Toll-7 is a Toll-family type I transmembrane receptor with an extracellular leucine-rich-repeat ectodomain and a cytoplasmic TIR domain, expressed at the plasma membrane and prominently in the central nervous system. It is a receptor for the Spätzle-family neurotrophins DNT1 (Spz2) and DNT2 (Spz5), and its ectodomain also binds Spätzle-1. In the nervous system Toll-7, together with its paralog Toll-6, regulates motor axon targeting, neuronal survival and locomotion, and cell-autonomously instructs olfactory receptor neuron axon targeting and synaptic partner matching. Toll-7 also contributes to antiviral defence: it associates with vesicular stomatitis virus and Rift Valley fever virus particles at the cell surface and is required for virus-induced autophagy that restricts these viruses, through a MyD88- and NF-kappaB-independent mechanism. Whether it also drives canonical Toll pathway antimicrobial peptide induction is disputed.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002225 positive regulation of antimicrobial peptide production | IMP PMID:31088910 Toll family members bind multiple Spätzle proteins and activ... | UNDECIDED | Summary: Toll-7 overexpression with Spätzle-family ligands or VSV activated AMP promoter reporters in S2 cells. Reason: Same conflict as the Toll signaling pathway annotation: other studies found no AMP induction by Toll-7 in cells or flies. Supporting Evidence: PMID:31088910 Spz-1, -2, and -5 also activated the drosomycin promoter in S2 cells expressing full-length Toll-7 98-, 87-, and 83-fold PMID:10973475 neither the 18W nor the Toll-6 to Toll-8 chimerae were able to induce drosomycin PMID:24374193 Toll-7 is also dispensable for antimicrobial peptide induction after bacterial infection |
| GO:0002752 cell surface pattern recognition receptor signaling pathway | IC PMID:22464169 Virus recognition by Toll-7 activates antiviral autophagy in... | KEEP AS NON CORE | Summary: Curator inference that Toll-7 initiates a cell-surface PRR signalling pathway leading to antiviral autophagy. Reason: Depends on the PRR inference above. The pathway downstream of Toll-7 is undefined: autophagy induction is MyD88- and NF-kB-independent, and no signalling components have been identified. The term is not a GO:0002224 (toll-like receptor signaling pathway) term, which is appropriate. Kept as non-core with the same caveats as GO:0038187. Supporting Evidence: PMID:22464169 MyD88 was also not required for the induction of antiviral autophagy PMID:22464169 Unlike Toll-7 deficient flies, flies lacking core Toll pathway components did not demonstrate increased susceptibility to VSV. PMID:22464169 We found that VSV interacted with endogenous Toll-7 at the plasma membrane, and that this interaction was lost upon RNAi depletion of Toll-7 file:DROME/Toll-7/Toll-7-deep-research-falcon.md Toll-7's involvement in the response to viral infection remains unresolved and should not be treated as established functional annotation |
| GO:0004888 transmembrane signaling receptor activity | IDA PMID:31088910 Toll family members bind multiple Spätzle proteins and activ... | ACCEPT | Summary: Full-length Toll-7 transduces signals from Spätzle-family cystine-knot ligands in S2 cells. Reason: Generic transmembrane receptor activity is well supported; neurotrophin receptor activity (GO:0005030) is the more specific in vivo function. Supporting Evidence: PMID:31088910 Spz-1, -2, and -5 also activated the drosomycin promoter in S2 cells expressing full-length Toll-7 98-, 87-, and 83-fold PMID:23892553 DNT1 and DNT2 bind to Toll-6 and Toll-7 promiscuously |
| GO:0005030 neurotrophin receptor activity | IMP PMID:23892553 Toll-6 and Toll-7 function as neurotrophin receptors in the ... | ACCEPT | Summary: Toll-7 is a receptor for the Drosophila neurotrophins DNT1 (Spz2) and DNT2 (Spz5). Reason: Genetic interaction, in vitro binding and neuronal survival data show Toll-7 functions as a neurotrophin receptor; core molecular function. Supporting Evidence: PMID:23892553 Here we show that Toll paralogs unrelated to the mammalian neurotrophin receptors function as neurotrophin receptors in fruit flies. PMID:23892553 DNT1 and DNT2 bind to Toll-6 and Toll-7 promiscuously |
| GO:0005886 plasma membrane | EXP PMID:22464169 Virus recognition by Toll-7 activates antiviral autophagy in... | ACCEPT | Summary: Toll-7 is a plasma-membrane (cell-surface) receptor. Reason: Surface biotinylation recovers endogenous Toll-7. Supporting Evidence: PMID:22464169 Similar to the known surface resident protein Toll, Toll-7 was precipitated by avidin while tubulin, an intracellular protein, was not found in the precipitate |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Toll-7 is a plasma-membrane (cell-surface) receptor. Reason: Consistent with surface biotinylation data. Supporting Evidence: PMID:22464169 Similar to the known surface resident protein Toll, Toll-7 was precipitated by avidin while tubulin, an intracellular protein, was not found in the precipitate |
| GO:0005886 plasma membrane | IDA PMID:31088910 Toll family members bind multiple Spätzle proteins and activ... | ACCEPT | Summary: Toll-7 is a plasma-membrane (cell-surface) receptor. Reason: Consistent with other experimental data. Supporting Evidence: PMID:22464169 Similar to the known surface resident protein Toll, Toll-7 was precipitated by avidin while tubulin, an intracellular protein, was not found in the precipitate |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Toll-7 is a plasma-membrane (cell-surface) receptor. Reason: Consistent with experimental data. Supporting Evidence: PMID:22464169 Similar to the known surface resident protein Toll, Toll-7 was precipitated by avidin while tubulin, an intracellular protein, was not found in the precipitate |
| GO:0007165 signal transduction | IEA GO_REF:0000120 | ACCEPT | Summary: Signal transduction (TIR domain). Reason: General and correct. Supporting Evidence: PMID:23892553 Here we show that Toll paralogs unrelated to the mammalian neurotrophin receptors function as neurotrophin receptors in fruit flies. |
| GO:0007411 axon guidance | IMP PMID:25741726 Toll receptors instruct axon and dendrite targeting and part... | ACCEPT | Summary: Toll-7 cell-autonomously instructs targeting of VA1d olfactory receptor neuron axons. Reason: Direct loss-of-function evidence; together with motor axon targeting defects this is a core neural function. Supporting Evidence: PMID:25741726 Toll-6 and Toll-7, members of the Toll receptor family best known for functions in innate immunity and embryonic patterning, cell autonomously instruct the targeting of specific classes of PN dendrites and ORN axons, respectively PMID:23892553 Toll-6 and Toll-7 are expressed in the CNS throughout development and regulate locomotion, motor axon targeting and neuronal survival. |
| GO:0008063 Toll signaling pathway | IMP PMID:31088910 Toll family members bind multiple Spätzle proteins and activ... | UNDECIDED | Summary: Spätzle-family ligands and VSV activated drosomycin and other AMP promoters in S2 cells overexpressing Toll-7. Reason: Conflicting evidence: a Toll-ectodomain/Toll-7 cytoplasmic chimera did not induce drosomycin (Tauszig et al. 2000), Toll-7 is dispensable for AMP induction after bacterial infection (cited by Moy et al. 2014), and VSV-induced Toll-7 responses were distinct from the canonical Toll pathway (Nakamoto et al. 2012). The positive data rest on overexpression in S2 cells. Supporting Evidence: PMID:31088910 Spz-1, -2, and -5 also activated the drosomycin promoter in S2 cells expressing full-length Toll-7 98-, 87-, and 83-fold PMID:10973475 neither the 18W nor the Toll-6 to Toll-8 chimerae were able to induce drosomycin PMID:24374193 Toll-7 is also dispensable for antimicrobial peptide induction after bacterial infection PMID:22464169 Unlike Toll-7 deficient flies, flies lacking core Toll pathway components did not demonstrate increased susceptibility to VSV. |
| GO:0009597 detection of virus | IDA PMID:31088910 Toll family members bind multiple Spätzle proteins and activ... | KEEP AS NON CORE | Summary: VSV virions bound Toll-7 ectodomain and activated AMP promoters in Toll-7-expressing S2 cells. Reason: Detection of virus asserts that Toll-7 is the sensor. Virion binding at the surface is supported by two labs, but no defined viral ligand has been identified and the downstream pathway (autophagy vs AMP induction) is disputed; kept as non-core. Supporting Evidence: PMID:31088910 We found that the Toll-1 and Toll-7 ectodomains bind Spz-1, -2, and -5, and also vesicular stomatitis virus (VSV) virions, and that Spz-1, -2, -5, and VSV all activated the promoters of drosomycin and several other AMP genes in S2 cells expressing full-length Toll-1 or Toll-7. PMID:22464169 We found that VSV interacted with endogenous Toll-7 at the plasma membrane, and that this interaction was lost upon RNAi depletion of Toll-7 |
| GO:0009653 anatomical structure morphogenesis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Anatomical structure morphogenesis (ARBA). Reason: Very general; the documented morphogenetic roles of Toll-7 are neuronal (axon and dendrite targeting), which are captured more precisely elsewhere. Supporting Evidence: PMID:25741726 Toll-6 and Toll-7, members of the Toll receptor family best known for functions in innate immunity and embryonic patterning, cell autonomously instruct the targeting of specific classes of PN dendrites and ORN axons, respectively |
| GO:0009897 external side of plasma membrane | IDA PMID:22464169 Virus recognition by Toll-7 activates antiviral autophagy in... | ACCEPT | Summary: Toll-7 is accessible to cell-impermeable biotin at the cell surface. Reason: Correct. Supporting Evidence: PMID:22464169 Similar to the known surface resident protein Toll, Toll-7 was precipitated by avidin while tubulin, an intracellular protein, was not found in the precipitate |
| GO:0010508 positive regulation of autophagy | IMP PMID:22464169 Virus recognition by Toll-7 activates antiviral autophagy in... | ACCEPT | Summary: Toll-7 is required for VSV-induced but not starvation-induced autophagy. Reason: Specific requirement shown in cells and adult fat body; this is the effector mechanism proposed for Toll-7 antiviral defence. Supporting Evidence: PMID:22464169 Taken together, these results indicate that Toll-7 is specifically required for antiviral autophagy but dispensable for starvation-induced autophagy. |
| GO:0038023 signaling receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of signaling receptor activity (PTN002809265). Reason: General and correct; Toll-7 is a receptor for DNT1/DNT2 (Spätzle-family neurotrophins). Supporting Evidence: PMID:23892553 Here we show that Toll paralogs unrelated to the mammalian neurotrophin receptors function as neurotrophin receptors in fruit flies. |
| GO:0038179 neurotrophin signaling pathway | IEA GO_REF:0000108 | ACCEPT | Summary: Inferred from neurotrophin receptor activity. Reason: Consistent with the experimental neurotrophin receptor data. Supporting Evidence: PMID:23892553 Here we show that Toll paralogs unrelated to the mammalian neurotrophin receptors function as neurotrophin receptors in fruit flies. |
| GO:0038187 pattern recognition receptor activity | IC PMID:22464169 Virus recognition by Toll-7 activates antiviral autophagy in... | KEEP AS NON CORE | Summary: Curator inference of pattern recognition receptor activity from virion binding at the cell surface and Toll-7-dependent antiviral autophagy. Reason: This is the only PRR-branch MF on a Drosophila Toll and the only one with direct pathogen-binding data behind it: Toll-7 co-precipitates VSV and RVFV virions at the cell surface, and the authors conclude it is a PRR. The inference falls short of the standard for vertebrate TLRs in three ways: (1) binding is shown only by co-precipitation of whole virions, with no defined viral ligand molecule, affinity or structure; (2) the specificity control (Toll does not bind VSV) is contradicted by Chowdhury et al. 2019, who found Toll-1 ectodomain also binds VSV; (3) an independent study reported that Toll-7 is not required for hemocyte VSV defence. Toll-7 is otherwise a neurotrophin receptor for Spätzle-family ligands. Kept as non-core pending ligand identification, not accepted as core. Supporting Evidence: PMID:22464169 Here we have shown that Toll-7 is a PRR both in vitro and in adult flies; loss of Toll-7 led to increased vesicular stomatitis virus (VSV) replication and mortality. PMID:22464169 We found that VSV interacted with endogenous Toll-7 at the plasma membrane, and that this interaction was lost upon RNAi depletion of Toll-7 PMID:22464169 Our findings that Toll-7 interacts with VSV virions suggest that Toll-7 might act directly as a pattern recognition receptor more similar to mammalian TLRs, a previously unknown mechanism for an insect Toll receptor. PMID:31088910 our results corroborate that Toll-7 binds VSV while showing that Toll-1 also binds this virus PMID:31088910 other results indicate that autophagy plays a minor role in hemocyte-mediated defense against VSV and does not depend on Toll-7 file:DROME/Toll-7/Toll-7-deep-research-falcon.md Toll-7's involvement in the response to viral infection remains unresolved and should not be treated as established functional annotation |
| GO:0045087 innate immune response | IMP PMID:31088910 Toll family members bind multiple Spätzle proteins and activ... | ACCEPT | Summary: Toll-7 mutant males showed reduced survival after systemic infections. Reason: General parent of the antiviral role; acceptable at this level. Supporting Evidence: PMID:31088910 We found that the Toll-1 and Toll-7 ectodomains bind Spz-1, -2, and -5, and also vesicular stomatitis virus (VSV) virions, and that Spz-1, -2, -5, and VSV all activated the promoters of drosomycin and several other AMP genes in S2 cells expressing full-length Toll-1 or Toll-7. PMID:22464169 Here we have shown that Toll-7 is a PRR both in vitro and in adult flies; loss of Toll-7 led to increased vesicular stomatitis virus (VSV) replication and mortality. |
| GO:0046790 virion binding | IDA PMID:22464169 Virus recognition by Toll-7 activates antiviral autophagy in... | ACCEPT | Summary: Endogenous Toll-7 co-precipitates with surface-bound biotinylated VSV virions; binding lost on Toll-7 RNAi and not seen with IgG. Reason: Direct experimental observation, independently corroborated for VSV (Chowdhury et al. 2019) and extended to RVFV (Moy et al. 2014). The term records the observation of virion association, not a claim about the viral ligand molecule. Supporting Evidence: PMID:22464169 We found that VSV interacted with endogenous Toll-7 at the plasma membrane, and that this interaction was lost upon RNAi depletion of Toll-7 PMID:24374193 Biotinylated RVFV but not control immunoglobulin G (IgG) precipitated endogenous Toll-7, suggesting that RVFV and Toll-7 physically interact at the cell surface |
| GO:0046790 virion binding | IDA PMID:31088910 Toll family members bind multiple Spätzle proteins and activ... | ACCEPT | Summary: Toll-7 ectodomain co-precipitated VSV virions in vitro. Reason: Independent corroboration of the Nakamoto et al. observation. Supporting Evidence: PMID:31088910 our results corroborate that Toll-7 binds VSV while showing that Toll-1 also binds this virus |
| GO:0048666 neuron development | IEA GO_REF:0000117 | ACCEPT | Summary: Neuron development (ARBA). Reason: Supported experimentally: Toll-7 regulates motor axon targeting, ORN axon targeting and neuronal survival. Supporting Evidence: PMID:23892553 Toll-6 and Toll-7 are expressed in the CNS throughout development and regulate locomotion, motor axon targeting and neuronal survival. PMID:25741726 Toll-6 and Toll-7, members of the Toll receptor family best known for functions in innate immunity and embryonic patterning, cell autonomously instruct the targeting of specific classes of PN dendrites and ORN axons, respectively |
| GO:0050688 regulation of defense response to virus | IMP PMID:24374193 Antiviral autophagy restrictsRift Valley fever virus infecti... | ACCEPT | Summary: Toll-7 mutants are more susceptible to RVFV because virus-triggered antiviral autophagy fails; Toll-7 overexpression reduces viral RNA. Reason: Loss- and gain-of-function data support Toll-7 as a positive regulator of antiviral defence. Supporting Evidence: PMID:24374193 We found that Toll-7 mutant flies are more susceptible to RVFV infection as a result of a defect in virus-triggered antiviral autophagy, which is essential for controlling viral replication and survival. |
| GO:0051607 defense response to virus | IMP PMID:22464169 Virus recognition by Toll-7 activates antiviral autophagy in... | ACCEPT | Summary: Toll-7 loss increases VSV replication and mortality in adult flies. Reason: Supported in cells and flies, and extended to RVFV (Moy et al. 2014) by the same lab; restriction is virus-specific. A later study (not cached here) reported that Toll-7 is not required for hemocyte-mediated VSV defence, so the breadth of this role remains open. Supporting Evidence: PMID:22464169 Here we have shown that Toll-7 is a PRR both in vitro and in adult flies; loss of Toll-7 led to increased vesicular stomatitis virus (VSV) replication and mortality. PMID:24374193 We found that Toll-7 mutant flies are more susceptible to RVFV infection as a result of a defect in virus-triggered antiviral autophagy, which is essential for controlling viral replication and survival. PMID:31088910 other results indicate that autophagy plays a minor role in hemocyte-mediated defense against VSV and does not depend on Toll-7 |
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Download this section (compressed HTML)Q: Is whole-virion co-precipitation sufficient to annotate GO:0038187 pattern recognition receptor activity, whose definition requires binding a pathogen-associated molecular pattern? Which VSV/RVFV component (e.g. envelope glycoprotein) binds Toll-7, and is the interaction direct?
Q: Given conflicting reports on Toll-1 binding VSV and on Toll-7 requirement in hemocyte antiviral defence, should the Toll-7 PRR and cell-surface PRR signalling annotations be retained, downgraded, or replaced by virion binding plus defense response to virus alone?
Q: Does Toll-7 activate the canonical MyD88/Tube/Pelle/Dif pathway in vivo, or is its reported AMP-promoter activation an overexpression artefact in S2 cells?
Experiment: Measure binding of purified Toll-7 ectodomain to purified VSV-G and RVFV Gn/Gc glycoproteins (SPR/BLI), with Toll ectodomain as a specificity control, and map the binding site by mutagenesis.
Experiment: Test VSV and RVFV restriction in Toll-7 null flies carrying ectodomain point mutants that abolish virion binding but retain DNT binding.
Experiment: Compare drosomycin induction after DNT1/DNT2 or virus stimulation in Toll-7 null versus wild-type fat body in vivo.
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Download this section (compressed HTML)Toll-7 (Toll-7) encodes a plasma membrane Toll receptor that binds to viral glycoproteins, leading to the activation of antiviral defenses including autophagy.
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