Toll-like receptor of the TLR11/TLR12 pair, found in rodents and in some other mammals including horses, where both paralogues are transcribed, but with no human counterpart. It has a leucine-rich-repeat ectodomain, one transmembrane segment and a cytoplasmic TIR domain, and is expressed in macrophages and in liver, kidney and bladder epithelium. Unlike the surface TLRs it is an intracellular receptor: it resides in the endoplasmic reticulum, binds the trafficking chaperone UNC93B1 directly and engages ligand in endolysosomal compartments. Two chemically defined ligands are established, bacterial flagellin and the profilin protein of apicomplexan parasites such as Toxoplasma gondii, and the receptor does not respond to the standard panel of agonists for other TLRs. On ligand binding it recruits MyD88 through its TIR domain and drives IL-12 and IL-6 production and Th1 polarisation; the IL-12 response of dendritic cells to profilin was shown to require MyD88 and IRF8 rather than NF-kappa-B1 or NF-kappa-B2, so the transcriptional route downstream of the receptor is cell-type dependent; it can act as a homodimer and also as a heterodimer with its close paralogue, to which it supplies the MyD88-recruiting function. Animals lacking the receptor are highly susceptible to kidney infection by uropathogenic bacteria and mount impaired IL-12 responses to Toxoplasma. The literature names of the two paralogues are interchanged relative to the MGI and UniProt gene symbols, so published work on "TLR11" refers to this protein.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002224 toll-like receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Correct: this is a TIR-domain receptor that recruits MyD88 and drives IL-12 responses on ligand binding. Reason: The phylogenetic assertion is well placed, and there is direct experimental grounding on this gene product: defined ligands, MyD88 recruitment and UNC93B1-dependent activation. GO's numbered children for this pair (GO:0034170, GO:0034174) are named after the receptors as the literature names them, and those names are inverted relative to the MGI and UniProt symbols, so assigning a child would assert a nomenclature resolution neither GO nor MGI has made; the unnumbered parent is therefore kept, as on the paralogue's review. Supporting Evidence: PMID:24078692 only TLR11 is capable of recruiting MyD88 to the receptor complex PMID:24078692 neither NF-ΞΊB1 nor NF-ΞΊB2 were required for DC IL-12 production PMID:15001781 Cells expressing TLR11 fail to respond to known TLR ligands but instead respond |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | MODIFY | Summary: An ER-resident, UNC93B1-dependent receptor that engages ligand in endolysosomes; the plasma-membrane location was inherited from surface-TLR donors. Reason: The PAINT node's donors are cell-surface receptors (TLR1, TLR2, TLR4, TLR5, TLR6, Drosophila Toll), and the location did not transfer: this receptor resides in the endoplasmic reticulum in resting cells, interacts directly with UNC93B1, and both members of the pair were shown to act as endosomal TLRs. Endosome is proposed as the compartment of action; the resting ER pool is recorded in the description rather than as a competing annotation, because the published evidence describes trafficking from ER to endolysosome rather than steady-state residence in one place. Ligand-binding biochemistry supports endosome for at least the flagellin response: binding to flagellin requires acidic pH and works with the cathepsin-generated C-terminal fragment, so the authors place that recognition event in an acidic endolysosomal compartment. The same study notes that profilin binding needs the uncleaved receptor and is seen at neutral pH, leaving open a pre-cleavage compartment for profilin recognition; this nuance is recorded in the notes and as a suggested question rather than as a second competing location annotation. 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, for which plasma membrane is correct; this branch is UNC93B1-dependent and intracellular. Proposed replacements: endosome Supporting Evidence: PMID:21097503 we show that TLR11, an innate sensor for the Toxoplasma protein profilin, is an PMID:23290966 both TLR11 and TLR12 are endosomal TLRs and act as heterodimers in the recognition of Toxoplasma molecules PMID:26859749 Cathepsin-derived C-terminal region of TLR11 interacts with FliC within an acidic endolysosomal compartment. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: True but generic; the TIR-domain mapping yields the top-level process. Reason: Sound for a TIR-domain protein but uninformative beside GO:0002224, which is annotated on the same gene. |
| GO:0016020 membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Correct at the generic level for a single-pass type I membrane protein. Reason: True but uninformative; the informative locations are the endoplasmic reticulum and the endosome. |
| GO:0038023 signaling receptor activity | IBA GO_REF:0000033 | MODIFY | Summary: Two chemically defined microbial patterns, bacterial flagellin and apicomplexan profilin, are bound directly by this receptor, so the pattern recognition receptor activity child applies. Reason: GO:0038023 is right but generic. Flagellin binding to this receptor was shown by pull-down with His-tagged flagellin, and Toxoplasma profilin is the chemically defined ligand of the same receptor; the pair was also shown to interact with profilin directly at endolysosomal pH. GO:0038187 is the conventional molecular function for characterised TLRs (human TLR2, TLR5 and TLR9 all carry it by IDA), and it states what this receptor does rather than what any receptor does. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002808045 SUPPORTS TRANSFER The node assertion is correct; it is the generic parent, and ligand-binding data on this gene product support the specific child. Proposed replacements: pattern recognition receptor activity Supporting Evidence: PMID:23101627 Flagellin binds TLR11 and induces innate responses in mice independent of TLR5. PMID:15860593 TLR11 is required in vivo for parasite-induced IL-12 production PMID:26859749 Thus only full-length TLR11-Flag interacts with His-TPRF, while both cleaved and full-length TLR11-Flag binds to His-FliC. |
| GO:0042832 defense response to protozoan | IMP PMID:19050265 Recognition of Toxoplasma gondii by TLR11 prevents parasite-... | ACCEPT | Summary: Knockout of this gene reduces IL-12 and impairs control of Toxoplasma gondii, whose profilin the receptor recognises. Reason: Both the paper and the allele belong to this entry. The WITH field cites MGI:3045751, which MGI records as Tlr12<tm1Gho> and notes to be a Tlr12 allele on sequence grounds even though the papers call it Tlr11; and the receptor called TLR11 in this literature is Q6QNU9 on independent primer evidence. Participation is direct: the receptor binds the parasite profilin PAMP and initiates the MyD88 and IL-12 response that controls the infection, rather than merely being required downstream. Supporting Evidence: PMID:19050265 TLR11-deficient mice developed dramatically reduced serum IL-12 levels PMID:19050265 the critical parasite ligand involved is the actin-binding protein profilin PMID:15860593 TLR11 is required in vivo for parasite-induced IL-12 production |
| GO:0051707 response to other organism | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Correct but very general; the specific responses are to bacteria and to a protozoan parasite, both annotated more precisely. Reason: The ARBA assertion is true. It is superseded in informativeness by GO:0042832 and by the proposed GO:0009617, both descendants. |
| GO:0009617 response to bacterium | IMP PMID:15001781 A toll-like receptor that prevents infection by uropathogeni... | NEW | Summary: Animals lacking this receptor are highly susceptible to kidney infection by uropathogenic bacteria, and the receptor binds bacterial flagellin directly. Reason: The knockout characterised in PMID:15001781 is allele MGI:3045751, recorded by MGI as Tlr12<tm1Gho> and noted there to be a Tlr12 allele on sequence grounds; UniProt cites the same paper under this entry for FUNCTION, TISSUE SPECIFICITY and DISRUPTION PHENOTYPE. The later identification of flagellin as the ligand of the same receptor supplies the molecular mechanism, so this is not a bare necessity argument: the gene product performs the recognition step of the response. Comparator check: the paralogue Q6R5P0 currently carries this exact term from this exact paper and allele, which is what prompted the review of the pair; characterised TLRs are conventionally annotated to the response term for the class of microbe they sense, so the term belongs on whichever entry the allele belongs to, and the evidence says this one. Kept at the general GO:0009617 rather than a child such as defense response to Gram-negative bacterium because flagellated Gram-positive species were not excluded. Supporting Evidence: PMID:15001781 susceptible to infection of the kidneys by uropathogenic bacteria PMID:15001781 Cells expressing TLR11 fail to respond to known TLR ligands but instead respond PMID:23101627 Flagellin is also the TLR11 ligand from UPECs. |
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Download this section (compressed HTML)Q: Is an NF-kappa-B-dependent branch downstream of this receptor pair annotatable? The profilin-induced IL-12 response of dendritic cells required MyD88 and IRF8 and not NF-kappa-B1 or NF-kappa-B2, while NF-kappa-B activation was reported in macrophages and plasmacytoid dendritic cells.
Q: Which of GO:0034170 (toll-like receptor 11 signaling pathway) and GO:0034174 (toll-like receptor 12 signaling pathway) applies to Q6QNU9 and which to Q6R5P0? The term names follow the literature receptor names, which are inverted relative to the MGI and UniProt symbols, so the numbered terms cannot be annotated until GO and MGI agree a mapping, and the definitions may be clearer if they cite accessions.
Q: Should the GO:0009617 row currently on Tlr11 (IMP, PMID:15001781, WITH allele MGI:3045751) be moved here, where the allele and the UniProt reference assignment both point? This review proposes the annotation on this entry but does not remove the paralogue's row.
Q: Are flagellin and profilin recognised by the same surface of this receptor? The two ligands are unrelated in structure, and no binding site has been mapped for either, so it is unknown whether one ectodomain site is promiscuous or two distinct sites exist.
Q: Does the receptor function as a flagellin sensor in the same intracellular compartment in which it senses profilin? Flagellin recognition by surface TLR5 is extracellular, whereas this receptor is UNC93B1-dependent and endolysosomal, which implies that flagellin must reach an endosomal compartment to be detected.
Experiment: Publish a sequence-verified mapping of the reagents: sequence the Tlr12<tm1Gho> line, the commercial expression plasmids and the widely shared cDNAs, and report which of NP_991392 (Q6QNU9) or NP_991388 (Q6R5P0) each corresponds to.
Hypothesis: The literature names of the pair are interchanged relative to the database symbols; a single public mapping would let MGI, UniProt and GO align and would resolve the split annotations across the two entries.
Type: sequence verification of reagents
Experiment: Compare flagellin and profilin responses side by side in cells expressing this receptor alone, the paralogue alone, or both, in wild-type and UNC93B1-deficient backgrounds, reading NF-kappa-B activation, IL-12 and receptor localisation.
Hypothesis: Flagellin sensing requires this receptor as a homodimer and is UNC93B1-dependent, whereas profilin sensing additionally requires the paralogue.
Type: receptor activation assay
Experiment: Map the ligand-binding surfaces by crosslinking or cryo-EM of the ectodomain with flagellin and with Toxoplasma profilin, followed by mutagenesis of the contact residues and functional testing in macrophages.
Hypothesis: The two structurally unrelated protein ligands engage distinct leucine-rich-repeat surfaces of the same ectodomain.
Type: structural biology with structure-guided mutagenesis
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