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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    • "LPS binds to TLR-4 on the cell membrane and induces NF-κB transcription, mainly through the MyD88 signaling pathway. NF-κB is a transcriptional factor that controls the expression of numerous genes involved in inflammation, which leads to a release of the critical inflammatory molecules, conducting the appropriate immune response (Kagan and Medzhitov, 2006; Peng et al., 2012). Taken together, data presented here from in vivo and in vitro studies show the mechanisms of the antiinflammatory actions of R. officinalis aqueous extract in early phases of inflammation. "
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    • "fused to penetratin, to give the property of membrane permeability, were used in this assay [14] [27]. After serum starvation for 16 h, differentiated 3T3-L1 adipocytes were preincubated with 5 mM penetratin, ARF1p-penetratin or ARF6p- penetratin for 30 min. "
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    Biochemical Pharmacology 06/2014; 90(4). DOI:10.1016/j.bcp.2014.06.012 · 4.65 Impact Factor
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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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    Cell 02/2014; 156(4):705-16. DOI:10.1016/j.cell.2014.01.019 · 33.12 Impact Factor
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