The IRAK Homolog Pelle Is the Functional Counterpart of IκB Kinase in the Drosophila Toll Pathway

Toll receptors transduce signals that activate Rel-family transcription factors, such as NF-kappa B, by directing proteolytic degradation of inhibitor proteins. In mammals, the I kappa B Kinase (IKK) phosphorylates the inhibitor I kappa B alpha. A beta TrCP protein binds to phosphorylated I kappa B alpha, triggering ubiquitination and proteasome mediated degradation. In Drosophila, Toll signaling directs Cactus degradation via a sequence motif that is highly similar to that in I kappa B alpha, but without involvement of IKK. Here we show that Pelle, the homolog of a mammalian regulator of IKK, acts as a Cactus kinase. We further find that the fly beta TrCP protein Slimb is required in cultured cells to mediate Cactus degradation. These findings enable us for the first time to trace an uninterrupted pathway from the cell surface to the nucleus for Drosophila Toll signaling.