title: Drosophila MyD88 is an adapter in the Toll signaling pathway.
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.
authors.affiliation: Howard Hughes Medical Institute and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: T
authors.initials: T
authors.lastname: Horng
authors.forename: R
authors.initials: R
authors.lastname: Medzhitov
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology*; D017209:Apoptosis; D002352:Carrier Proteins / Q000502:physiology; D020169:Caspases / Q000502:physiology; D029721:Drosophila Proteins; D053200:Fas-Associated Death Domain Protein; D019476:Insect Proteins / Q000494:pharmacology / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D002352:Carrier Proteins; D029721:Drosophila Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D019476:Insect Proteins; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C068721:Tl protein, Drosophila; D051193:Toll-Like Receptors; C091227:DRS protein, Drosophila; D020169:Caspases; C431887:dredd protein, Drosophila