Article

Phosphoinositide-Mediated Adaptor Recruitment Controls Toll-like Receptor Signaling

Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Cell (Impact Factor: 33.12). 07/2006; 125(5):943-55. DOI: 10.1016/j.cell.2006.03.047
Source: PubMed

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.

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    • "WT TIRAP-GFP, PLC- TIRAP-GFP, and PX-TIRAP-GFP were described previously (Kagan and Medzhitov, 2006) and are present in the retroviral vector MSCV202 IRES- hCD2. pEGFP-N1-based TIRAP loc-GFP (amino acids 1–85 of TIRAP fused in frame to GFP) was described previously (Kagan and Medzhitov, 2006). SLP2a-TIRAP-GFP was cloned similarly to the TIRAP alleles described above. "
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