The regulation of some immune responses in insects and humans are remarkably closely conserved, and the signalling pathways in Drosophila, unraveled through elegant genetic studies, are providing an invaluable framework for understanding mammalian innate immunity — the rapid response to pathogen invasion. Vidal et al. now report a new and essential component of the innate immune response to Gram-negative bacteria in Drosophila — dTAK1 — which, as a homologue of a mammalian MAPKKK kinase, has a conserved role in host defence.

In Drosophila, two innate immune response pathways induce distinct classes of antimicrobial peptides. Immunity to fungi depends on the Toll pathway, whereas the Imd pathway is required for resistance to Gram-negative bacteria. Although some components of the Imd pathway are known — for example, members of the IκB kinase (IKK) complex, Dredd (a caspase) and Relish (Rel, an NFκB homologue) — others remain to be found. To fill these gaps, this group had previously screened mutagenized Drosophila for susceptibility to infection with Gram-negative bacteria, uncovering two genes — Dredd, and a second gene described here.

Four recessive mutations were identified that block the induction of the antimicrobial peptide Diptericin — a target of the Imd pathway — without impairing the functioning of the Toll pathway. The mutations map to a region that contains 25 genes, one of which is dTAK1. As mammalian TAK1 is a potential regulator of NFκB, dTAK1 was an obvious candidate gene to study. Its role was confirmed in three ways. First, a wild-type dTAK1 transgene rescued the mutants' lack of an antimicrobial response. Second, sequencing identified mutations within the catalytic domain of dTAK1 in mutant flies. Third, expression of a dominant-negative form of dTAK1 in wild-type Drosophila inhibited Diptericin induction in response to bacterial infection.

But where is dTAK1 positioned relative to the other Imd-pathway components? This was resolved by overexpressing Dredd and dTAK1 in Imd-, DmIKKβ-, DmIKKγ-, and Rel-deficient backgrounds, and then assessing Diptericin expression. These experiments revealed epistatic relationships between the genes (see picture), placing dTAK1 upstream of DmIKKβ/DmIKKγ and Dredd downstream of the IKK complex.

According to this model, Imd pathway activation results in the cleavage of Relish, possibly by Dredd, and the subsequent nuclear translocation of the Rel activation domain. The authors predict that antimicrobial genes integrate signals from the Imd and Toll pathways by responding to specific combinations of the different Rel proteins that are end targets of these pathways. This combinatorial regulation of target genes might be key to how insects raise tailored immune responses to many different pathogens from a limited number of recognition pathways.