The Drosophila Toll Pathway: A Model of Innate Immune Signalling Activated by Endogenous Ligands

The Drosophila Toll signalling pathway is partially homologous to the mammalian TLR innate immune pathway, but also has marked differences. The Drosophila Toll pathway is mainly activated by the endogenous ligand Spatzle, instead of by direct recognition of microbial molecules; and downstream signalling from adaptor molecules/kinases, MyD88/IRAKs, to the inhibitor of NF-κB (IκB) is a blackbox in Drosophila. These differences provide an interesting opportunity to decipher molecular mechanisms underlying microbial-independent activation of innate immunity. In our laboratory, we have performed ex vivo genome-wide RNAi screening and identified a HECT-type E3 ligase, Sherpa, as an essential component of intracellular Toll signalling; two protein kinases, Pitslre and Doa, as downstream kinases in the blackbox; and a Jumonji-like histone demethylase, Jarid2, as a transcription factor. Additionally, we found that the Drosophila larval peptide fraction has strong stimulatory activity on the Toll receptor. These findings and future analyses are likely to provide information on the as yet unclear molecular mechanisms of ‘sterile inflammation’ in mammals.