Regulated assembly of the Toll signaling complex drives Drosophila dorsoventral patterning

• Published in: The EMBO journal 2004-01, Vol.23 (1), p.100-110
• Main Authors: Sun, Huaiyu, Towb, Par, Chiem, Daniel N, Foster, Byron A, Wasserman, Steven A
• Format: Article
• Language: English
• Subjects: Alleles; Amino Acid Sequence; Amino Acid Substitution; Animals; Body Patterning; Cells, Cultured; death domain; Dimerization; dorsoventral patterning; Drosophila; Drosophila - cytology; Drosophila - embryology; Drosophila Proteins - chemistry; Drosophila Proteins - metabolism; EMBO11; EMBO37; Epidermal Growth Factor - metabolism; Gene Expression Regulation, Developmental; Genes, Reporter; IRAK; Luciferases - metabolism; Lysine - metabolism; Models, Molecular; Molecular Sequence Data; Mortality; MyD88; NF-κB; Pelle; Precipitin Tests; Protein Structure, Secondary; Protein Structure, Tertiary; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - metabolism; Recombinant Proteins - metabolism; Signal Transduction; Toll; Toll-Like Receptors; Tube
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/sj.emboj.7600033

In Drosophila , the Toll pathway establishes the embryonic dorsoventral axis and triggers innate immune responses to infection. The transmembrane receptor Toll acts through three death domain‐containing proteins, the kinase Pelle and the adapters Tube and MyD88, in signaling to downstream NF‐κB‐like transcription factors. Here, we delineate the critical events in the earliest stages of Toll signaling. Mutational studies based on structural modeling reveal that the direct interaction of the bivalent Tube death domain with MyD88 is critical for signaling in vivo . The complex of MyD88 and Tube forms prior to signaling and is localized to the embryonic plasma membrane by MyD88. Upon Toll homodimerization, this complex is rapidly recruited to Toll. Binding of Pelle to the MyD88–Tube complex promotes Pelle activation, leading to degradation of the IκB‐like inhibitor, Cactus. Together, these experiments convert a linear picture of gene function into a dynamic mechanistic and structural understanding of signaling complex assembly and function.