module: dmel_toll_signaling title: Toll signaling pathway in Drosophila melanogaster label: Toll signaling pathway module_type: SIGNALING_PATHWAY description: >- 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. summary: >- 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. concepts: - {id: GO:0008063, label: Toll signaling pathway} parts: - id: spaetzle_activation_cascades label: Spaetzle-activating protease cascades role: extracellular ligand activation variant_sets: - id: spaetzle_cascade_variants label: Embryonic or immune Spaetzle-activating cascade selection: ONE_OR_MORE variants: - id: embryonic_dv_cascade label: Embryonic dorsal-ventral protease cascade description: >- 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. genes: [wbl, pip, ndl, gd, snk, ea] unit_functions: gd: {id: GO:0004252, label: serine-type endopeptidase activity} snk: {id: GO:0004252, label: serine-type endopeptidase activity} ea: {id: GO:0004252, label: serine-type endopeptidase activity} processes: - {id: GO:0009950, label: dorsal/ventral axis specification} - id: immune_cascade label: Immune Spaetzle-activating cascade parts: - id: immune_recognition label: Pattern-recognition proteins role: microbial pattern recognition description: >- 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. genes: [PGRP-SA, GNBP1, GNBP3, GNBP-like3, PGRP-SC1a, PGRP-SC1b, PGRP-SC2] - id: immune_proteases label: Immune serine protease cascade role: protease cascade converging on SPE description: >- 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. genes: [modSP, grass, psh, Hayan, SPE, spirit, sphinx1, sphinx2, sphe, MP1, CtsK1] unit_functions: modSP: {id: GO:0004252, label: serine-type endopeptidase activity} grass: {id: GO:0004252, label: serine-type endopeptidase activity} psh: {id: GO:0004252, label: serine-type endopeptidase activity} Hayan: {id: GO:0004252, label: serine-type endopeptidase activity} SPE: {id: GO:0004252, label: serine-type endopeptidase activity} processes: - {id: GO:0160032, label: Toll receptor ligand protein activation cascade} connections: - {source: immune_recognition, target: immune_proteases, connection_type: POSITIVELY_REGULATES, description: "Recognition complexes activate ModSP and the downstream protease cascade."} - id: spaetzle_family_ligands label: Spaetzle-family ligands role: ligands genes: [spz, spz5, NT1] unit_functions: spz: {id: GO:0005121, label: Toll binding} - id: toll_receptors label: Toll receptors and associated membrane protein role: receptors description: >- 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. genes: [Tl, Toll-7, Tehao] unit_functions: Tl: {id: GO:0004888, label: transmembrane signaling receptor activity} - id: toll_adaptor_complex label: MyD88-Tube-Pelle adaptor complex role: intracellular signal transduction description: >- MyD88 binds the Toll TIR domain and assembles a death-domain complex with Tube and the kinase Pelle; Weckle helps recruit MyD88 to Toll. complex: true genes: [Myd88, tub, pll, wek] unit_functions: pll: {id: GO:0004674, label: protein serine/threonine kinase activity} - id: nfkb_factors label: NF-kappaB factors Dorsal and Dif role: transcriptional output genes: [dl, Dif] function: {id: GO:0000981, label: "DNA-binding transcription factor activity, RNA polymerase II-specific"} connections: - {source: spaetzle_activation_cascades, target: spaetzle_family_ligands, connection_type: POSITIVELY_REGULATES, description: "The terminal protease (Easter or SPE) cleaves pro-Spaetzle into its active form."} - {source: spaetzle_family_ligands, target: toll_receptors, connection_type: POSITIVELY_REGULATES, description: "Processed Spaetzle binds and activates Toll."} - {source: toll_receptors, target: toll_adaptor_complex, connection_type: POSITIVELY_REGULATES, description: "Activated Toll recruits MyD88, Tube and Pelle."} - {source: toll_adaptor_complex, target: nfkb_factors, connection_type: POSITIVELY_REGULATES, description: "Pelle signaling leads to Cactus degradation and nuclear entry of Dorsal and Dif."} notes: >- 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.