Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling

Authors:
Kagan JC, Medzhitov R
In:
Source: Cell
Publication Date: (2006)
Issue: 125(5): 943-55
Research Area:
Cancer Research/Cell Biology
Immunotherapy / Hematology
Cells used in publication:
Macrophage, mouse
Species: mouse
Tissue Origin: bone marrow
Macrophage, mouse - C57BL/6
Species: mouse
Tissue Origin: bone marrow
Macrophage, mouse - BALB/c
Species: mouse
Tissue Origin: bone marrow
Platform:
Nucleofectorâ„¢ I/II/2b
Abstract
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 TIRAP. These adaptors play essential roles in TLR signaling, but the mechanism of their function is currently unknown. Here we demonstrate that TIRAP and MyD88 have distinct functions and describe a mechanism of recruitment of TIRAP and MyD88 to TLR4. We find that TIRAP contains a phosphatidylinositol 4,5-bisphosphate (PIP2) binding domain, which mediates TIRAP recruitment to the plasma membrane. TIRAP 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.