SpƤtzle (spz) is a secreted cystine-knot cytokine of Drosophila melanogaster and the principal ligand of the Toll receptor. It is made as a disulfide-linked dimeric pro-protein, encoded by many maternally supplied splice isoforms that share a C-terminal cystine-knot domain related to the neurotrophins (NGF family) and differ in their pro-domains. The pro-domain is needed for folding and secretion and masks the receptor-binding surface. Extracellular serine protease cascades cleave pro-SpƤtzle after Arg220 to release the active C-106 dimer: in the early embryo the ventrally activated protease Easter does so in the perivitelline space, and during infection or tissue damage the SpƤtzle-processing enzyme SPE (and other proteases downstream of Persephone, Hayan and the ModSP/Grass pathway) does so in the haemolymph. Mature SpƤtzle binds the concave face of the N-terminal leucine-rich-repeat region of the Toll ectodomain with nanomolar affinity, releasing the pro-domain and driving formation of a signalling-competent Toll dimer that recruits MyD88, Tube and Pelle and ends in degradation of Cactus and nuclear entry of Dorsal and Dif. Unlike vertebrate Toll-like receptors, Toll is thus activated by an endogenous cytokine rather than by microbial molecules. Through this pathway SpƤtzle specifies the embryonic dorsal-ventral axis, and in larvae and adults it drives induction of antifungal and antibacterial peptides such as drosomycin and is required for defence against fungi and Gram-positive bacteria. SpƤtzle also binds Toll-7, has neurotrophic activity (neuronal survival and motor axon targeting) shared with its paralogues DNT1 and DNT2, and acts through Toll in muscle patterning, wound-induced epidermal gene expression, cell competition and responses to tumours.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002225 positive regulation of antimicrobial peptide production | IGI PMID:25901322 Dynamic regulation of innate immune responses in Drosophila ... | ACCEPT | Summary: Spz-triggered Toll signalling activates Dif/Dorsal and induces antimicrobial peptide genes such as drosomycin. Reason: Direct transcriptional output of the Spz-Toll pathway; spz mutation abolishes Drs induction in senju mutants. Supporting Evidence: PMID:25901322 By contrast, the senju 1 and spz rm7 double mutant exhibited markedly reduced expression of Drs mRNA. |
| GO:0002347 response to tumor cell | IMP PMID:24582964 Transformed epithelia trigger non-tissue-autonomous tumor su... | KEEP AS NON CORE | Summary: Haemocyte-derived Spz activates Toll in fat body, contributing to tumour cell death. Reason: Context-specific Toll signalling output; non-core. Supporting Evidence: PMID:24582964 Hemocytes play a critical role in this system by producing the ligands SpƤtzle and Eiger, which are required for Toll activation in the fat body and tumor cell death. |
| GO:0002804 positive regulation of antifungal peptide production | IMP PMID:8808632 The dorsoventral regulatory gene cassette spƤtzle/Toll/cactu... | ACCEPT | Summary: Spz-triggered Toll signalling activates Dif/Dorsal and induces antimicrobial peptide genes such as drosomycin. Reason: spz controls expression of the antifungal peptide gene drosomycin. Supporting Evidence: PMID:8808632 the extracellular Toll ligand, spƤtzle, control expression of the antifungal peptide gene drosomycin in adults |
| GO:0002807 positive regulation of antimicrobial peptide biosynthetic process | IDA PMID:15197269 Multimerization and interaction of Toll and SpƤtzle in Droso... | ACCEPT | Summary: Spz-triggered Toll signalling activates Dif/Dorsal and induces antimicrobial peptide genes such as drosomycin. Reason: Spz stimulates drosomycin expression. Supporting Evidence: PMID:15197269 We demonstrate here that the host protein SpƤtzle can function as a ligand for Toll because SpƤtzle forms a complex with Toll in transgenic fly extracts and stimulates the expression of a Toll-dependent immunity gene, drosomycin, in adult flies. |
| GO:0005121 Toll binding | IBA GO_REF:0000033 | ACCEPT | Summary: Mature SpƤtzle (C-106 dimer) binds the N-terminal LRR region of the Toll ectodomain directly and with high affinity. Reason: Phylogenetically sound: Toll binding is the defining activity of SpƤtzle and its fly paralogues; spz itself has multiple direct binding studies (ITC, co-IP, crystal structures) that ground the IBA node. Supporting Evidence: PMID:12872120 in vitro experiments showed that the mature form of SpƤtzle bound to the Toll ectodomain with high affinity and with a stoichiometry of one SpƤtzle dimer to two receptors PMID:24733933 SpƤtzle binds to the concave surface of the membrane-distal LRR domain, in contrast to the flanking ligand interactions observed for mammalian Toll-like receptors, with asymmetric contributions from each SpƤtzle protomer. |
| GO:0005121 Toll binding | IDA PMID:15197269 Multimerization and interaction of Toll and SpƤtzle in Droso... | ACCEPT | Summary: Mature SpƤtzle (C-106 dimer) binds the N-terminal LRR region of the Toll ectodomain directly and with high affinity. Reason: Spz forms a complex with Toll in transgenic fly extracts. Supporting Evidence: PMID:15197269 We demonstrate here that the host protein SpƤtzle can function as a ligand for Toll because SpƤtzle forms a complex with Toll in transgenic fly extracts and stimulates the expression of a Toll-dependent immunity gene, drosomycin, in adult flies. |
| GO:0005121 Toll binding | IDA PMID:31088910 Toll family members bind multiple SpƤtzle proteins and activ... | ACCEPT | Summary: Mature SpƤtzle (C-106 dimer) binds the N-terminal LRR region of the Toll ectodomain directly and with high affinity. Spz-1 also binds Toll-7 ectodomain. Reason: Reciprocal co-IP of Spz-1 cystine knot with Toll-1 and Toll-7 ectodomains. Supporting Evidence: PMID:31088910 Thus, three Spz family members (Spz-1, -2, and -5) exhibit features consistent with functioning as cytokines that bind to Toll-1 and Toll-7, which activates downstream Toll signaling and the drosomycin promoter. |
| GO:0005121 Toll binding | IPI PMID:12872120 Binding of the Drosophila cytokine SpƤtzle to Toll is direct... | ACCEPT | Summary: Mature SpƤtzle (C-106 dimer) binds the N-terminal LRR region of the Toll ectodomain directly and with high affinity. Reason: Direct binding of mature Spz to purified Toll ectodomain; pro-Spz does not bind. Supporting Evidence: PMID:12872120 in vitro experiments showed that the mature form of SpƤtzle bound to the Toll ectodomain with high affinity and with a stoichiometry of one SpƤtzle dimer to two receptors |
| GO:0005121 Toll binding | IPI PMID:17324925 Role of the Spatzle Pro-domain in the generation of an activ... | ACCEPT | Summary: Mature SpƤtzle (C-106 dimer) binds the N-terminal LRR region of the Toll ectodomain directly and with high affinity. Reason: Processed Spz (C-106 with associated pro-domain) binds the Toll ectodomain, which releases the pro-domain. Supporting Evidence: PMID:17324925 A dimeric precursor of SpƤtzle is processed by an endoprotease to produce a form (C-106) that cross-links Toll receptor ectodomains and establishes signaling. |
| GO:0005121 Toll binding | IPI PMID:18347020 Structural insight into the mechanism of activation of the T... | ACCEPT | Summary: Mature SpƤtzle (C-106 dimer) binds the N-terminal LRR region of the Toll ectodomain directly and with high affinity. Reason: EM and native mass spectrometry of Spz-Toll ectodomain complexes. Supporting Evidence: PMID:18347020 Instead, Spz binding at the N-terminal end of Toll predominantly induces the formation of a 2:2 complex |
| GO:0005121 Toll binding | IPI PMID:24733933 Structure of the Toll-Spatzle complex, a molecular hub in Dr... | ACCEPT | Summary: Mature SpƤtzle (C-106 dimer) binds the N-terminal LRR region of the Toll ectodomain directly and with high affinity. Reason: Crystal structure of the Toll ectodomain-Spz C-106 complex. Supporting Evidence: PMID:24733933 SpƤtzle binds to the concave surface of the membrane-distal LRR domain, in contrast to the flanking ligand interactions observed for mammalian Toll-like receptors, with asymmetric contributions from each SpƤtzle protomer. |
| GO:0005125 cytokine activity | TAS PMID:12888789 Toll gets tied in a knot. | ACCEPT | Summary: SpƤtzle is a secreted cystine-knot cytokine that activates the Toll receptor to control embryonic patterning and immune effector gene expression. Reason: Cytokine activity (is_a receptor ligand activity) is the most informative MF for Spz: a soluble extracellular ligand that changes receptor activity to control differentiation (DV patterning), survival (neurons) and effector function (antimicrobial peptide expression). The cited item is a news commentary on PMID:12872120, but the claim is fully supported by the primary paper. Supporting Evidence: PMID:12872120 in vitro experiments showed that the mature form of SpƤtzle bound to the Toll ectodomain with high affinity and with a stoichiometry of one SpƤtzle dimer to two receptors PMID:31088910 Thus, three Spz family members (Spz-1, -2, and -5) exhibit features consistent with functioning as cytokines that bind to Toll-1 and Toll-7, which activates downstream Toll signaling and the drosomycin promoter. |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: SpƤtzle is secreted: into the perivitelline space of the embryo and into haemolymph during immunity. Reason: Secreted ligand family; supported by direct evidence on spz. Supporting Evidence: PMID:8124709 The spƤtzle gene encodes a novel secreted protein that appears to require activation by a proteolytic processing reaction PMID:31088910 Immunoblotting assays showed that each Spz cystine knot was present in both S2 cell lysates and the medium that indicated each was secreted |
| GO:0005576 extracellular region | IDA PMID:12421704 Regulation of Easter activity is required for shaping the Do... | ACCEPT | Summary: SpƤtzle is secreted: into the perivitelline space of the embryo and into haemolymph during immunity. Reason: Consistent with secretion of Spz and its extracellular processing and activity. Supporting Evidence: PMID:12421704 These mutant ea(D) proteins retain protease activity, as determined by the production of processed SpƤtzle both in the embryo and in cultured Drosophila cells. |
| GO:0005576 extracellular region | IDA PMID:19934223 Toll-dependent antimicrobial responses in Drosophila larval ... | ACCEPT | Summary: SpƤtzle is secreted: into the perivitelline space of the embryo and into haemolymph during immunity. Reason: Consistent with secretion of Spz and its extracellular processing and activity. Supporting Evidence: PMID:19934223 after infection spz rm7 larvae exhibited a severely reduced level of drs activation (on average 30% of wild-type levels) |
| GO:0005576 extracellular region | IDA PMID:24492611 Persephone/SpƤtzle pathogen sensors mediate the activation o... | ACCEPT | Summary: SpƤtzle is secreted: into the perivitelline space of the embryo and into haemolymph during immunity. Reason: Consistent with secretion of Spz and its extracellular processing and activity. Supporting Evidence: PMID:24492611 we found that Drosophila mutants deficient for Dronc, the key initiator caspase required for apoptosis, produced the active form of the endogenous Toll ligand SpƤtzle (Spz). |
| GO:0005576 extracellular region | IDA PMID:31088910 Toll family members bind multiple SpƤtzle proteins and activ... | ACCEPT | Summary: SpƤtzle is secreted: into the perivitelline space of the embryo and into haemolymph during immunity. Reason: Consistent with secretion of Spz and its extracellular processing and activity. Supporting Evidence: PMID:31088910 Immunoblotting assays showed that each Spz cystine knot was present in both S2 cell lysates and the medium that indicated each was secreted |
| GO:0005576 extracellular region | IDA PMID:8124709 The spƤtzle gene encodes a component of the extracellular si... | ACCEPT | Summary: SpƤtzle is secreted: into the perivitelline space of the embryo and into haemolymph during immunity. Reason: Consistent with secretion of Spz and its extracellular processing and activity. Supporting Evidence: PMID:8124709 The spƤtzle gene encodes a novel secreted protein that appears to require activation by a proteolytic processing reaction |
| GO:0005576 extracellular region | IDA PMID:9533958 Proteolytic processing of the Drosophila SpƤtzle protein by ... | ACCEPT | Summary: SpƤtzle is secreted: into the perivitelline space of the embryo and into haemolymph during immunity. Reason: Consistent with secretion of Spz and its extracellular processing and activity. Supporting Evidence: PMID:9533958 An active form of Easter protease cleaves the SpƤtzle protein, generating a carboxyterminal polypeptide fragment which, when microinjected into the perivitelline space of a spƤtzle deficient embryo, directs production of ventrolateral pattern elements. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: SpƤtzle is secreted: into the perivitelline space of the embryo and into haemolymph during immunity. Reason: Electronic annotation consistent with experimental data. |
| GO:0005576 extracellular region | TAS Reactome:R-DME-209057 | ACCEPT | Summary: Reactome places the Spz dimer bound to the Toll ectodomain in the extracellular region. Reason: Correct: in all Toll signalling complex reactions the Spz component is the extracellular ligand bound to the Toll ectodomain. |
| GO:0005576 extracellular region | TAS Reactome:R-DME-209072 | ACCEPT | Summary: Reactome places the Spz dimer bound to the Toll ectodomain in the extracellular region. Reason: Correct: in all Toll signalling complex reactions the Spz component is the extracellular ligand bound to the Toll ectodomain. |
| GO:0005576 extracellular region | TAS Reactome:R-DME-209076 | ACCEPT | Summary: Reactome places the Spz dimer bound to the Toll ectodomain in the extracellular region. Reason: Correct: in all Toll signalling complex reactions the Spz component is the extracellular ligand bound to the Toll ectodomain. |
| GO:0005576 extracellular region | TAS Reactome:R-DME-209100 | ACCEPT | Summary: Reactome places the Spz dimer bound to the Toll ectodomain in the extracellular region. Reason: Correct: in all Toll signalling complex reactions the Spz component is the extracellular ligand bound to the Toll ectodomain. |
| GO:0005576 extracellular region | TAS Reactome:R-DME-209130 | ACCEPT | Summary: Reactome places the Spz dimer bound to the Toll ectodomain in the extracellular region. Reason: Correct: in all Toll signalling complex reactions the Spz component is the extracellular ligand bound to the Toll ectodomain. Supporting Evidence: Reactome:R-DME-209130 In dorsoventral patterning, the trypsin-like serine protease Easter (EA) is known to cleave full-length Spatzle (SPZ) dimer between residues Arg220 and Val221. |
| GO:0005576 extracellular region | TAS Reactome:R-DME-209141 | ACCEPT | Summary: Reactome places the Spz dimer bound to the Toll ectodomain in the extracellular region. Reason: Correct: in all Toll signalling complex reactions the Spz component is the extracellular ligand bound to the Toll ectodomain. Supporting Evidence: Reactome:R-DME-209141 On binding to the Toll (TL) receptor ectodomain, Spatzle (SPZ) dimer sheds its Pro-domains. |
| GO:0005576 extracellular region | TAS Reactome:R-DME-214845 | ACCEPT | Summary: Reactome places the Spz dimer bound to the Toll ectodomain in the extracellular region. Reason: Correct: in all Toll signalling complex reactions the Spz component is the extracellular ligand bound to the Toll ectodomain. |
| GO:0005576 extracellular region | TAS Reactome:R-DME-214847 | ACCEPT | Summary: Reactome places the Spz dimer bound to the Toll ectodomain in the extracellular region. Reason: Correct: in all Toll signalling complex reactions the Spz component is the extracellular ligand bound to the Toll ectodomain. |
| GO:0005576 extracellular region | TAS Reactome:R-DME-214853 | ACCEPT | Summary: Reactome places the Spz dimer bound to the Toll ectodomain in the extracellular region. Reason: Correct: in all Toll signalling complex reactions the Spz component is the extracellular ligand bound to the Toll ectodomain. |
| GO:0005576 extracellular region | TAS Reactome:R-DME-214857 | ACCEPT | Summary: Reactome places the Spz dimer bound to the Toll ectodomain in the extracellular region. Reason: Correct: in all Toll signalling complex reactions the Spz component is the extracellular ligand bound to the Toll ectodomain. |
| GO:0005576 extracellular region | TAS Reactome:R-DME-214859 | ACCEPT | Summary: Reactome places the Spz dimer bound to the Toll ectodomain in the extracellular region. Reason: Correct: in all Toll signalling complex reactions the Spz component is the extracellular ligand bound to the Toll ectodomain. |
| GO:0005576 extracellular region | TAS Reactome:R-DME-214860 | ACCEPT | Summary: Reactome places the Spz dimer bound to the Toll ectodomain in the extracellular region. Reason: Correct: in all Toll signalling complex reactions the Spz component is the extracellular ligand bound to the Toll ectodomain. |
| GO:0005576 extracellular region | TAS Reactome:R-DME-214864 | ACCEPT | Summary: Reactome places the Spz dimer bound to the Toll ectodomain in the extracellular region. Reason: Correct: in all Toll signalling complex reactions the Spz component is the extracellular ligand bound to the Toll ectodomain. |
| GO:0005576 extracellular region | TAS Reactome:R-DME-214878 | ACCEPT | Summary: Reactome places the Spz dimer bound to the Toll ectodomain in the extracellular region. Reason: Correct: in all Toll signalling complex reactions the Spz component is the extracellular ligand bound to the Toll ectodomain. |
| GO:0005576 extracellular region | TAS Reactome:R-DME-214880 | ACCEPT | Summary: Reactome places the Spz dimer bound to the Toll ectodomain in the extracellular region. Reason: Correct: in all Toll signalling complex reactions the Spz component is the extracellular ligand bound to the Toll ectodomain. |
| GO:0006965 positive regulation of biosynthetic process of antibacterial peptides active against Gram-positive bacteria | IMP PMID:16399077 A SpƤtzle-processing enzyme required for toll signaling acti... | ACCEPT | Summary: Spz-Toll signalling induces antibacterial peptides active against Gram-positive bacteria. Reason: Supported by the SPE/Spz processing study; the curator had the full-text AMP induction data. Supporting Evidence: PMID:16399077 Here, we report a protease, called SpƤtzle-processing enzyme (SPE), required for Toll-dependent antimicrobial response. |
| GO:0006965 positive regulation of biosynthetic process of antibacterial peptides active against Gram-positive bacteria | IMP PMID:19934223 Toll-dependent antimicrobial responses in Drosophila larval ... | ACCEPT | Summary: Spz-Toll signalling induces antibacterial peptides active against Gram-positive bacteria. Reason: Supported by larval fat body analyses. Supporting Evidence: PMID:19934223 after infection spz rm7 larvae exhibited a severely reduced level of drs activation (on average 30% of wild-type levels) |
| GO:0006967 positive regulation of antifungal peptide biosynthetic process | IMP PMID:10369678 A mosaic analysis in Drosophila fat body cells of the contro... | ACCEPT | Summary: Spz-triggered Toll signalling activates Dif/Dorsal and induces antimicrobial peptide genes such as drosomycin. Reason: Spz-Toll-Cactus-Dorsal/DIF cascade induces drosomycin in fat body. Supporting Evidence: PMID:10369678 a linear activation cascade Spaetzle--> Toll-->Cactus-->Dorsal/DIF leads to the induction of the drosomycin gene in larval fat body cells |
| GO:0007310 oocyte dorsal/ventral axis specification | IEP PMID:8124709 The spƤtzle gene encodes a component of the extracellular si... | MARK AS OVER ANNOTATED | Summary: Spz is a maternal-effect gene product whose ventrally restricted processing in the perivitelline space defines the embryonic dorsal-ventral axis. Reason: GO:0007310 describes establishment of the oocyte dorsal/ventral axis. Spz acts after fertilisation, reading out a polarity already set in the egg chamber by upstream genes, and the evidence code (IEP, expression pattern) cannot support a process role. The accurate, experimentally supported parent GO:0009950 dorsal/ventral axis specification is already annotated. Supporting Evidence: PMID:8124709 The spƤtzle gene encodes a novel secreted protein that appears to require activation by a proteolytic processing reaction PMID:8124709 We propose that proteolytic processing of the spƤtzle protein is confined to the ventral side of the embryo and that the localization of processed spƤtzle determines where the receptor, Toll, is active. |
| GO:0007526 larval somatic muscle development | IMP PMID:9676200 The Toll pathway is required in the epidermis for muscle dev... | KEEP AS NON CORE | Summary: spz is required, with Toll, tube and pelle, for embryonic muscle patterning via epidermal Toll signalling. Reason: Supported; non-core developmental role. Supporting Evidence: PMID:9676200 We find that spƤtzle, tube, and pelle, but not easter, are necessary for muscle development. |
| GO:0008045 motor neuron axon guidance | IMP PMID:19018662 Drosophila neurotrophins reveal a common mechanism for nervo... | KEEP AS NON CORE | Summary: Loss of Spz affects targeting of SNa motor axons. Reason: Supported neurotrophin-like role; non-core. Supporting Evidence: PMID:19018662 Loss of Spz function affects predominantly targeting by the SNa motor axons |
| GO:0008063 Toll signaling pathway | IDA PMID:12872120 Binding of the Drosophila cytokine SpƤtzle to Toll is direct... | ACCEPT | Summary: Spz is the ligand that initiates Toll signalling; the pathway term (initiated by ligand binding to Toll) directly includes Spz. Reason: Core process. GO:0008063 is defined as initiated by an extracellular ligand binding to Toll, so Spz as that ligand participates (unlike the proteolytic activation cascade upstream, for which Spz is only the substrate). Supporting Evidence: PMID:12872120 We show here that the mature form of SpƤtzle triggers a Toll-dependent immune response after injection into the hemolymph of flies. |
| GO:0008063 Toll signaling pathway | IDA PMID:24282309 Cytokine Spatzle binds to the Drosophila immunoreceptor Toll... | ACCEPT | Summary: Spz is the ligand that initiates Toll signalling; the pathway term (initiated by ligand binding to Toll) directly includes Spz. Reason: Core process. GO:0008063 is defined as initiated by an extracellular ligand binding to Toll, so Spz as that ligand participates (unlike the proteolytic activation cascade upstream, for which Spz is only the substrate). Supporting Evidence: PMID:24282309 D55 is located in the loop following the second beta-strand of the cystine-knot structure, and the mutant Spz protein is severely defective in signaling |
| GO:0008063 Toll signaling pathway | IDA PMID:31088910 Toll family members bind multiple SpƤtzle proteins and activ... | ACCEPT | Summary: Spz is the ligand that initiates Toll signalling; the pathway term (initiated by ligand binding to Toll) directly includes Spz. Reason: Core process. GO:0008063 is defined as initiated by an extracellular ligand binding to Toll, so Spz as that ligand participates (unlike the proteolytic activation cascade upstream, for which Spz is only the substrate). Supporting Evidence: PMID:31088910 Thus, three Spz family members (Spz-1, -2, and -5) exhibit features consistent with functioning as cytokines that bind to Toll-1 and Toll-7, which activates downstream Toll signaling and the drosomycin promoter. |
| GO:0008063 Toll signaling pathway | IDA PMID:7705656 Cactus protein degradation mediates Drosophila dorsal-ventra... | ACCEPT | Summary: Spz is the ligand that initiates Toll signalling; the pathway term (initiated by ligand binding to Toll) directly includes Spz. Reason: Core process. GO:0008063 is defined as initiated by an extracellular ligand binding to Toll, so Spz as that ligand participates (unlike the proteolytic activation cascade upstream, for which Spz is only the substrate). Supporting Evidence: PMID:7705656 We show that Cactus, like I kappa B, is rapidly degraded in response to signaling. |
| GO:0008063 Toll signaling pathway | IDA PMID:9533958 Proteolytic processing of the Drosophila SpƤtzle protein by ... | ACCEPT | Summary: Spz is the ligand that initiates Toll signalling; the pathway term (initiated by ligand binding to Toll) directly includes Spz. Reason: Core process. GO:0008063 is defined as initiated by an extracellular ligand binding to Toll, so Spz as that ligand participates (unlike the proteolytic activation cascade upstream, for which Spz is only the substrate). Supporting Evidence: PMID:9533958 An active form of Easter protease cleaves the SpƤtzle protein, generating a carboxyterminal polypeptide fragment which, when microinjected into the perivitelline space of a spƤtzle deficient embryo, directs production of ventrolateral pattern elements. |
| GO:0008063 Toll signaling pathway | IGI PMID:14654000 A serpin regulates dorsal-ventral axis formation in the Dros... | ACCEPT | Summary: Spz is the ligand that initiates Toll signalling; the pathway term (initiated by ligand binding to Toll) directly includes Spz. Reason: Core process. GO:0008063 is defined as initiated by an extracellular ligand binding to Toll, so Spz as that ligand participates (unlike the proteolytic activation cascade upstream, for which Spz is only the substrate). Supporting Evidence: PMID:14654000 Female flies deficient in Serpin-27A produce embryos that lack dorsal-ventral polarity and show uniform high levels of Toll signaling. |
| GO:0008063 Toll signaling pathway | IMP PMID:10369678 A mosaic analysis in Drosophila fat body cells of the contro... | ACCEPT | Summary: Spz is the ligand that initiates Toll signalling; the pathway term (initiated by ligand binding to Toll) directly includes Spz. Reason: Core process. GO:0008063 is defined as initiated by an extracellular ligand binding to Toll, so Spz as that ligand participates (unlike the proteolytic activation cascade upstream, for which Spz is only the substrate). Supporting Evidence: PMID:10369678 a linear activation cascade Spaetzle--> Toll-->Cactus-->Dorsal/DIF leads to the induction of the drosomycin gene in larval fat body cells |
| GO:0008063 Toll signaling pathway | IMP PMID:10973475 Toll-related receptors and the control of antimicrobial pept... | ACCEPT | Summary: Spz is the ligand that initiates Toll signalling; the pathway term (initiated by ligand binding to Toll) directly includes Spz. Reason: Core process. GO:0008063 is defined as initiated by an extracellular ligand binding to Toll, so Spz as that ligand participates (unlike the proteolytic activation cascade upstream, for which Spz is only the substrate). Supporting Evidence: PMID:10973475 the processed form of Spaetzle markedly induced expression of drosomycin |
| GO:0008063 Toll signaling pathway | IMP PMID:16399077 A SpƤtzle-processing enzyme required for toll signaling acti... | ACCEPT | Summary: Spz is the ligand that initiates Toll signalling; the pathway term (initiated by ligand binding to Toll) directly includes Spz. Reason: Core process. GO:0008063 is defined as initiated by an extracellular ligand binding to Toll, so Spz as that ligand participates (unlike the proteolytic activation cascade upstream, for which Spz is only the substrate). Supporting Evidence: PMID:16399077 Here, we report a protease, called SpƤtzle-processing enzyme (SPE), required for Toll-dependent antimicrobial response. |
| GO:0008063 Toll signaling pathway | IMP PMID:17324925 Role of the Spatzle Pro-domain in the generation of an activ... | ACCEPT | Summary: Spz is the ligand that initiates Toll signalling; the pathway term (initiated by ligand binding to Toll) directly includes Spz. Reason: Core process. GO:0008063 is defined as initiated by an extracellular ligand binding to Toll, so Spz as that ligand participates (unlike the proteolytic activation cascade upstream, for which Spz is only the substrate). Supporting Evidence: PMID:17324925 A dimeric precursor of SpƤtzle is processed by an endoprotease to produce a form (C-106) that cross-links Toll receptor ectodomains and establishes signaling. |
| GO:0008063 Toll signaling pathway | IMP PMID:18724373 Sensing of 'danger signals' and pathogen-associated molecula... | ACCEPT | Summary: Spz is the ligand that initiates Toll signalling; the pathway term (initiated by ligand binding to Toll) directly includes Spz. Reason: Core process. GO:0008063 is defined as initiated by an extracellular ligand binding to Toll, so Spz as that ligand participates (unlike the proteolytic activation cascade upstream, for which Spz is only the substrate). Supporting Evidence: PMID:18724373 Following a fungal infection, Toll pathway activation was always totally suppressed in spz mutant flies |
| GO:0008063 Toll signaling pathway | IMP PMID:26843333 SpƤtzle-Processing Enzyme-independent Activation of the Toll... | ACCEPT | Summary: Spz is the ligand that initiates Toll signalling; the pathway term (initiated by ligand binding to Toll) directly includes Spz. Reason: Core process. GO:0008063 is defined as initiated by an extracellular ligand binding to Toll, so Spz as that ligand participates (unlike the proteolytic activation cascade upstream, for which Spz is only the substrate). Supporting Evidence: PMID:26843333 Toll activation induced by immune challenge was almost suppressed in spƤtzle mutant larvae and adults |
| GO:0008063 Toll signaling pathway | IMP PMID:37319131 Damage sensing mediated by serine proteases Hayan and Persep... | ACCEPT | Summary: Spz is the ligand that initiates Toll signalling; the pathway term (initiated by ligand binding to Toll) directly includes Spz. Reason: Core process. GO:0008063 is defined as initiated by an extracellular ligand binding to Toll, so Spz as that ligand participates (unlike the proteolytic activation cascade upstream, for which Spz is only the substrate). Supporting Evidence: PMID:37319131 Activated Hayan and Psh activate unknown SPs, and then pro-Spz is cleaved in the secretory pathway. |
| GO:0008063 Toll signaling pathway | IMP PMID:8026333 A processed form of the SpƤtzle protein defines dorsal-ventr... | ACCEPT | Summary: Spz is the ligand that initiates Toll signalling; the pathway term (initiated by ligand binding to Toll) directly includes Spz. Reason: Core process. GO:0008063 is defined as initiated by an extracellular ligand binding to Toll, so Spz as that ligand participates (unlike the proteolytic activation cascade upstream, for which Spz is only the substrate). Supporting Evidence: PMID:8026333 The purified protein is recognized by antibodies to the C-terminal half of the SpƤtzle protein, indicating that this polarizing activity is a product of the spƤtzle gene. |
| GO:0008063 Toll signaling pathway | IMP PMID:8808632 The dorsoventral regulatory gene cassette spƤtzle/Toll/cactu... | ACCEPT | Summary: Spz is the ligand that initiates Toll signalling; the pathway term (initiated by ligand binding to Toll) directly includes Spz. Reason: Core process. GO:0008063 is defined as initiated by an extracellular ligand binding to Toll, so Spz as that ligand participates (unlike the proteolytic activation cascade upstream, for which Spz is only the substrate). Supporting Evidence: PMID:8808632 the extracellular Toll ligand, spƤtzle, control expression of the antifungal peptide gene drosomycin in adults |
| GO:0008063 Toll signaling pathway | NAS PMID:8124709 The spƤtzle gene encodes a component of the extracellular si... | ACCEPT | Summary: Spz is the ligand that initiates Toll signalling; the pathway term (initiated by ligand binding to Toll) directly includes Spz. Reason: Core process. GO:0008063 is defined as initiated by an extracellular ligand binding to Toll, so Spz as that ligand participates (unlike the proteolytic activation cascade upstream, for which Spz is only the substrate). Supporting Evidence: PMID:8124709 We propose that proteolytic processing of the spƤtzle protein is confined to the ventral side of the embryo and that the localization of processed spƤtzle determines where the receptor, Toll, is active. |
| GO:0008083 growth factor activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Spz belongs to the neurotrophin-like cystine-knot family with DNT1 and DNT2, whose members promote neuronal survival. Reason: The IBA is consistent with the neurotrophic activity shown for spz (weaker than DNT1), but for spz the dominant, best-characterised activity is cytokine/Toll ligand activity; growth factor activity is retained as non-core. Supporting Evidence: PMID:19018662 Altogether, these data show that spz also has neurotrophic function, but it is weaker than DNT1. |
| GO:0008083 growth factor activity | IMP PMID:19018662 Drosophila neurotrophins reveal a common mechanism for nervo... | KEEP AS NON CORE | Summary: Spz has neurotrophic activity: spz mutant embryos show increased CNS apoptosis, rescued partially by activated Spz. Reason: Real but secondary function; keep as non-core. Supporting Evidence: PMID:19018662 Apoptosis increases in the CNS of spz2 and Tollr3/Df(3R)ro80b mutant embryos, indicating that both Spz and Toll are required for neuronal survival PMID:19018662 Altogether, these data show that spz also has neurotrophic function, but it is weaker than DNT1. |
| GO:0009611 response to wounding | IEP PMID:28289197 Toll pathway is required for wound-induced expression of bar... | KEEP AS NON CORE | Summary: spz is transcriptionally induced at wounds and required for wound-induced epidermal gene expression. Reason: Non-core Toll-dependent context. Supporting Evidence: PMID:28289197 clean puncture wounding results in the transcriptional activation of the dorsal and spz genes in epidermal cells adjacent to wounds PMID:28289197 These results suggest that spz functions downstream of hydrogen peroxide within the epidermal wound response pathway. |
| GO:0009950 dorsal/ventral axis specification | IDA PMID:9533958 Proteolytic processing of the Drosophila SpƤtzle protein by ... | ACCEPT | Summary: Easter-processed Spz C-106 injected into spz-deficient embryos directs ventrolateral pattern. Reason: Core developmental function of Spz. Supporting Evidence: PMID:9533958 An active form of Easter protease cleaves the SpƤtzle protein, generating a carboxyterminal polypeptide fragment which, when microinjected into the perivitelline space of a spƤtzle deficient embryo, directs production of ventrolateral pattern elements. |
| GO:0009950 dorsal/ventral axis specification | IGI PMID:14654000 A serpin regulates dorsal-ventral axis formation in the Dros... | ACCEPT | Summary: Spz/Toll signalling defines embryonic dorsal-ventral polarity; Serpin-27A restrains the protease cascade that activates it. Reason: Core developmental function of Spz (the curator had the full genetic interaction data). Supporting Evidence: PMID:14654000 Female flies deficient in Serpin-27A produce embryos that lack dorsal-ventral polarity and show uniform high levels of Toll signaling. |
| GO:0009950 dorsal/ventral axis specification | IGI PMID:8026333 A processed form of the SpƤtzle protein defines dorsal-ventr... | ACCEPT | Summary: Purified ventralising (polarizing) activity is a processed form of Spz. Reason: Core developmental function. Supporting Evidence: PMID:8026333 The purified protein is recognized by antibodies to the C-terminal half of the SpƤtzle protein, indicating that this polarizing activity is a product of the spƤtzle gene. |
| GO:0009953 dorsal/ventral pattern formation | IDA PMID:18790733 Biophysical characterization of refolded Drosophila SpƤtzle,... | ACCEPT | Summary: Refolded Spz rescues spz-deficient embryos. Reason: Supported; dorsal/ventral axis specification is the more specific co-annotation. Supporting Evidence: PMID:18790733 Dimeric full-length SpƤtzle isoforms have been refolded from insoluble inclusion bodies and are able to rescue SpƤtzle-deficient embryos. |
| GO:0010628 positive regulation of gene expression | IMP PMID:34432851 The Drosophila Baramicin polypeptide gene protects against f... | MODIFY | Summary: Toll signalling (spz-dependent) induces expression of the antifungal Baramicin A gene. Reason: Positive regulation of gene expression is uninformatively general; the relevant output is induction of an antifungal effector peptide. Proposed replacements: positive regulation of antifungal peptide production Supporting Evidence: PMID:34432851 BaraA is also tightly regulated by the Toll pathway, which orchestrates the antifungal response. |
| GO:0021556 central nervous system formation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Spz shares neurotrophic roles in nervous system development with its paralogues DNT1 and DNT2. Reason: The IBA node reflects neurotrophin-like functions in the family; for spz the evidence is for neuronal survival and axon targeting rather than CNS formation per se, so it is kept as non-core. Supporting Evidence: PMID:19018662 Altogether, these data show that spz also has neurotrophic function, but it is weaker than DNT1. |
| GO:0035212 cell competition in a multicellular organism | IMP PMID:30146479 Spatially Restricted Regulation of SpƤtzle/Toll Signaling du... | KEEP AS NON CORE | Summary: Locally activated Spz provides a Toll-mediated killing signal in loser cells during cell competition. Reason: Well supported, non-core. Supporting Evidence: PMID:30146479 Altogether, these results provide compelling evidence that once activated, Spz provides a local killing signal that is mediated by Toll during cell competition. |
| GO:0042542 response to hydrogen peroxide | IDA PMID:28289197 Toll pathway is required for wound-induced expression of bar... | KEEP AS NON CORE | Summary: spz is required for H2O2-induced activation of epidermal wound reporter genes and acts downstream of H2O2. Reason: Spz acts as the ligand relaying an H2O2-triggered epidermal wound signal to Toll; a genuine but non-core context. Supporting Evidence: PMID:28289197 These results suggest that spz functions downstream of hydrogen peroxide within the epidermal wound response pathway. |
| GO:0042803 protein homodimerization activity | IDA PMID:18790733 Biophysical characterization of refolded Drosophila SpƤtzle,... | KEEP AS NON CORE | Summary: Both pro-Spz and C-106 are covalent (disulfide-linked) homodimers. Reason: Accurate but weakly informative; homodimerisation is a structural property of the ligand rather than its function. Supporting Evidence: PMID:18790733 The structure of C106 reveals a T-shaped dimer with significant differences to NGF and a deep internal cavity. PMID:9533958 This SpƤtzle carboxyterminal fragment is a disulfide-linked dimer |
| GO:0043524 negative regulation of neuron apoptotic process | IMP PMID:19018662 Drosophila neurotrophins reveal a common mechanism for nervo... | KEEP AS NON CORE | Summary: Spz and Toll are required for survival of CNS neurons in late embryos. Reason: Supported; non-core. Supporting Evidence: PMID:19018662 Apoptosis increases in the CNS of spz2 and Tollr3/Df(3R)ro80b mutant embryos, indicating that both Spz and Toll are required for neuronal survival |
| GO:0045087 innate immune response | IBA GO_REF:0000033 | ACCEPT | Summary: Spz links extracellular microbial sensing to Toll-dependent immune gene induction. Reason: Correct general term; more specific terms carry the detail. Supporting Evidence: PMID:18724373 the transmembrane receptor Toll does not directly recognize microbial determinants but is activated by binding of an endogenous ligand, the proteolytically cleaved form of the cytokine-like protein Spaetzle (Spz) |
| GO:0045087 innate immune response | IDA PMID:17018283 RalB GTPase-mediated activation of the IkappaB family kinase... | ACCEPT | Summary: Spz is required for the Toll-mediated innate immune response. Reason: The cached abstract concerns human RalB/Sec5/TBK1 and does not mention Spz, but the full text (not cached) may contain fly experiments; the function is clearly correct for spz, so the annotation is kept in deference to the curator. Supporting Evidence: PMID:12872120 We show here that the mature form of SpƤtzle triggers a Toll-dependent immune response after injection into the hemolymph of flies. |
| GO:0045087 innate immune response | IMP PMID:18724373 Sensing of 'danger signals' and pathogen-associated molecula... | ACCEPT | Summary: Toll pathway activation after fungal infection is abolished in spz mutants. Reason: Supported. Supporting Evidence: PMID:18724373 Following a fungal infection, Toll pathway activation was always totally suppressed in spz mutant flies |
| GO:0045087 innate immune response | IMP PMID:19934223 Toll-dependent antimicrobial responses in Drosophila larval ... | ACCEPT | Summary: spz mutant larvae show strongly reduced drosomycin induction after infection. Reason: Supported. Supporting Evidence: PMID:19934223 after infection spz rm7 larvae exhibited a severely reduced level of drs activation (on average 30% of wild-type levels) |
| GO:0045087 innate immune response | IMP PMID:26843333 SpƤtzle-Processing Enzyme-independent Activation of the Toll... | ACCEPT | Summary: Toll activation after immune challenge is almost abolished in spz mutant larvae and adults. Reason: Supported. Supporting Evidence: PMID:26843333 Toll activation induced by immune challenge was almost suppressed in spƤtzle mutant larvae and adults |
| GO:0048018 receptor ligand activity | IDA PMID:12872120 Binding of the Drosophila cytokine SpƤtzle to Toll is direct... | ACCEPT | Summary: Mature Spz binds and activates Toll; injection triggers a Toll-dependent immune response. Reason: Direct evidence of ligand activity. Supporting Evidence: PMID:12872120 in vitro experiments showed that the mature form of SpƤtzle bound to the Toll ectodomain with high affinity and with a stoichiometry of one SpƤtzle dimer to two receptors PMID:12872120 We show here that the mature form of SpƤtzle triggers a Toll-dependent immune response after injection into the hemolymph of flies. |
| GO:0048018 receptor ligand activity | IDA PMID:15197269 Multimerization and interaction of Toll and SpƤtzle in Droso... | ACCEPT | Summary: Spz complexes with Toll and stimulates Toll-dependent drosomycin expression. Reason: Supports receptor ligand activity. Supporting Evidence: PMID:15197269 We demonstrate here that the host protein SpƤtzle can function as a ligand for Toll because SpƤtzle forms a complex with Toll in transgenic fly extracts and stimulates the expression of a Toll-dependent immunity gene, drosomycin, in adult flies. |
| GO:0048018 receptor ligand activity | IDA PMID:24282309 Cytokine Spatzle binds to the Drosophila immunoreceptor Toll... | ACCEPT | Summary: Structure-function analysis of the Spz-Toll complex; interface mutations abolish signalling. Reason: Supports receptor ligand activity; cytokine activity (child term) is the preferred core term. Supporting Evidence: PMID:24282309 Spz C106 interacts via its cystine-knot structure in an asymmetric binding mode that is reminiscent of the neurotrophin NGF bound to the receptor p75 NTR PMID:24282309 D55 is located in the loop following the second beta-strand of the cystine-knot structure, and the mutant Spz protein is severely defective in signaling |
| GO:0048018 receptor ligand activity | IDA PMID:31088910 Toll family members bind multiple SpƤtzle proteins and activ... | ACCEPT | Summary: Spz-1 cystine knot activates the drosomycin promoter in S2 cells expressing Toll-1 or Toll-7. Reason: Supports receptor ligand activity for Toll-1 and Toll-7. Supporting Evidence: PMID:31088910 Thus, three Spz family members (Spz-1, -2, and -5) exhibit features consistent with functioning as cytokines that bind to Toll-1 and Toll-7, which activates downstream Toll signaling and the drosomycin promoter. |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:26843333 SpƤtzle-Processing Enzyme-independent Activation of the Toll... | REMOVE | Summary: The cited paper tests spz only against Gram-positive bacteria; the Gram-negative term is a wrong-term row. Reason: The open-access full text of PMID:26843333 (J-STAGE, read 2026-11-12) challenges larvae with Micrococcus luteus and adults with Bacillus subtilis, "which is a Gram-positive bacterium", and uses no Gram-negative bacterium. UniProt's parallel rows from this paper on SPE, psh and modSP use GO:0050830, and PMID:16894030 found spz mutants sensitised only to Gram-positive bacteria and fungi. The Gram-positive defence term is captured on other rows. Supporting Evidence: PMID:26843333 SPE mutant larvae challenged with Micrococcus luteus and adults challenged with Bacillus subtilis PMID:16894030 a mutation in the spatzle gene ( spatzle rm7 ), which blocks Toll activation, sensitized animals only to infection by gram-positive bacteria and fungi |
| GO:0050830 defense response to Gram-positive bacterium | IDA PMID:12872120 Binding of the Drosophila cytokine SpƤtzle to Toll is direct... | ACCEPT | Summary: Spz is required for resistance to Gram-positive bacterial infection via Toll. Reason: Supported by the known role of Spz-Toll in Gram-positive defence. Supporting Evidence: PMID:12872120 We show here that the mature form of SpƤtzle triggers a Toll-dependent immune response after injection into the hemolymph of flies. |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:11823479 Cutting edge: the toll pathway is required for resistance to... | ACCEPT | Summary: Spz is required for resistance to Gram-positive bacterial infection via Toll. Reason: The Toll pathway (including spz) is required for resistance to Gram-positive bacteria. Supporting Evidence: PMID:11823479 the Toll pathway, but not that of immune deficiency, is required for resistance to other Gram-positive bacteria |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:16894030 The Drosophila inhibitor of apoptosis protein DIAP2 function... | ACCEPT | Summary: Spz is required for resistance to Gram-positive bacterial infection via Toll. Reason: spz mutants are sensitised to Gram-positive bacteria. Supporting Evidence: PMID:16894030 a mutation in the spatzle gene ( spatzle rm7 ), which blocks Toll activation, sensitized animals only to infection by gram-positive bacteria and fungi PMID:16894030 Induced expression of Drosomycin in response to gram-positive bacterial infection was abrogated only in spatzle mutant flies. |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:26843333 SpƤtzle-Processing Enzyme-independent Activation of the Toll... | ACCEPT | Summary: Spz is required for resistance to Gram-positive bacterial infection via Toll. Reason: Toll activation after M. luteus / B. subtilis challenge requires spz. Supporting Evidence: PMID:26843333 Toll activation induced by immune challenge was almost suppressed in spƤtzle mutant larvae and adults |
| GO:0050832 defense response to fungus | IMP PMID:16399077 A SpƤtzle-processing enzyme required for toll signaling acti... | ACCEPT | Summary: Spz is required for the Toll-dependent antifungal response, including drosomycin induction and survival after fungal infection. Reason: Supported; overlaps antifungal innate immune response. Supporting Evidence: PMID:16399077 Flies with reduced SPE expression show no noticeable pro-SpƤtzle processing and become highly susceptible to microbial infection. |
| GO:0050832 defense response to fungus | IMP PMID:16894030 The Drosophila inhibitor of apoptosis protein DIAP2 function... | ACCEPT | Summary: Spz is required for the Toll-dependent antifungal response, including drosomycin induction and survival after fungal infection. Reason: spz mutants are sensitised to fungal infection. Supporting Evidence: PMID:16894030 a mutation in the spatzle gene ( spatzle rm7 ), which blocks Toll activation, sensitized animals only to infection by gram-positive bacteria and fungi |
| GO:0061760 antifungal innate immune response | IDA PMID:12872120 Binding of the Drosophila cytokine SpƤtzle to Toll is direct... | ACCEPT | Summary: Spz is required for the Toll-dependent antifungal response, including drosomycin induction and survival after fungal infection. Reason: Core immune process. Supporting Evidence: PMID:12872120 We show here that the mature form of SpƤtzle triggers a Toll-dependent immune response after injection into the hemolymph of flies. |
| GO:0061760 antifungal innate immune response | IMP PMID:10973475 Toll-related receptors and the control of antimicrobial pept... | ACCEPT | Summary: Spz is required for the Toll-dependent antifungal response, including drosomycin induction and survival after fungal infection. Reason: Processed Spz induces drosomycin via Toll in S2 cells. Supporting Evidence: PMID:10973475 the processed form of Spaetzle markedly induced expression of drosomycin |
| GO:0061760 antifungal innate immune response | IMP PMID:17190605 Dual detection of fungal infections in Drosophila via recogn... | ACCEPT | Summary: Spz is required for the Toll-dependent antifungal response, including drosomycin induction and survival after fungal infection. Reason: spz mutants fail to induce drosomycin after fungal challenge and are susceptible to Candida. Supporting Evidence: PMID:17190605 Hardly any Drosomycin expression was detected in Dif or spz mutant flies infected with spores, whether dead or alive PMID:17190605 survival of the Toll pathway mutants spz and Dif was compromised, indicating that the Toll pathway is required for defense against this opportunistic yeast |
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Download this section (compressed HTML)Q: Which protease processes pro-SpƤtzle when SPE is absent (e.g. after M. luteus challenge of SPE mutant larvae), and does it cut at the same Arg220 site?
Q: Does the pro-domain-associated form of SpƤtzle circulating in haemolymph have any signalling activity of its own, and do the maternal isoforms that lack the cleavage site (8.24, 11.27) have a function?
Q: Should the enzyme-substrate relationship between SPE/Easter and SpƤtzle be captured with has_input on the protease activity (e.g. in a GO-CAM of the Toll ligand activation cascade), rather than by annotating SpƤtzle to GO:0160032?
Q: Is SpƤtzle required for defence against any Gram-negative bacterium? The one row asserting this (IMP, PMID:26843333) is removed here because that paper tests only Gram-positive bacteria; a Gram-negative infection phenotype in spz mutants would reinstate the term.
Experiment: Survival and drosomycin/AMP induction assays in spz null flies infected with a panel of Gram-negative bacteria (including Lys-type peptidoglycan-containing strains), with Relish mutants as controls, to test whether spz contributes to Gram-negative defence; a phenotype would support reinstating GO:0050829.
Experiment: Mass spectrometry of haemolymph SpƤtzle fragments in SPE, Hayan and psh single and double mutants after infection or sterile injury to identify alternative processing sites and proteases.
Experiment: In vivo binding and signalling assays of SpƤtzle C-106 with Toll-7 and other Toll paralogues in neurons to test which receptors mediate its neurotrophic function.
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Download this section (compressed HTML)spatzle (spz) encodes a secreted protein which, after cleavage by an extracellular serine protease (encoded by ea or SPE), can induce the dimerization of the product of Tl, and the subsequent activation of the Toll pathway. It contributes to function of the Toll signaling cascade, which plays a key role in various developmental and immune processes, notably embryonic dorso-ventral patterning and regulation of antimicrobial peptides.
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