Signaling through mammalian and Drosophila Toll-family receptors (TLRs). The left-hand side of the figure shows signaling through mammalian TLR4 in response to bacterial lipopolysaccharide (LPS). LPS monomers from bacterial membranes bind to LPS-binding protein (LBP) which transfers the LPS monomer to CD14 in the membrane of phagocytes. CD14 and MD2 promote the binding of LPS to TLR4 which signals to the cell interior. Binding of LPS by TLR4 recruits the adaptor molecule MyD88 to the cytoplasmic domain of the receptor and MyD88 in turn binds to TRAF6, which binds the serine-threonine kinase IRAK. This complex is believed to activate the phosphorylation of the two subunits of the NFκB kinase (NIK) and cause them to form a heterodimer, IκB kinase (IKK). The IKK dimer then phosphorylates IκB, causing it to dissociate from NFκB which is thereby released to migrate to the nucleus and bind to DNA, activating the transcription of genes encoding inflammatory mediators. The right-hand side of the figure shows signaling through Drosophila Toll in response to fungal components. Components of the fungal cell wall are believed to activate a protease which cleaves the precursor proSpätzle to Spätzle, the ligand for Toll. In the Drosophila pathway, Tube and Pelle are homologous to MyD88 and TRAF6, and Cactus and Dif are homologous to IκB and NFκB. The intervening components in the Drosophila pathway are not known. MyD88 and TRAF6, and Tube and Pelle, bind through a motif known as the death domain which occurs widely in regulatory interactions including those that mediate apoptosis. Modified from Immunity by Anthony DeFranco, Richard Locksley and Miranda Robertson, to be published by New Science Press Ltd.