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Drosophila MyD88 is an adapter in the Toll signaling pathway
1Howard Hughes Medical Institute and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Abstract:
Toll-like receptors comprise a family of cell surface receptors that play a crucial role in the innate immune recognition of both Drosophila and mammals. Previous studies have shown that Drosophila Toll-1 mediates the induction of antifungal peptides during fungal infection of adult flies. Through genetic studies, Tube, Pelle, Cactus, and Dif have been identified as downstream components of the Toll-1 signaling pathway. Here we report characterization of a Drosophila homologue of human MyD88, dMyD88. We show that dMyD88 is an adapter in the Toll signaling pathway that associates with both the Toll receptor and the downstream kinase Pelle. 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. We also show that dMyD88 associates with the death domain-containing adapter Drosophila Fas-associated death domain-containing protein (dFADD), which in turn interacts with the apical caspase Dredd. This pathway links a cell surface receptor to an apical caspase in invertebrate cells and therefore suggests that the Toll-mediated pathway of caspase activation may be the evolutionary ancestor of the death receptor-mediated pathway for apoptosis induction in mammals.
Insights
Researchers identified dMyD88, a key adapter protein in the Drosophila Toll signaling pathway. This discovery reveals a link between cell surface receptors and caspase activation, suggesting an ancient pathway for apoptosis.
Area of Science:
- Immunology
- Cell Biology
- Genetics
Background:
- Toll-like receptors (TLRs) are crucial for innate immunity in Drosophila and mammals.
- Drosophila Toll-1 mediates antifungal peptide induction during fungal infections.
- Key downstream components of the Toll-1 pathway include Tube, Pelle, Cactus, and Dif.
Purpose of the Study:
- To characterize dMyD88, a Drosophila homologue of human MyD88.
- To elucidate the role of dMyD88 in the Toll signaling pathway.
- To investigate the evolutionary relationship between invertebrate and mammalian cell death pathways.
Main Methods:
- Genetic studies to identify downstream components of the Toll-1 pathway.
- Biochemical assays to determine dMyD88 interactions with Toll and Pelle.
- Reporter gene assays (Drosomycin) to assess dMyD88's effect on signaling.
- Analysis of dMyD88 interaction with dFADD and Dredd.
Main Results:
- dMyD88 functions as an adapter protein in the Toll signaling pathway.
- dMyD88 associates with both the Toll receptor and the Pelle kinase.
- dMyD88 expression induces Drosomycin reporter gene activity, while dominant-negative dMyD88 inhibits Toll signaling.
- dMyD88 interacts with dFADD, which links to the caspase Dredd.
Conclusions:
- dMyD88 is a critical component of the Drosophila Toll pathway, connecting the receptor to downstream signaling.
- The identified pathway represents a link between cell surface receptors and apical caspases in invertebrates.
- This pathway may be an evolutionary precursor to mammalian death receptor-mediated apoptosis.