Endosomal Toll-like receptor of rodents, with no counterpart in the human genome, that senses bacterial ribosomal RNA. Its leucine-rich-repeat ectodomain binds a short, conserved single-stranded sequence of bacterial 23S rRNA, recognising it in a sequence- and conformation-specific manner: in the complex the RNA adopts a stem-loop-like fold quite different from its conformation within the ribosome, and binding drives receptor dimerisation. The recognised site is the binding site of macrolide, lincosamide and streptogramin antibiotics, so the methylation that confers erythromycin resistance in bacteria also abolishes detection by this receptor, linking antibiotic resistance to immune evasion. The receptor is expressed mainly in spleen, dendritic cells and macrophages, reaches its endosomal compartment with the trafficking factor UNC93B1, which it binds directly, and signals through its cytoplasmic TIR domain via MyD88 and TAK1 to activate NF-kappa-B, with type I interferon induction through IRF7. A single-stranded RNA of viral origin predicted to fold like the rRNA ligand can also activate it, and an early report of a response to vesicular stomatitis virus remains less well substantiated than the bacterial RNA recognition. Loss of the receptor impairs control of Streptococcus pneumoniae in the brain, and together with the surface receptor TLR2 it accounts for much of the sensing of that bacterium in the central nervous system, where the same signalling also drives the inflammatory brain damage of meningitis. Besides responding to pathogens, the receptor is activated in tissue macrophages by ribosomal RNA derived from the commensal microbiota, and in mice whose endosomal RNase T2 is missing this drives the accumulation of liver and spleen macrophages with a tissue-protective, interleukin-10-expressing phenotype. Humans have no counterpart gene, and TLR8 is regarded as the receptor that performs the equivalent endosomal bacterial-RNA sensing in human cells.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002224 toll-like receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Correct, and independently grounded on this gene product by experiment. Reason: The node placement is sound and the target has its own experimental support: ligand recognition, MyD88 and TAK1 dependence and NF-kappa-B activation. The receptor-specific child GO:0034178 is also annotated by IDA, so this row functions as the parent of a better-supported annotation rather than as the only statement. Supporting Evidence: PMID:22821982 the orphan receptor TLR13 in mice recognizes a conserved 23S ribosomal RNA |
| GO:0002755 MyD88-dependent toll-like receptor signaling pathway | IGI PMID:21131352 A novel Toll-like receptor that recognizes vesicular stomati... | ACCEPT | Summary: Signalling by this receptor requires MyD88, so the MyD88-dependent branch of the TLR pathway is the right process. Reason: The genetic-interaction evidence with Myd88 matches the published characterisation of the receptor, which activates a MyD88- and TAK1-dependent cascade; UniProt records the same MyD88 dependence for this protein. This is the informative pathway statement for the gene, alongside the receptor-specific GO:0034178. Supporting Evidence: PMID:21131352 MyD88- and TAK1-dependent TLR signaling pathway, inducing the activation of |
| GO:0005515 protein binding | IPI PMID:17452530 The interaction between the ER membrane protein UNC93B and T... | MODIFY | Summary: Records the interaction with the trafficking factor UNC93B1, identified by mass spectrometry of UNC93B immunoprecipitates; the generic binding term should be replaced by an informative one. Reason: The interaction itself is well supported, but GO:0005515 states nothing about function. UNC93B1 is the endoplasmic-reticulum-resident chaperone-like factor that escorts the nucleic-acid-sensing TLRs to their signalling compartment, and binding it is what allows this receptor to reach the endosome; GO:0051087 protein-folding chaperone binding captures that relationship. Proposed rather than removed because the interaction is mechanistically load-bearing for this receptor rather than incidental. Proposed replacements: protein-folding chaperone binding Supporting Evidence: PMID:17452530 we identified TLR3, 7, 9, and 13 with extensive sequence coverage over the entire length of the proteins file:mouse/Tlr13/Tlr13-uniprot.txt Interacts with UNC93B1 |
| GO:0005515 protein binding | IPI PMID:21131352 A novel Toll-like receptor that recognizes vesicular stomati... | MODIFY | Summary: Records the interaction with MyD88, which for a TLR is a TIR-domain to TIR-domain association; the generic term should be replaced. Reason: Bare protein binding is uninformative, and the informative statement is available: the receptor recruits the adaptor through the TIR domains of both partners, which is what UniProt records for this protein and what the pathway annotations (GO:0002755) depend on. GO:0070976 TIR domain binding states this without asserting anything about which downstream events follow. Proposed replacements: TIR domain binding Supporting Evidence: file:mouse/Tlr13/Tlr13-uniprot.txt Binds MYD88 via their respective TIR domains PMID:21131352 MyD88- and TAK1-dependent TLR signaling pathway, inducing the activation of |
| GO:0005737 cytoplasm | IDA PMID:21131352 A novel Toll-like receptor that recognizes vesicular stomati... | KEEP AS NON CORE | Summary: True of an endosomal membrane protein but uninformative; the compartment is recorded precisely by other rows. Reason: The observation behind it is that the receptor is intracellular rather than on the cell surface, which is correct. GO:0005768 endosome and GO:0010008 endosome membrane are annotated on the same gene and say where in the cytoplasm it acts, so this row adds nothing to the functional picture. Supporting Evidence: PMID:21131352 Tlr13 seems to be another intracellular TLR |
| GO:0005768 endosome | IDA PMID:22896636 Cutting edge: TLR13 is a receptor for bacterial RNA. | ACCEPT | Summary: The receptor resides and functions in endosomes. Reason: Direct assay in the cited study, consistent with UNC93B1 dependence, with the requirement for endosomal maturation in related receptors, and with UniProt's subcellular location for this protein. Supporting Evidence: PMID:22896636 Small interfering RNA against TLR13 reduced |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | MODIFY | Summary: This is an endosomal receptor; plasma membrane was inherited from the surface TLRs that seeded the ancestral node. Reason: The donors of the node are cell-surface receptors, for which the location is right, but it does not transfer to this branch: the receptor is UNC93B1-dependent and both the cited experimental work and UniProt place it in the endosome membrane. Endosome membrane is proposed rather than plain endosome because the protein is a single-pass type I membrane protein and the membrane term is already independently annotated, so the replacement is consistent with the rest of the record. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN002808045 SUPPORTS SOURCE BUT NOT TARGET Node seeded by surface TLRs and Drosophila Toll; the nucleic-acid-sensing branch to which this receptor belongs is intracellular and UNC93B1-dependent. Proposed replacements: endosome membrane Supporting Evidence: PMID:22896636 Small interfering RNA against TLR13 reduced file:mouse/Tlr13/Tlr13-uniprot.txt SUBCELLULAR LOCATION: Endosome membrane |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: True but generic. Reason: Sound TIR-domain-based inference, superseded by GO:0002224, GO:0002755 and GO:0034178 on the same gene. |
| GO:0009615 response to virus | IMP PMID:21131352 A novel Toll-like receptor that recognizes vesicular stomati... | KEEP AS NON CORE | Summary: Rests on the single early report of a vesicular stomatitis virus response; retained but not treated as a core function. Reason: The cited study reported that cells expressing the receptor responded specifically to vesicular stomatitis virus and that knockdown increased susceptibility, and UniProt reproduces the claim while stating that it requires additional evidence. The subsequent literature converged on bacterial 23S rRNA as the physiological ligand, and the structural work supports the viral connection only indirectly, by showing that a viral-derived single-stranded RNA predicted to fold like the rRNA ligand can also activate the receptor. That is enough to keep the annotation as a secondary, contextual role, and not enough to make it core. Supporting Evidence: PMID:21131352 specifically to vesicular stomatitis virus PMID:26323037 a viral-derived 16-nt ssRNA file:mouse/Tlr13/Tlr13-uniprot.txt May also recognize vesicular stomatitis virus; however, |
| GO:0010008 endosome membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Correct, and matches the experimental localisation. Reason: The UniProt subcellular-location mapping here reproduces an experimentally determined location rather than a guess: UniProt cites PMID:22896636 for endosome membrane, and the same paper supports the IDA endosome row. Supporting Evidence: PMID:22896636 Small interfering RNA against TLR13 reduced |
| GO:0019843 rRNA binding | IDA PMID:22821982 TLR13 recognizes bacterial 23S rRNA devoid of erythromycin r... | ACCEPT | Summary: The receptor binds a defined conserved sequence of bacterial 23S rRNA. Reason: This is the central molecular function of the protein. The cited work identified the ligand and showed that the erythromycin-resistance methylation of that exact site abolishes stimulation, and the later crystal structure of the ectodomain with a 13-nucleotide rRNA-derived ligand makes the binding claim structural rather than inferential. Supporting Evidence: PMID:22821982 the orphan receptor TLR13 in mice recognizes a conserved 23S ribosomal RNA PMID:22821982 failed PMID:26323037 The ssRNA induces TLR13 dimerization but assumes PMID:39853307 TLR13 activation by microbiota-derived ribosomal |
| GO:0019843 rRNA binding | IDA PMID:22896636 Cutting edge: TLR13 is a receptor for bacterial RNA. | ACCEPT | Summary: Independent support that the receptor is a bacterial RNA sensor. Reason: A second laboratory reached the same conclusion by a different route, knocking down the receptor in dendritic cells and reconstituting bacterial RNA responsiveness in transfected cells. Two independent IDA rows for one molecular function is duplication in the record, not redundancy in the evidence. Supporting Evidence: PMID:22896636 Small interfering RNA against TLR13 reduced |
| GO:0034178 toll-like receptor 13 signaling pathway | IDA PMID:22821982 TLR13 recognizes bacterial 23S rRNA devoid of erythromycin r... | ACCEPT | Summary: The receptor-specific pathway term, supported by the study that defined the ligand. Reason: This is exactly the annotation the ligand-specific term exists for: the series of signals initiated by ligand binding to this receptor was demonstrated directly, in cells expressing it and in animals lacking it. Unlike the TLR11/TLR12 pair, the identity of this receptor is unambiguous, so the numbered child can be used with confidence. Supporting Evidence: PMID:22821982 the orphan receptor TLR13 in mice recognizes a conserved 23S ribosomal RNA |
| GO:0034178 toll-like receptor 13 signaling pathway | IDA PMID:22896636 Cutting edge: TLR13 is a receptor for bacterial RNA. | ACCEPT | Summary: Independent support for the receptor-specific pathway. Reason: The second study showed NF-kappa-B activation in response to bacterial RNA specifically in cells transfected with this receptor and not with TLR7 or TLR8, which is pathway-level evidence for the same numbered term. Supporting Evidence: PMID:22896636 Small interfering RNA against TLR13 reduced |
| GO:0038023 signaling receptor activity | IBA GO_REF:0000033 | MODIFY | Summary: A defined microbial pattern is bound directly, with a structure of the complex, so the pattern recognition receptor activity child applies. Reason: GO:0038023 is correct but is the generic parent. Bacterial 23S rRNA is a pathogen-associated molecular pattern, its recognition by this receptor has been demonstrated functionally by two groups and structurally at the level of base-specific contacts, and GO:0038187 is the conventional molecular function for characterised TLRs (human TLR2, TLR5 and TLR9 all carry it by IDA). The rRNA-binding rows state what is bound; this states what the binding accomplishes. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002808045 SUPPORTS TRANSFER The ancestral assertion is correct; the target has direct evidence licensing the more specific child. Proposed replacements: pattern recognition receptor activity Supporting Evidence: PMID:22821982 the orphan receptor TLR13 in mice recognizes a conserved 23S ribosomal RNA PMID:26323037 The ssRNA induces TLR13 dimerization but assumes |
| GO:0042802 identical protein binding | IPI PMID:21131352 A novel Toll-like receptor that recognizes vesicular stomati... | MODIFY | Summary: Records self-association; the specific homodimerisation term states the same fact informatively. Reason: Identical protein binding is the generic parent of protein homodimerization activity, and the more specific term is justified here because the structural work shows that ligand binding drives dimerisation of the ectodomain, which is the activation mechanism of the receptor rather than an incidental interaction. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:26323037 The ssRNA induces TLR13 dimerization but assumes |
| GO:0042802 identical protein binding | IPI PMID:26323037 Structural basis for specific recognition of single-stranded... | MODIFY | Summary: The structural study's self-interaction row; same reasoning as the other identical-protein-binding row. Reason: This row comes from the paper that determined the ligand-bound ectodomain structure and showed that the single-stranded RNA ligand induces dimerisation, so the specific homodimerisation term is directly supported. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:26323037 The ssRNA induces TLR13 dimerization but assumes |
| GO:0043408 regulation of MAPK cascade | IGI PMID:21131352 A novel Toll-like receptor that recognizes vesicular stomati... | KEEP AS NON CORE | Summary: Reflects the TAK1 dependence of signalling downstream of this receptor; true but peripheral to the receptor's own function. Reason: The genetic interaction with the TAK1 kinase gene is consistent with the cited characterisation of the pathway. The receptor acts upstream of the cascade rather than regulating MAP kinase activity itself, and the informative statements about its signalling are GO:0002755 and GO:0034178, so this is retained as a secondary process annotation. Supporting Evidence: PMID:21131352 MyD88- and TAK1-dependent TLR signaling pathway, inducing the activation of |
| GO:0045087 innate immune response | IDA PMID:22821982 TLR13 recognizes bacterial 23S rRNA devoid of erythromycin r... | ACCEPT | Summary: Recognition of bacterial rRNA by this receptor initiates an innate immune response. Reason: Directly demonstrated: ligand engagement induces inflammatory cytokine production in macrophages and dendritic cells, and loss of recognition through ligand methylation is an immune-evasion mechanism for the bacterium. The term is general but is the standard umbrella process for a pattern recognition receptor. Supporting Evidence: PMID:22821982 the orphan receptor TLR13 in mice recognizes a conserved 23S ribosomal RNA |
| GO:0045087 innate immune response | IDA PMID:22896636 Cutting edge: TLR13 is a receptor for bacterial RNA. | ACCEPT | Summary: Independent support for the innate immune response role. Reason: The second study showed cytokine induction by bacterial RNA and by Gram-positive bacteria depending on this receptor in dendritic cells. Supporting Evidence: PMID:22896636 Small interfering RNA against TLR13 reduced |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:32209688 Nucleic Acid-Sensing Toll-Like Receptors Play a Dominant Rol... | NEW | Summary: Mice lacking this receptor control Streptococcus pneumoniae less well, and it is one of the two receptors that account for most pneumococcal sensing in the central nervous system. Reason: The participation test is met by the receptor's own activity rather than by necessity alone: the gene product binds the bacterial 23S rRNA ligand directly, with a structure of the complex, and that recognition is the step which initiates the chemokine and cytokine output that recruits neutrophils. The phenotype follows: single-knockout animals have moderately impaired antipneumococcal defence with late-onset lethality, microglia lacking the receptor produce less CXCL1 and TNF, and animals lacking it together with the other two endosomal nucleic-acid sensors are extremely susceptible because their resident macrophages cannot recruit neutrophils. A second study, using double-knockout animals, concluded that this receptor and TLR2 are the major pneumococcal sensors in the subarachnoid space. The comparator check supports the proposal: mouse Tlr2, the surface sensor of the same bacterium and the partner in that double knockout, carries GO:0050830 by IMP from three separate papers, so a sensor receptor is conventionally annotated to this term. The Gram-positive child is used rather than a general bacterial-response parent because the phenotypes are all with Streptococcus pneumoniae; the ligand, a conserved 23S rRNA sequence, is not itself restricted to Gram-positive species, so the term should be revisited if Gram-negative infection phenotypes are reported. Note that in the meningitis model the same signalling also drives brain pathology, so the receptor's contribution is protective in the lung and damaging in the central nervous system; GO:0050830 covers the protective side and the pathology is recorded in the description rather than annotated. Supporting Evidence: PMID:32209688 Collectively, these data indicate that mice with single defects in TLR7, TLR9, or TLR13 have moderately impaired antipneumococcal defenses in the brain resulting in late-onset lethality PMID:32209688 the simultaneous absence of TLR7, TLR9, and TLR13 was associated with extreme susceptibility to infection PMID:38358825 TLR13 and TLR2 are major pneumococcal sensors in the subarachnoid space |
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Download this section (compressed HTML)Q: Is the vesicular stomatitis virus response a genuine function of this receptor, or a consequence of viral single-stranded RNA happening to fold like the rRNA ligand? The structural work shows a viral-derived 16-nucleotide RNA can activate the receptor, which would make the virus response a special case of RNA recognition rather than a separate viral-sensing activity.
Q: Which human receptor, if any, senses bacterial 23S rRNA? UniProt suggests a different human rRNA-sensing receptor may exist; establishing it would determine whether this gene's function has a human counterpart to which annotations could be related, or is genuinely rodent-specific.
Q: Should GO acquire a term for recognition of ribosomal RNA as a pathogen-associated pattern, more specific than GO:0019843 rRNA binding? The existing term is shared with ribosome-assembly and RNA-processing proteins, and nothing in it conveys that the binding is an immune recognition event.
Q: Does the receptor sense rRNA from the host as well as from bacteria? The recognised sequence is described as conserved, so the discrimination between bacterial and host ribosomal RNA, and the role of compartmentalisation in it, is worth establishing explicitly.
Experiment: Test the specificity of the receptor against a panel of natural ribosomal RNAs and their modified variants, comparing bacterial 23S rRNA, host 28S rRNA and synthetic oligoribonucleotides carrying each known resistance modification, in cells expressing the receptor and in primary macrophages from knockout animals.
Hypothesis: Recognition depends on a bacterium-specific sequence and conformation rather than on ribosomal RNA in general, which is what keeps host RNA from triggering the receptor.
Type: ligand specificity assay
Experiment: Determine whether the reported vesicular stomatitis virus response requires viral single-stranded RNA of the stem-loop fold identified structurally, by testing defined viral RNA fragments and fold-disrupting substitutions for receptor activation, in parallel with infection of cells lacking the receptor.
Hypothesis: The virus response is RNA-fold-dependent recognition rather than a distinct antiviral sensing function, which would settle whether GO:0009615 belongs on this gene at all.
Type: structure-guided ligand mapping
Experiment: Test whether epidemiologically relevant macrolide-resistant clinical isolates evade this receptor in vivo, by infecting wild-type and receptor-deficient animals with isogenic resistant and sensitive strain pairs and measuring early cytokine induction and bacterial burden.
Hypothesis: The methylation that confers antibiotic resistance also confers immune evasion, so the receptor's contribution to control of infection should disappear with resistant strains.
Type: in vivo infection with isogenic strain pairs
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