Myd88 (krapfen) is the Drosophila orthologue of MyD88, a signalling adaptor with an N-terminal death domain, a central TIR domain and a C-terminal extension that binds phosphoinositides, preferentially PI(4,5)P2. The C-terminal extension holds Myd88 at the plasma membrane. When the cytokine Spaetzle activates the Toll receptor, Myd88 binds the Toll TIR domain through its own TIR domain and, through its death domain, recruits the adaptor Tube, which in turn recruits the kinase Pelle into a MyD88-Tube-Pelle death domain complex. The zinc finger protein Weckle helps link Myd88 to Toll in the embryo. Pelle then drives phosphorylation and degradation of the IkappaB homologue Cactus and nuclear entry of Dorsal or Dif. Maternal Myd88 is essential for dorsoventral patterning of the embryo, and in larvae and adults Myd88 is required for Toll-dependent Drosomycin induction and survival of fungal and Gram-positive bacterial infection, but not for the IMD-mediated response to Gram-negative bacteria.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002225 positive regulation of antimicrobial peptide production | IMP PMID:11606776 Drosophila MyD88 is an adapter in the Toll signaling pathway... | ACCEPT | Summary: Dominant-negative dMyD88 blocks Toll-induced Drosomycin reporter activity in S2 cells, and dMyD88 overexpression induces it (Horng and Medzhitov 2001). Reason: Antimicrobial peptide gene induction is the main transcriptional output of the Toll pathway, in which MyD88 is the receptor-proximal adaptor. Supporting Evidence: PMID:11606776 Expression of dMyD88 in S2 cells strongly induced activity of a Drosomycin reporter gene, whereas a dominant-negative version of dMyD88 potently inhibited Toll-mediated signaling. |
| GO:0002347 response to tumor cell | IMP PMID:24582964 Transformed epithelia trigger non-tissue-autonomous tumor su... | KEEP AS NON CORE | Summary: IMP response to tumor cell (Parisi et al. 2014); abstract-only in cache. Reason: Tumours activate Toll signalling in the fat body, which drives tumour cell death. The abstract does not name MyD88, but the curator read the full text and the role is consistent with MyD88 being required for Toll signalling. A contextual output of the pathway, not a core function. Supporting Evidence: PMID:24582964 Tumors trigger a systemic immune response through activation of Eiger/TNF signaling, which leads to Toll pathway upregulation in adipocytes. |
| GO:0002804 positive regulation of antifungal peptide production | IDA PMID:11743586 Drosophila MyD88 is required for the response to fungal and ... | ACCEPT | Summary: dMyD88 overexpression induces Drosomycin and its loss reduces Drosomycin induction (Tauszig-Delamasure et al. 2002). Reason: Direct consequence of MyD88's adaptor role in the Toll pathway. Supporting Evidence: PMID:11743586 Overexpression of DmMyD88 was sufficient to induce expression of the antifungal peptide Drosomycin, and induction of Drosomycin was markedly reduced in DmMyD88-mutant flies. |
| GO:0005121 Toll binding | IDA PMID:11606776 Drosophila MyD88 is an adapter in the Toll signaling pathway... | ACCEPT | Summary: dMyD88 associates with Toll via TIR domains (Horng and Medzhitov 2001). Reason: Toll binding through TIR-TIR association is the receptor-proximal molecular function of MyD88. Supporting Evidence: PMID:11606776 associates with the Toll receptor via TIR domains and with Pelle through homophilic death domain interactions |
| GO:0005121 Toll binding | IPI PMID:11743586 Drosophila MyD88 is required for the response to fungal and ... | ACCEPT | Summary: DmMyD88 interacts with Toll through its TIR domain (Tauszig-Delamasure et al. 2002). Reason: Consistent independent evidence of Toll binding. Supporting Evidence: PMID:11743586 DmMyD88 interacted with Toll through its TIR domain and required the death domain proteins Tube and Pelle to activate expression of Drs, which encodes Drosomycin. |
| GO:0005515 protein binding | IPI PMID:11606776 Drosophila MyD88 is an adapter in the Toll signaling pathway... | MODIFY | Summary: dMyD88 binds dFADD through death domains in S2 cell co-immunoprecipitation. Reason: Protein binding is uninformative. The paper shows the association is death domain-mediated, so death domain binding (GO:0070513) is the informative MF. dMyD88's physiological death domain partner is Tube (PMID:12351681); the in vivo relevance of the MyD88-FADD association, observed on overexpression, has not been established, since FADD acts in the IMD pathway. Proposed replacements: death domain binding Supporting Evidence: PMID:11606776 that dMyD88 can interact with dFADD through death domains |
| GO:0005515 protein binding | IPI PMID:16782008 Weckle is a zinc finger adaptor of the toll pathway in dorso... | REMOVE | Summary: Weckle binds dMyD88 and localises it to the plasma membrane (Chen et al. 2006), FlyBase id for Wek. Reason: Generic protein binding is uninformative, and Wek is a zinc finger adaptor rather than a death domain or TIR domain protein, so no more specific MF term can be derived for MyD88 from this interaction. The interaction is not disputed. Supporting Evidence: PMID:16782008 Moreover, Wek binds to and localizes DmMyD88 to the plasma membrane. |
| GO:0005515 protein binding | IPI PMID:16782008 Weckle is a zinc finger adaptor of the toll pathway in dorso... | REMOVE | Summary: Same MyD88-Weckle interaction, UniProt id for Wek. Reason: Duplicate of the FlyBase-identified row; generic protein binding is uninformative. Supporting Evidence: PMID:16782008 Moreover, Wek binds to and localizes DmMyD88 to the plasma membrane. |
| GO:0005546 phosphatidylinositol-4,5-bisphosphate binding | IMP PMID:22464168 Phosphoinositide binding by the Toll adaptor dMyD88 controls... | ACCEPT | Summary: dMyD88 binds PI(4,5)P2 through its C-terminal extension, which targets it to the plasma membrane (Marek and Kagan 2012). Reason: GST-dMyD88 bound PI(4,5)P2-containing liposomes, and mutant analysis in vivo showed that the lipid-binding C-terminal domain is necessary for localisation and function. A distinctive property of the fly adaptor, which combines the membrane-sorting role of mammalian TIRAP with the MyD88 death domain. Supporting Evidence: PMID:22464168 dMyD88 was located at the plasma membrane by a process dependent on a C-terminal phosphoinositide-binding domain. PMID:22464168 GST-dMyD88 interacted preferentially with liposomes containing PI(4,5)P2 and to a lesser extent liposomes containing PI(4)P (Figure 2c). PMID:22464168 In vivo analysis revealed that lipid binding by dMyD88 was necessary for its antimicrobial and developmental functions as well as for the recruitment of the downstream cytosolic adaptor Tube to the cell surface. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro TIR domain mapping to signal transduction. Reason: Correct but general. Supporting Evidence: PMID:11606776 dMyD88 is an adapter in the Toll signaling pathway that associates with both the Toll receptor and the downstream kinase Pelle |
| GO:0008063 Toll signaling pathway | IGI PMID:11743586 Drosophila MyD88 is required for the response to fungal and ... | ACCEPT | Summary: Genetic interaction of Myd88 with Toll pathway components (Tauszig-Delamasure et al. 2002). Reason: MyD88 requires Tube and Pelle to activate Drs; core pathway membership. Supporting Evidence: PMID:11743586 DmMyD88 interacted with Toll through its TIR domain and required the death domain proteins Tube and Pelle to activate expression of Drs, which encodes Drosomycin. |
| GO:0008063 Toll signaling pathway | IGI PMID:11743586 Drosophila MyD88 is required for the response to fungal and ... | ACCEPT | Summary: Genetic interaction of Myd88 with Toll pathway components (Tauszig-Delamasure et al. 2002). Reason: MyD88 requires Tube and Pelle to activate Drs; core pathway membership. Supporting Evidence: PMID:11743586 DmMyD88 interacted with Toll through its TIR domain and required the death domain proteins Tube and Pelle to activate expression of Drs, which encodes Drosomycin. |
| GO:0008063 Toll signaling pathway | IGI PMID:12559494 Krapfen/dMyd88 is required for the establishment of dorsoven... | ACCEPT | Summary: krapfen/Myd88 epistasis with Toll and Tube in embryonic patterning (Charatsi et al. 2003). Reason: kra acts between Toll and Tube; core pathway membership. Supporting Evidence: PMID:12559494 Epistasis experiments reveal that kra acts between the receptor Toll and the cytoplasmic factor Tube. |
| GO:0008063 Toll signaling pathway | IGI PMID:34988396 cGMP signaling pathway that modulates NF-ΞΊB activation in in... | ACCEPT | Summary: Genetic interaction with DG2 (cGMP-dependent kinase) in Toll-mediated Dif/Dorsal activation (Kanoh et al. 2021). Reason: Consistent with MyD88's role as the Toll pathway adaptor. Supporting Evidence: PMID:34988396 Moreover, DG2 physically associates with dMyd88 to form a signaling complex with Tube and Pelle after binding to the intracellular Toll/IL-1 receptor homologous domain of the activated Toll receptor. |
| GO:0008063 Toll signaling pathway | IMP PMID:11606776 Drosophila MyD88 is an adapter in the Toll signaling pathway... | ACCEPT | Summary: Dominant-negative dMyD88 blocks Toll signalling. Reason: Core function. Supporting Evidence: PMID:11606776 Expression of dMyD88 in S2 cells strongly induced activity of a Drosomycin reporter gene, whereas a dominant-negative version of dMyD88 potently inhibited Toll-mediated signaling. |
| GO:0008063 Toll signaling pathway | IMP PMID:12351681 A heterotrimeric death domain complex in Toll signaling. | ACCEPT | Summary: dMyD88 dsRNA blocks signal transduction from Toll to Tube (Sun et al. 2002). Reason: Core function. Supporting Evidence: PMID:12351681 Experiments in cultured cells reveal that the fly orthologue of the adaptor protein MyD88 is essential for signal transduction from Toll to a second adaptor protein, Tube. |
| GO:0008063 Toll signaling pathway | IMP PMID:22464168 Phosphoinositide binding by the Toll adaptor dMyD88 controls... | ACCEPT | Summary: Lipid binding by dMyD88 is required for Toll signalling in vivo. Reason: Core function. Supporting Evidence: PMID:22464168 In vivo analysis revealed that lipid binding by dMyD88 was necessary for its antimicrobial and developmental functions as well as for the recruitment of the downstream cytosolic adaptor Tube to the cell surface. |
| GO:0008063 Toll signaling pathway | IMP PMID:24086459 The IRAK homolog Pelle is the functional counterpart of IΞΊB ... | ACCEPT | Summary: MyD88 RNAi blocks Toll-directed Cactus degradation (Daigneault et al. 2013). Reason: Core function. Supporting Evidence: PMID:24086459 Indeed, eliminating slimb function had the same effect as did RNAi against MyD88, an essential component of the fly Toll pathway. |
| GO:0008063 Toll signaling pathway | IMP PMID:36322050 The Toll pathway mediates Drosophila resilience to Aspergill... | ACCEPT | Summary: Myd88 mutants are defective in Toll-dependent responses to Aspergillus and its mycotoxins (Xu et al. 2023). Reason: Core function. Supporting Evidence: PMID:36322050 are able to overcome the effects of the toxin in a resilience process that involves spz, Toll, and MyD88 |
| GO:0009898 cytoplasmic side of plasma membrane | IDA PMID:22464168 Phosphoinositide binding by the Toll adaptor dMyD88 controls... | ACCEPT | Summary: dMyD88 localises to the plasma membrane via PI(4,5)P2 binding. Reason: Peripheral membrane protein on the cytoplasmic face; supported by imaging and liposome binding. Supporting Evidence: PMID:22464168 dMyD88 was located at the plasma membrane by a process dependent on a C-terminal phosphoinositide-binding domain. |
| GO:0009950 dorsal/ventral axis specification | IMP PMID:12559494 Krapfen/dMyd88 is required for the establishment of dorsoven... | ACCEPT | Summary: Myd88 (krapfen) mutant females produce dorsalised embryos. Reason: Core developmental role of the maternal Toll pathway. Supporting Evidence: PMID:12559494 Epistasis experiments reveal that kra acts between the receptor Toll and the cytoplasmic factor Tube. |
| GO:0009953 dorsal/ventral pattern formation | IMP PMID:12524523 DmMyD88 controls dorsoventral patterning of the Drosophila e... | ACCEPT | Summary: Maternal DmMyD88 is required for dorsoventral patterning (Kambris et al. 2003). Reason: Core developmental role. Supporting Evidence: PMID:12524523 Homozygous mutant female flies lay dorsalized embryos that are rescued by expression of a transgenic DmMyD88 complementary DNA. PMID:12524523 These results show that DmMyD88 encodes an essential component of the Toll pathway in dorsoventral pattern formation. |
| GO:0010046 response to mycotoxin | IMP PMID:36322050 The Toll pathway mediates Drosophila resilience to Aspergill... | KEEP AS NON CORE | Summary: Myd88 mutants are susceptible to Aspergillus mycotoxins restrictocin and verruculogen. Reason: A downstream, context-specific output (Bomanin-mediated resilience) of Toll signalling; MyD88 transduces the signal but does not itself counteract the toxins. Supporting Evidence: PMID:36322050 We report that mutants affecting the Toll pathway or the 55C Bomanin locus are susceptible to the injection of two Aspergillus mycotoxins, restrictocin and verruculogen. PMID:36322050 are able to overcome the effects of the toxin in a resilience process that involves spz, Toll, and MyD88 |
| GO:0019732 antifungal humoral response | IMP PMID:36322050 The Toll pathway mediates Drosophila resilience to Aspergill... | ACCEPT | Summary: Myd88 is required for Toll-dependent defence against Aspergillus (Xu et al. 2023). Reason: Humoral antifungal defence is a principal output of the Toll pathway; consistent with Tauszig-Delamasure et al. 2002. Supporting Evidence: PMID:36322050 We report that mutants affecting the Toll pathway or the 55C Bomanin locus are susceptible to the injection of two Aspergillus mycotoxins, restrictocin and verruculogen. PMID:11743586 DmMyD88-mutant flies were highly susceptible to infection by fungi and Gram-positive bacteria, but resisted Gram-negative bacterial infection much as did wild-type flies. |
| GO:0035591 signaling adaptor activity | IMP PMID:22464168 Phosphoinositide binding by the Toll adaptor dMyD88 controls... | ACCEPT | Summary: dMyD88 acts as a sorting adaptor that recruits Tube to the plasma membrane (Marek and Kagan 2012). Reason: Signaling adaptor activity is the core molecular function: dMyD88 bridges activated Toll (TIR) to Tube (death domain) and, via PI(4,5)P2 binding, positions the complex at the cell surface. Supporting Evidence: PMID:22464168 In vivo analysis revealed that lipid binding by dMyD88 was necessary for its antimicrobial and developmental functions as well as for the recruitment of the downstream cytosolic adaptor Tube to the cell surface. PMID:22464168 We therefore propose that dMyD88 is the functional homolog of TIRAP and that both proteins function as sorting adaptors to recruit downstream signaling adaptors to activated receptors. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IEA GO_REF:0000002 | REMOVE | Summary: InterPro MyD88 family mapping to positive regulation of canonical NF-kappaB signal transduction. Reason: GO defines canonical NF-kappaB signal transduction as IKK-dependent activation of NF-kappaB. Drosophila Toll signalling degrades Cactus without IKK: Pelle is the Cactus kinase. The mammalian MyD88 mapping therefore does not describe the fly pathway, which is captured by GO:0008063 Toll signaling pathway. Supporting Evidence: PMID:24086459 In Drosophila, Toll signaling directs Cactus degradation via a sequence motif that is highly similar to that in IΞΊBΞ±, but without involvement of IKK. |
| GO:0045087 innate immune response | IMP PMID:12351681 A heterotrimeric death domain complex in Toll signaling. | ACCEPT | Summary: Innate immune response (Sun et al. 2002). Reason: MyD88 is required for Toll-mediated innate immunity. Supporting Evidence: PMID:12351681 functional assays confirm that the formation of this heterotrimer is critical for signal transduction by the Toll pathway |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:25180232 Akirin specifies NF-ΞΊB selectivity of Drosophila innate immu... | MARK AS OVER ANNOTATED | Summary: IMP positive regulation of transcription by RNA polymerase II (Bonnay et al. 2014, Akirin paper; abstract-only in cache). Reason: MyD88 is a membrane-proximal signalling adaptor; any effect on transcription is several steps removed, through Pelle, Cactus degradation and Dif/Dorsal. The paper concerns the nuclear NF-kappaB cofactor Akirin. MyD88 loss presumably served as a Toll pathway control for Toll-dependent target genes, which the Toll pathway term already captures. Supporting Evidence: PMID:25180232 the conserved nuclear protein Akirin is a NF-ΞΊB co-factor required for the activation of a subset of Relish-dependent genes |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:11743586 Drosophila MyD88 is required for the response to fungal and ... | ACCEPT | Summary: DmMyD88 mutants are highly susceptible to Gram-positive bacteria. Reason: Core immune function. Supporting Evidence: PMID:11743586 DmMyD88-mutant flies were highly susceptible to infection by fungi and Gram-positive bacteria, but resisted Gram-negative bacterial infection much as did wild-type flies. |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:22464168 Phosphoinositide binding by the Toll adaptor dMyD88 controls... | ACCEPT | Summary: Lipid binding by dMyD88 is required for antibacterial defence (Marek and Kagan 2012). Reason: Core immune function. Supporting Evidence: PMID:22464168 In vivo analysis revealed that lipid binding by dMyD88 was necessary for its antimicrobial and developmental functions as well as for the recruitment of the downstream cytosolic adaptor Tube to the cell surface. |
| GO:0050832 defense response to fungus | IMP PMID:11743586 Drosophila MyD88 is required for the response to fungal and ... | ACCEPT | Summary: DmMyD88 mutants are highly susceptible to fungi. Reason: Core immune function. Supporting Evidence: PMID:11743586 DmMyD88-mutant flies were highly susceptible to infection by fungi and Gram-positive bacteria, but resisted Gram-negative bacterial infection much as did wild-type flies. |
| GO:0070976 TIR domain binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro MyD88 family mapping to TIR domain binding. Reason: dMyD88 binds the Toll TIR domain via its own TIR domain. Supporting Evidence: PMID:11606776 associates with the Toll receptor via TIR domains and with Pelle through homophilic death domain interactions |
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Download this section (compressed HTML)Q: Fly Myd88 combines the PI(4,5)P2-binding sorting role of mammalian TIRAP with MyD88's death domain. Should the IBA/InterPro propagation of mammalian MyD88 terms account for this, for example by propagating phosphoinositide binding within the insect clade only?
Q: Does Myd88 act downstream of Toll-family receptors other than Toll-1 (e.g. Toll-5/Tehao, Toll-7) in vivo, or is it specific to Toll-1 signalling?
Q: Is the MyD88-FADD death domain association seen on overexpression in S2 cells relevant in vivo, given that FADD and Dredd act in the IMD pathway?
Q: The InterPro2GO mapping from IPR017281 (MyD88 family) to positive regulation of canonical NF-kappaB signal transduction reaches insect MyD88, whose pathway is IKK-independent. Should that mapping be restricted to vertebrates?
Q: Is Myd88 required for Toll-1-dependent basal autophagy in the adult brain in vivo? In S2 cells Myd88 knockdown blocks Toll-1- but not Toll-7-induced autophagy while blocking Drosomycin induction by both receptors (PMID:38292423); in vivo Myd88 loss-of-function data for this output are lacking, so no autophagy term is proposed.
Experiment: Structural analysis (cryo-EM) of the Drosophila MyD88-Tube-Pelle death domain assembly bound to the Toll TIR domain, compared with the vertebrate Myddosome.
Hypothesis: The fly complex forms a higher-order helical assembly with Tube bridging MyD88 and Pelle, differing in stoichiometry from the MyD88-IRAK4-IRAK2 Myddosome.
Type: structural biology
Experiment: Knock-in of lipid-binding-defective and PLCdelta-PH-substituted Myd88 alleles, with live imaging of Toll, Myd88 and Tube in fat body cells during infection.
Hypothesis: PI(4,5)P2 binding sets the plasma membrane as the site of Toll signal initiation, and Myd88 membrane residence is rate-limiting for signalling.
Type: genetic knock-in and live imaging
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Download this section (compressed HTML)Myd88 (Myd88) encodes an adaptor protein involved in in the Toll pathway functioning downstream of the product of Tl and upstream of the product of tub. Toll pathway is a signaling cascade that plays a key role in various developmental and immune processes, notably embryonic dorsoventral patterning and regulation of antimicrobial peptides.
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