Toll Signaling

Toll was identified in genetic screens exploring the maternal specification ofbody axes in the Drosophila embryo. Subsequent studies revealed that Toll is also used for innate immune signaling and is conserved from insects to humans. Three proteins in the Drosophila Toll pathway – MyD88, Tube, and Pelle – contain a protein interaction motif called the death domain (first identified in a programmed cell death pathway). We have characterized a trimeric complex of these death domains that transduces signals from Toll to downstream effectors. Our demonstration that counterparts of Tube and Pelle exist across a wide range of animal species (1) led us to predict that the trimeric architecture of the Drosophila pathway would be preserved in human (2)s, a prediction born out by crystallographic studies in the laboratory of Hao Wu (Cornell).

1. Animal Genomes Encode One Tube and One Pelle Gene

 

Current Research

We have extended our studies to explore how formation of the death domain trimer leads to phosphorylation and degradation of the inhibitor protein, Cactus, releasing the NF-kappaB protein Dorsal (and its close relative Dif) to translocate into nuclei and activate transcriptional responses to Toll activation. In particular, we are focusing on the activity of Pelle as a protein kinase required for signaling downstream of Toll.

2. Model for Death Domain Trimer in Toll Signaling