Toll-like receptors (TLRs) residing in distinct subcellular compartments activate a common signal-transduction pathway. The sorting adaptor TIRAP recruits the signaling adaptor MyD88 to plasma membrane–localized TLRs, but TIRAP-deficient cells respond normally to synthetic ligands of TLR7 and TLR9, suggesting that endosomal TLRs signaling is TIRAP independent. In Cell, Kagan and colleagues show that TIRAP is required for signaling from endosomal TLRs in response to natural ligands, such as herpes simplex virus (HSV) DNA. High concentrations of ligands bypass the requirement for TIRAP in all TLRs, explaining the previous observations. The authors show that TIRAP is a component of the MyD88-IRAK2-IRAK4 signaling complex induced by either TLR4 or TLR9, and is required for its assembly. The lipid-binding domain of TIRAP allows promiscuous binding to various lipid targets, such as PI(4,5)P2 at the plasma membrane and PI(3)P on endosomes, resulting in functional formation of MyD88-IRAK signaling complexes in both locations.

Cell 156, 705–716 (2014)