IRAK-4 is a protein kinase involved in signaling innate immune responses from Toll-like receptors. It also supports signaling from T-cell receptors.Animals without IRAK-4 are more susceptible to viruses and bacteria but completely resistant to LPS challenge.Unlike the other IRAK proteins, however, but similar to Pelle, IRAK4 has a short C-terminal domain. Northern blot analysis revealed expression of 3.0- and 4.4-kb transcripts, with strongest expression in kidney and liver. Luciferase reporter analysis showed that IRAK4 lacking the kinase domain inhibited IL1- but not tumor necrosis factor (TNF)- induced NFKB and IRAK1 activation. SDS-PAGE and autoradiographic analysis indicated that IRAK4 phosphorylates and activates IRAK1 at thr387, but not vice versa.