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 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.
Kagan
Jonathan C
JC
Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Medzhitov
Ruslan
R
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D016466:CHO Cells; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008563:Membrane Lipids / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D053594:Myeloid Differentiation Factor 88; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D020239:Receptor Cross-Talk / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*
D000089982:ADP-Ribosylation Factor 6; D048868:Adaptor Proteins, Signal Transducing; D016023:Integrins; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D008563:Membrane Lipids; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D019269:Phosphatidylinositol 4,5-Diphosphate; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D020727:ADP-Ribosylation Factors