Phosphoinositide-mediated adaptor recruitment controls toll-like receptor signaling

Toll-like receptors (TLRs) play a critical role in the immune system as sensors of microbial infection. Signaling downstream from TLRs is initiated by the recruitment of adaptor proteins, including MyD88 and TRAP. These adaptors play essential roles in TLR signaling, but the mechanism of their function is currently unknown. Here we demonstrate that TRAP and MyD88 have distinct functions and describe a mechanism of recruitment of TRAP and MyD88 to TLR4. We find that TRAP contains a phosphatidylinositol 4,5-bisphosphate (PIP2) binding domain, which mediates TRAP recruitment to the plasma membrane. TRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction. These results establish that phosphoinositide-mediated adaptor recruitment initiates a specific signal-transduction pathway.