 initiates innate defence against RNA viruses. The specific pathway and antiviral terms carry the information. Supporting Evidence: PMID:38697119 Toll-like receptor 7 (TLR7) is essential for recognition of RNA viruses and initiation of antiviral immunity. |
| GO:0006955 immune response | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA assignment of immune response. Reason: True but very general. TLR7 is a receptor of innate immunity with downstream effects on adaptive immunity; the specific terms are preferred. Supporting Evidence: PMID:38697119 Toll-like receptor 7 (TLR7) is essential for recognition of RNA viruses and initiation of antiviral immunity. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro TIR-domain mapping to signal transduction. Reason: Correct but uninformative: the TIR domain recruits MyD88. The TLR7 signalling pathway term is preferred. Supporting Evidence: PMID:35477763 Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. |
| 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: Correct; the myddosome assembled on ligand-bound TLR7 activates canonical NF-kappaB, and TLR7 agonists drive IkappaB-alpha phosphorylation and p65 nuclear translocation in human cells. Supporting Evidence: PMID:19740627 Triggering of TLRs in melanocytes resulted in the up-regulation of phosphorylated IkappaBalpha and in the nucleus translocation of NF-kappaBp65. PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. |
| GO:0007249 canonical NF-kappaB signal transduction | IMP PMID:35477763 TLR7 gain-of-function genetic variation causes human lupus. | ACCEPT | Summary: IMP from the lupus study, where the gain-of-function TLR7 variant increases signalling and MyD88 deficiency rescues the phenotype. Reason: Core downstream branch of TLR7 signalling; MyD88 dependence establishes that the effect runs through the receptor's own pathway. Supporting Evidence: PMID:35477763 The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10-12, and was sufficient to cause lupus when introduced into mice. PMID:35477763 Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. |
| GO:0007254 JNK cascade | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer from mouse Tlr7 of JNK cascade. Reason: A downstream MAP-kinase branch of TLR7 signalling rather than a function of the receptor itself. Non-core. Supporting Evidence: PMID:35477763 Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-167983 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9679029 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9724670 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975098 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975100 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975106 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975111 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975115 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975118 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975125 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975134 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975156 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975160 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975170 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975175 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975180 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-975188 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9755765 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9836773 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endosome membrane for ligand binding and myddosome assembly. Reason: Core location. Reactome models the C-terminal TLR7 dimer binding imidazoquinolines, guanosine analogues and viral GU-rich ssRNA in this compartment, which matches the experimental requirement for endosomal maturation. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0032009 early phagosome | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer from mouse Tlr7 of early phagosome. Reason: Phagosomal TLR7 is recorded for mouse Tlr7 and is plausible in phagocytic cells, but there is no direct evidence for human TLR7 in this compartment and it is not where the receptor normally acts. Non-core. Supporting Evidence: PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0032009 early phagosome | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator transfer of early phagosome from mouse Tlr7. Reason: Same as the electronic row: plausible by orthology, not established for human TLR7, not the canonical signalling compartment. Supporting Evidence: PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0032722 positive regulation of chemokine production | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | ACCEPT | Summary: IDA in human melanocytes: a TLR7 agonist induced CCL2, CCL3 and CCL5 mRNA. Reason: A direct transcriptional output of TLR7 signalling through NF-kappaB in a primary human cell type. 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:19740627 Triggering of TLRs in melanocytes resulted in the up-regulation of phosphorylated IkappaBalpha and in the nucleus translocation of NF-kappaBp65. |
| 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: IFN-alpha induction by TLR7 agonists in human blood cells, abolished in IRAK-4 deficiency. Reason: Type I interferon is the signature TLR7 output in plasmacytoid dendritic cells, and IRAK-4 dependence places it downstream of the myddosome. 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-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent |
| GO:0032727 positive regulation of interferon-alpha production | IEA GO_REF:0000120 | ACCEPT | Summary: Combined electronic annotation (ARBA plus Compara transfer from mouse Tlr7) of positive regulation of interferon-alpha production. Reason: Consistent with the direct human evidence. 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: IFN-beta induction by TLR7 agonists in human blood cells, abolished in IRAK-4 deficiency. Reason: Type I interferon induction is a core TLR7 output; loss-of-function TLR7 patients also show reduced IFNB1 induction by imiquimod. 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:32706371 the patients displayed an impaired transcriptional host type I IFN response downstream of the TLR7 pathway, as evidenced by impaired upregulation expression of IRF7 , IFNB1 , and ISG15 |
| GO:0032728 positive regulation of interferon-beta production | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA assignment of positive regulation of interferon-beta production. Reason: Consistent with the direct human evidence. Supporting Evidence: PMID:32706371 the patients displayed an impaired transcriptional host type I IFN response downstream of the TLR7 pathway, as evidenced by impaired upregulation expression of IRF7 , IFNB1 , and ISG15 |
| 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 annotated as positive regulation of type II interferon production, from the IRAK-4 deficiency study. Reason: The cited paper measured IFN-alpha/beta (type I) and IFN-lambda (type III) after TLR-7/8/9 stimulation, not IFN-gamma; its title states as much. The finding therefore supports positive regulation of type III interferon production (GO:0034346). This matches the decision taken for the same row in the TLR9 review. TLR7 does have independent evidence for an IFN-gamma effect (PMID:32706371), which the separate electronic row carries. 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-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent |
| GO:0032729 positive regulation of type II interferon production | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA assignment of positive regulation of type II interferon production. Reason: Unlike TLR9, TLR7 has direct human evidence here: PBMCs from patients with loss-of-function TLR7 variants fail to make IFN-gamma in response to imiquimod while responding normally to an unrelated stimulus. But this is a seven-day whole-PBMC readout and the IFN-gamma producers are NK and T cells rather than the TLR7-expressing cells, so the effect is cell-extrinsic. Kept as non-core. Supporting Evidence: PMID:32706371 In addition, both index patients were completely deficient for IFN-Ξ³ production in response to TLR7 stimulation PMID:32706371 Additionally, an abrogated production of the type II IFN, IFN-Ξ³, was observed in the patientsβ PBMCs stimulated with imiquimod |
| GO:0032755 positive regulation of interleukin-6 production | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for positive regulation of interleukin-6 production at the TLR7/8/9 node. Reason: Correct; TLR7 agonists induce IL-6 in human cells, including primary cells, through the MyD88-NF-kappaB branch. 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:31608988 We conclude that dG induces an inflammatory response through TLR7 and propose that dG is an RNA-independent TLR7 agonist. |
| GO:0032757 positive regulation of interleukin-8 production | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | ACCEPT | Summary: IDA: a TLR7 ligand induced IL-8 secretion from cultured human melanocytes. Reason: A direct NF-kappaB-dependent output of TLR7 signalling in a primary human cell type. 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:19740627 Triggering of TLRs in melanocytes resulted in the up-regulation of phosphorylated IkappaBalpha and in the nucleus translocation of NF-kappaBp65. |
| GO:0032757 positive regulation of interleukin-8 production | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA assignment of positive regulation of interleukin-8 production. Reason: Consistent with the direct human evidence. 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 | IMP PMID:16188996 Activation of innate defense against a paramyxovirus is medi... | ACCEPT | Summary: IMP: ectopic TLR7 expression raised Sendai-virus-induced IL-8 in HEK293 cells, and chloroquine blocked the response. Reason: Gain-of-function in a TLR-null background plus chloroquine sensitivity make this a clean attribution to TLR7. Supporting Evidence: PMID:16188996 ectopic expression of TLR7 and TLR8 (but not TLR2, -3, -4, or -9) in HEK293 cells elevated SeV-induced activation of NF-ΞΊB and expression of IL-8 and IP-10 PMID:16188996 myeloid cells utilized both the single-stranded RNA sensing TLR7 and TLR8 and dsRNA-dependent mechanisms independent of RIG-I, TLR3, and dsRNA-activated protein kinase R to trigger this response |
| GO:0034154 toll-like receptor 7 signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for the toll-like receptor 7 signaling pathway. Reason: Core process, and the correctly specific term: TLR7 is the receptor that initiates it. Supporting Evidence: PMID:27742543 Our structural, biochemical, and mutagenesis studies indicated that TLR7 is a dual receptor for guanosine and uridine-containing ssRNA. PMID:35477763 Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. |
| GO:0034154 toll-like receptor 7 signaling pathway | IDA PMID:12032557 Human TLR7 or TLR8 independently confer responsiveness to th... | ACCEPT | Summary: IDA: human TLR7 alone confers responsiveness to the imidazoquinoline R-848. Reason: Direct demonstration that TLR7 initiates its own signalling pathway on ligand engagement; R-848 binds the first (small-ligand) site defined structurally. Supporting Evidence: PMID:12032557 Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. PMID:27742543 The first site preferentially recognized guanosine and the second site specifically bound to uridine moieties in ssRNA. |
| GO:0034154 toll-like receptor 7 signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from mouse Tlr7 of the toll-like receptor 7 signaling pathway. Reason: Correct; the pathway and its ligand specificity are conserved between mouse and human TLR7. Supporting Evidence: PMID:14976261 Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. |
| GO:0034154 toll-like receptor 7 signaling pathway | IMP PMID:38697119 Lysosomal endonuclease RNase T2 and PLD exonucleases coopera... | ACCEPT | Summary: IMP: loss of RNase T2 or of the PLD3/PLD4 exonucleases abolishes TLR7 activation, defining the ligands that drive the pathway. Reason: Core process. The study establishes the two pockets and the degradation products that occupy them, and shows that the pathway fails when those ligands cannot be generated. Supporting Evidence: PMID:38697119 TLR7 contains two ligand-binding pockets that recognize different RNA degradation products: pocket 1 recognizes guanosine, while pocket 2 coordinates pyrimidine-rich RNA fragments. PMID:38697119 PLD exonuclease activity further released the terminal 2',3'-cyclic guanosine monophosphate (2',3'-cGMP) to engage pocket 1 and was also needed to generate RNA fragments for pocket 2. PMID:38697119 We found that the endonuclease RNase T2, along with 5' exonucleases PLD3 and PLD4, collaboratively generate the ligands for TLR7. |
| GO:0034158 toll-like receptor 8 signaling pathway | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl Compara transfer from mouse Tlr7 of the toll-like receptor 8 signaling pathway. Reason: GO:0034158 is defined as the series of molecular signals initiated by a ligand binding to the endolysosomal toll-like receptor 8, so by definition TLR7 cannot execute it - whatever mouse Tlr7 was annotated to. The two receptors do share agonists (R-848 activates each independently), which is how such a transfer arises, but the correct term for TLR7 is GO:0034154, which it already carries from four independent lines of evidence. Supporting Evidence: PMID:12032557 Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. |
| GO:0035197 siRNA binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer from mouse Tlr7 of siRNA binding. Reason: siRNA is a short RNA duplex, while the two structurally defined TLR7 sites bind guanosine (or 2',3'-cGMP) and single-stranded uridine-containing RNA. Immunostimulatory siRNAs are plausibly recognised through single-stranded regions or degradation products rather than as duplexes, and no direct TLR7-siRNA binding measurement supports a distinct activity. Over-annotation of the general ssRNA-binding function. Supporting Evidence: PMID:27742543 The first site preferentially recognized guanosine and the second site specifically bound to uridine moieties in ssRNA. PMID:38697119 PLD exonuclease activity further released the terminal 2',3'-cyclic guanosine monophosphate (2',3'-cGMP) to engage pocket 1 and was also needed to generate RNA fragments for pocket 2. |
| GO:0035197 siRNA binding | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Curator transfer of siRNA binding from mouse Tlr7. Reason: Same objection as the electronic row: the TLR7 ligand-binding sites are defined for guanosine and single-stranded uridine-containing RNA, not for RNA duplexes. Supporting Evidence: PMID:27742543 The first site preferentially recognized guanosine and the second site specifically bound to uridine moieties in ssRNA. |
| GO:0036020 endolysosome membrane | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA assignment of endolysosome membrane. Reason: Core location: TLR7 signals from the acidified endolysosomal membrane, and blocking endosomal maturation blocks signalling. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-1678920 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-1678927 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-975098 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-975100 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-975106 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-975111 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-975115 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-975118 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-975125 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-975134 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-975156 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-975160 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-975170 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-975175 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-975180 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-975188 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-9824732 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-9824849 | ACCEPT | Summary: Reactome reactions placing TLR7 in the endolysosome membrane for processing, ligand binding and myddosome assembly. Reason: Core location, consistent with the experimental requirement for endosomal acidification and with the reported endolysosomal residence of TLR7. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| 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: Core molecular function. TLR7 binds microbial and self RNA degradation products directly at two sites and transduces the signal through its TIR domain; the human gene is itself among the descendant evidences for the node, which is the expected marker of experimental grounding on the target rather than circularity. There is no TLR-specific MF term, so pattern recognition receptor activity is the appropriate parent. Supporting Evidence: PMID:27742543 Our structural, biochemical, and mutagenesis studies indicated that TLR7 is a dual receptor for guanosine and uridine-containing ssRNA. PMID:38697119 TLR7 contains two ligand-binding pockets that recognize different RNA degradation products: pocket 1 recognizes guanosine, while pocket 2 coordinates pyrimidine-rich RNA fragments. |
| GO:0038187 pattern recognition receptor activity | IMP PMID:38697119 Lysosomal endonuclease RNase T2 and PLD exonucleases coopera... | ACCEPT | Summary: IMP: TLR7 activation requires RNase T2 and PLD3/PLD4 to generate the RNA degradation products that occupy its two pockets. Reason: Direct support for receptor activity on defined RNA-derived ligands. Supporting Evidence: PMID:38697119 TLR7 contains two ligand-binding pockets that recognize different RNA degradation products: pocket 1 recognizes guanosine, while pocket 2 coordinates pyrimidine-rich RNA fragments. PMID:38697119 PLD exonuclease activity further released the terminal 2',3'-cyclic guanosine monophosphate (2',3'-cGMP) to engage pocket 1 and was also needed to generate RNA fragments for pocket 2. file:human/TLR7/TLR7-deep-research-falcon.md TLR7 uses a dual-site recognition mechanism: binding a guanosine or related small molecule in one site (site 1), and a short uridine-rich ssRNA fragment (site 2) |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IDA PMID:12032557 Human TLR7 or TLR8 independently confer responsiveness to th... | ACCEPT | Summary: IDA: TLR7 expression confers R-848-induced NF-kappaB activation. Reason: Direct, receptor-attributable activation of canonical NF-kappaB. Supporting Evidence: PMID:12032557 Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | ACCEPT | Summary: IDA: a TLR7 ligand induced IkappaB-alpha phosphorylation and p65 nuclear translocation in human melanocytes. Reason: Direct evidence in a primary human cell type for positive regulation of canonical NF-kappaB downstream of TLR7. Supporting Evidence: PMID:19740627 Triggering of TLRs in melanocytes resulted in the up-regulation of phosphorylated IkappaBalpha and in the nucleus translocation of NF-kappaBp65. PMID:19740627 Human melanocytes constitutively expressed TLRs 1-4, 6, 7 and 9 mRNA. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IEA GO_REF:0000120 | ACCEPT | Summary: Combined electronic annotation of positive regulation of canonical NF-kappaB signal transduction. Reason: Consistent with the direct human evidence. 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:0043235 signaling receptor complex | IDA PMID:23382219 Structural basis for endosomal trafficking of diverse transm... | ACCEPT | Summary: IDA asserting that TLR7 is part of a signaling receptor complex. Reason: The claim is right but the citation is not. PMID:23382219 is the SNX17 PX-FERM crystal-structure paper; I retrieved its open full text (PMC3581954) and it contains no mention of TLR7 or of Toll-like receptors, so it cannot be the source. The underlying assertion is nonetheless well established: activated TLR7 is an m-shaped homodimer with two ligand-binding sites, and it is also found in a complex with UNC93B1. Kept with the real support attached; the reference is flagged as a wrong identifier and should be replaced rather than the annotation dropped. Supporting Evidence: PMID:27742543 we generated crystal structures of three TLR7 complexes, and found that all formed an activated m-shaped dimer with two ligand-binding sites PMID:33432245 Both TLRs interact with the UNC93B1 amino-terminal six-helix bundle through their transmembrane and luminal juxtamembrane regions |
| GO:0045087 innate immune response | IMP PMID:35477763 TLR7 gain-of-function genetic variation causes human lupus. | ACCEPT | Summary: IMP from the human TLR7 gain-of-function lupus study. Reason: Correct though general. TLR7 is an innate immune sensor, and the disease phenotype of increased ligand sensing, rescued by MyD88 deficiency, is a direct consequence of that role. More specific terms (TLR7 signalling pathway, defence response to virus) carry the detail. Supporting Evidence: PMID:35477763 The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10-12, and was sufficient to cause lupus when introduced into mice. PMID:35477763 We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis |
| GO:0045335 phagocytic vesicle | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping to phagocytic vesicle. Reason: Derived from the mouse Tlr7 phagosome annotation; plausible in phagocytes but not established for human TLR7 and not the canonical signalling compartment. Non-core. Supporting Evidence: PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer from mouse Tlr7 of positive regulation of transcription by RNA polymerase II. Reason: TLR7 signalling ultimately activates NF-kappaB and IRF7, which are transcription factors, but the receptor is several steps removed from transcription itself. Over-annotation for an endolysosomal membrane receptor; consistent with the TLR9 review. Supporting Evidence: PMID:35477763 Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. |
| GO:0050729 positive regulation of inflammatory response | IDA PMID:19740627 Cultured human melanocytes express functional toll-like rece... | ACCEPT | Summary: IDA: TLR7 ligation in human melanocytes drove NF-kappaB activation and release of inflammatory cytokines and chemokines. Reason: A direct inflammatory output of TLR7 signalling; the gain-of-function human disease is inflammatory as well. 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:35477763 The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10-12, and was sufficient to cause lupus when introduced into mice. |
| 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: Core process. TLR7 detects viral RNA in endosomes and is required for the interferon response to influenza; human loss-of-function variants cause severe COVID-19. Supporting Evidence: PMID:14976261 Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. PMID:38697119 Toll-like receptor 7 (TLR7) is essential for recognition of RNA viruses and initiation of antiviral immunity. PMID:32706371 the patients displayed an impaired transcriptional host type I IFN response downstream of the TLR7 pathway, as evidenced by impaired upregulation expression of IRF7 , IFNB1 , and ISG15 |
| GO:0051607 defense response to virus | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from mouse Tlr7 of defense response to virus. Reason: Correct and conserved; the mouse evidence (influenza genomic RNA sensing) and the human genetic evidence agree. Supporting Evidence: PMID:14976261 Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. |
| GO:0051607 defense response to virus | IEP PMID:32634389 Chikungunya virus infection induces differential inflammator... | ACCEPT | Summary: IEP: TLR transcript levels change in monocytes and macrophages on chikungunya virus infection. Reason: The IEP evidence is weak - an expression correlation, with the abstract not singling out TLR7 - but the term is correct for TLR7 on strong independent grounds (influenza RNA sensing; severe COVID-19 in loss-of-function patients). Accepted on that basis, consistent with the TLR3 review. Supporting Evidence: PMID:32634389 our data provides evidence that CHIKV infection activates the TLR pathways in primary monocytes and MDMs PMID:14976261 Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. |
| GO:0051607 defense response to virus | IMP PMID:16188996 Activation of innate defense against a paramyxovirus is medi... | ACCEPT | Summary: IMP: TLR7 mediates part of the myeloid-cell antiviral response to Sendai virus, chloroquine-sensitively. Reason: Direct antiviral function attributable to TLR7 in a gain-of-function and inhibitor-controlled setting. Supporting Evidence: PMID:16188996 myeloid cells utilized both the single-stranded RNA sensing TLR7 and TLR8 and dsRNA-dependent mechanisms independent of RIG-I, TLR3, and dsRNA-activated protein kinase R to trigger this response PMID:16188996 ectopic expression of TLR7 and TLR8 (but not TLR2, -3, -4, or -9) in HEK293 cells elevated SeV-induced activation of NF-ΞΊB and expression of IL-8 and IP-10 |
| 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; the specific antiviral and pathway terms carry the content. Supporting Evidence: PMID:38697119 Toll-like receptor 7 (TLR7) is essential for recognition of RNA viruses and initiation of antiviral immunity. |
| GO:0070305 response to cGMP | IMP PMID:35477763 TLR7 gain-of-function genetic variation causes human lupus. | MODIFY | Summary: IMP annotated as response to cGMP, from the finding that the TLR7 Y264H variant selectively increases sensing of guanosine and 2',3'-cGMP. Reason: The chemistry does not match the term. GO:0070305 is defined as a response to cGMP, guanosine 3',5'-cyclophosphate - the second messenger made by guanylate cyclases. The TLR7 ligand is the positional isomer guanosine 2',3'-cyclic monophosphate, released from RNA by RNase T2 and the PLD3/PLD4 exonucleases and bound in the receptor's first pocket; the cited paper says 'guanosine and 2',3'-cGMP', not 3',5'-cGMP. What the evidence establishes is direct recognition of a guanosine moiety at site 1, which is exactly GO:1905108 guanosine binding - independently supported by the crystal structures and by deoxyguanosine acting as an RNA-independent agonist. GO has no term for 2',3'-cyclic GMP binding or for a response to it; that gap is raised as a question rather than filled with an ill-fitting id. Proposed replacements: guanosine binding Supporting Evidence: PMID:35477763 The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10-12, and was sufficient to cause lupus when introduced into mice. PMID:38697119 PLD exonuclease activity further released the terminal 2',3'-cyclic guanosine monophosphate (2',3'-cGMP) to engage pocket 1 and was also needed to generate RNA fragments for pocket 2. PMID:35477763 TLR7 is a sensor of viral RNA8,9 and binds to guanosine10-12. PMID:31608988 We conclude that dG induces an inflammatory response through TLR7 and propose that dG is an RNA-independent TLR7 agonist. |
| GO:0071260 cellular response to mechanical stimulus | IEP PMID:19593445 Expression of the Bcl-2 protein BAD promotes prostate cancer... | UNDECIDED | Summary: IEP for cellular response to mechanical stimulus, citing a paper on BAD and prostate cancer growth. Reason: The cached record for PMID:19593445 carries full text and contains no occurrence of 'TLR', 'toll' or any mechanical stimulation; it is 'Expression of the Bcl-2 protein BAD promotes prostate cancer growth'. The identifier is therefore almost certainly wrong, but I cannot recover what was intended, and no other evidence in the literature reviewed here links TLR7 to mechanical stimuli. Left undecided pending a corrected reference; the same row exists on TLR8 and on TLR3, where it was also left undecided. The reference is flagged in references[].reference_review. Supporting Evidence: PMID:19593445 Expression of the Bcl-2 protein BAD promotes prostate cancer growth. |
| GO:0098586 cellular response to virus | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from mouse Tlr7 of cellular response to virus. Reason: Correct; TLR7 is the endosomal sensor through which infected cells respond to RNA viruses. Supporting Evidence: PMID:14976261 Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. PMID:38697119 Toll-like receptor 7 (TLR7) is essential for recognition of RNA viruses and initiation of antiviral immunity. |
| GO:0140894 endolysosomal toll-like receptor signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA assignment of endolysosomal toll-like receptor signaling pathway. Reason: Correct and well matched to TLR7's compartment; GO:0034154 is a child of this term and is the preferred, more specific annotation that TLR7 also carries. Supporting Evidence: PMID:12738885 The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. PMID:22164301 Thus, the localization site of TLR8 differed from TLR7 and TLR9, both of which reside in the endolysosome and the ER. |
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Download this section (compressed HTML)Q: GO:0070305 response to cGMP (IMP, PMID:35477763) is defined for guanosine 3',5'-cyclophosphate, but the TLR7 site-1 ligand is the 2',3'-cyclic isomer released from RNA by RNase T2 and PLD3/PLD4 (PMID:38697119). Should this row be replaced by GO:1905108 guanosine binding, and should GO create terms for 2',3'-cyclic GMP binding and for a response to it?
Q: GO:0034158 toll-like receptor 8 signaling pathway is annotated to TLR7 by Ensembl Compara transfer from mouse Tlr7. Since the term is defined by ligand binding to TLR8, should the transfer be blocked for receptor-specific pathway terms in this family generally?
Q: The TLR7/8/9 PAINT node carries is_active_in GO:0005886 plasma membrane. Given that all three receptors signal from endolysosomes and that forcing them to the surface abolishes function, should that assertion be retired or demoted at the node?
Q: GO:0071260 cellular response to mechanical stimulus (IEP) on TLR7, TLR8 and TLR3 all cite PMID:19593445, a paper on BAD and prostate cancer growth that never mentions TLRs. What was the intended reference?
Q: GO:0043235 signaling receptor complex (IDA, MGI) on TLR7 cites PMID:23382219, the SNX17 PX-FERM structure paper, whose full text does not mention TLR7. What was the intended reference - and should the activated TLR7 homodimer or the TLR7-UNC93B1 complex be the modelled complex?
Q: Does the IFN-gamma defect in TLR7 loss-of-function patients (PMID:32706371) justify involved_in GO:0032729 for TLR7 itself, given that IFN-gamma is produced by NK and T cells rather than by the TLR7-expressing cells in those PBMC cultures?
Q: Is siRNA binding (GO:0035197) defensible for TLR7 when both structurally defined sites bind a guanosine moiety and single-stranded uridine-containing RNA, and no direct TLR7-siRNA duplex binding has been measured?
Experiment: Direct binding measurements (ITC or SPR) of the purified TLR7 ectodomain against guanosine 2',3'-cyclic monophosphate, guanosine 3',5'-cyclic monophosphate and guanosine, to establish quantitatively whether TLR7 discriminates the two cyclic isomers and to settle which GO term describes the activity.
Experiment: Binding and activation assays of purified TLR7 with a defined siRNA duplex, the same duplex after denaturation, and its single strands, to test whether siRNA recognition requires duplex structure or proceeds through single-stranded RNA.
Experiment: Cell-type-resolved IFN-gamma measurement (single-cell cytokine capture or intracellular staining) in TLR7-deficient versus control PBMCs stimulated with imiquimod, to determine whether the IFN-gamma producers express TLR7 or respond as bystanders.
Experiment: Quantitative colocalisation of endogenous human TLR7 with Golgi, early-endosome, late-endosome and lysosome markers in plasmacytoid dendritic cells and B cells, using the same panel applied to TLR8 in PMID:22164301, to test the Reactome Golgi-transit step and the surface pool directly.
Experiment: Imiquimod and ssRNA stimulation of cells expressing TLR7 in which the first-site or second-site residues are separately mutated, reading out NF-kappaB, IRF7 and IL-8, to determine whether the two sites contribute to different output branches or only to a shared activation threshold.
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