The Toll pathway is activated when an extracellular serine protease cascade cleaves the pro-domain of the cytokine-like ligand Spaetzle, allowing it to bind the Toll receptor. In the early embryo, a maternally supplied cascade (Gastrulation defective, Snake and Easter), spatially restricted by the Pipe sulfotransferase in the ventral follicle cells, generates ventral Spaetzle and establishes the dorsal-ventral axis. In the immune response, pattern-recognition proteins (PGRP-SA, GNBP1, GNBP3) and the virulence sensor Persephone activate ModSP, Grass and Hayan, converging on the Spaetzle-processing enzyme. Activated Toll recruits the adaptors MyD88 and Tube and the kinase Pelle, which lead to degradation of the IkB protein Cactus and nuclear entry of the NF-kappaB factors Dorsal and Dif. Related Toll receptors such as Toll-7, bound by neurotrophin-like Spaetzle family ligands, act in the nervous system.
Boundary. The module combines the FlyBase dorsal group and the Toll pathway core subgroups. Windbeutel (wbl) is a dorsal-group member that acts as an ER chaperone for Pipe. The IkB protein Cactus is in the FlyBase negative regulator set and is therefore not modelled as a part, although it is the direct target of the pathway; serpins (Spn27A, Necrotic, Spn88Ea) are likewise regulators. PGRP-SC amidases scavenge peptidoglycan and may dampen rather than drive signaling. FlyBase groups realized by this module: DORS (FBgg0001054), TL-CAN (FBgg0001059). Subgroups folded into it: TL-SPZC, TL-NFC. FlyBase also curates regulator sets for this pathway, which are context and not modelled as parts: TL-NFN (negative regulators of toll-nf-kappab signaling pathway, 19 genes); TL-SPZN (negative regulators of spatzle activating pathway, 4 genes); TL-NFP (positive regulators of toll-nf-kappab signaling pathway, 23 genes). Participants were generated from the FlyBase gene-group membership and mapped to UniProtKB by projects/FLYBASE_GENE_GROUPS/generate_modules.py from module_specs/dmel_toll_signaling.yaml. Member genes with a gene review in this repository: Dif, dl, Myd88, pll, spz, Tl, Toll-7, tub.
All recommended fields populated.
✗ none found
No MODULE:dmel_toll_signaling deep-research report alongside the module YAML.
✓ every leaf node grounds to a representative protein.
✓ every declared conforms_to bundle matches its template motif.
6 gene-function check(s) reflected in core functions · 0 conflict(s) · 7 evidence or coverage gap(s) (13 comparison(s))
Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.
| Annoton | Participant | Function | Assessment |
|---|---|---|---|
| embryonic_dv_cascade_gd | gd UniProtKB:O62589 Gene |
serine-type endopeptidase activity GO:0004252 |
Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked. |
| embryonic_dv_cascade_snk | snk UniProtKB:P05049 Gene |
serine-type endopeptidase activity GO:0004252 |
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass). |
| embryonic_dv_cascade_ea | ea UniProtKB:P13582 Gene |
serine-type endopeptidase activity GO:0004252 |
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass). |
| immune_proteases_modsp | modSP UniProtKB:Q9VER6 Gene |
serine-type endopeptidase activity GO:0004252 |
Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked. |
| immune_proteases_grass | grass UniProtKB:Q9VB68 Gene |
serine-type endopeptidase activity GO:0004252 |
Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked. |
| immune_proteases_psh | psh UniProtKB:Q9VWU1 Gene |
serine-type endopeptidase activity GO:0004252 |
Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked. |
| immune_proteases_hayan | Hayan UniProtKB:A8JUP7 Gene |
serine-type endopeptidase activity GO:0004252 |
Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked. |
| immune_proteases_spe | SPE UniProtKB:Q9VCJ8 Gene |
serine-type endopeptidase activity GO:0004252 |
Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked. |
| spaetzle_family_ligands_spz | spz UniProtKB:P48607 Gene |
Toll binding GO:0005121 |
Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it. |
| toll_receptors_tl | Tl UniProtKB:P08953 Gene |
transmembrane signaling receptor activity GO:0004888 |
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass). |
| toll_adaptor_complex_complex/pll | pll UniProtKB:Q05652 Complex Unit |
protein serine/threonine kinase activity GO:0004674 |
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass). |
| nfkb_factors_dl | dl UniProtKB:P15330 Gene |
DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981 |
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass). |
| nfkb_factors_dif | Dif UniProtKB:P98149 Gene |
DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981 |
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass). |
8 complete review(s) · 11 with deep research · 24 missing review · 1 reviewed but lacking deep research
| Gene | Review | Complete | Deep research |
|---|---|---|---|
| MP1 A0A126GUP6 | ✗ | — | — |
| GNBP-like3 A1ZBU5 | ✗ | — | — |
| Hayan A8JUP7 | ✗ | — | — |
| PGRP-SC1a C0HK98 | ✗ | — | — |
| PGRP-SC1b C0HK99 | ✗ | — | — |
| Dif P98149 | ✓ | ✓ | ✓ |
| dl P15330 | ✓ | ✓ | ✓ |
| spirit E1JJG1 | ✗ | — | — |
| ea P13582 | ✓ | ✓ | ✓ |
| Myd88 A1Z7T8 | ✓ | ✓ | ✓ |
| NT1 B7TB45 | ✓ | ✓ | ✗ |
| wbl O44342 | ✗ | — | — |
| gd O62589 | ✗ | — | — |
| ndl P98159 | ✗ | — | — |
| pll Q05652 | ✓ | 75/76 | ✓ |
| pip Q86BJ3 | ✗ | — | — |
| sphinx1 Q8IQ79 | ✗ | — | — |
| GNBP3 Q9NHA8 | ✗ | — | — |
| GNBP1 Q9NHB0 | ✗ | — | — |
| CtsK1 Q9V3U6 | ✗ | — | — |
| PGRP-SC2 Q9V4X2 | ✗ | — | — |
| grass Q9VB68 | ✗ | — | — |
| SPE Q9VCJ8 | ✗ | — | — |
| modSP Q9VER6 | ✗ | — | — |
| wek Q9VJN5 | ✗ | — | — |
| Tehao Q9VJX9 | ✗ | — | — |
| sphinx2 Q9VS71 | ✗ | — | — |
| psh Q9VWU1 | ✗ | — | — |
| sphe Q9VXC8 | ✗ | — | — |
| PGRP-SA Q9VYX7 | ✗ | — | — |
| snk P05049 | ✓ | ✓ | ✓ |
| spz P48607 | ✓ | ✓ | ✓ |
| spz5 Q9VZX1 | ✓ | ✓ | ✓ |
| Tl P08953 | ✓ | 102/104 | ✓ |
| Toll-7 Q7KIN0 | ✓ | 22/24 | ✓ |
| tub P22812 | ✓ | 54/55 | ✓ |
Protease cascades that activate Spaetzle, the Toll receptor, the MyD88-Tube-Pelle adaptor complex and NF-kappaB factors Dorsal and Dif, used for dorsal-ventral patterning and antimicrobial defense.
Windbeutel is required in the follicle-cell ER for Pipe, which sulfates eggshell components ventrally; Nudel, Gastrulation defective, Snake and Easter form the protease cascade whose product, Easter, cleaves Spaetzle.
PGRP-SA and GNBP1 sense Lys-type peptidoglycan and GNBP3 senses fungal beta-glucan; the amidases PGRP-SC1a, SC1b and SC2, and GNBP-like3, are further FlyBase core members.
ModSP and Grass relay recognition signals, Persephone senses microbial proteases, and Hayan and SPE lead to Spaetzle cleavage. Other FlyBase core members (Spirit, Sphinx1, Sphinx2, Sphe, MP1, CtsK1) contribute to Spaetzle activation in specific contexts.
Toll is the receptor for processed Spaetzle; Toll-7 is a neuronal Toll receptor bound by NT1. Tehao is a membrane protein that FlyBase places among the core components; its mechanism is not well defined.
MyD88 binds the Toll TIR domain and assembles a death-domain complex with Tube and the kinase Pelle; Weckle helps recruit MyD88 to Toll.