Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling.
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.
- SourceAvailable from: Xiaomo Jiang
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ABSTRACT: Within a few years of the discovery of Toll-like receptors (TLRs) and their role in innate immunity, viral and bacterial proteins were recognized to antagonize TLR signal transduction. Since then, as TLR signaling networks were unraveled, microbial systems have been discovered that target nearly every component within these pathways. However, recent findings as well as some notable exceptions promote the idea that more of these systems have yet to be discovered. For example, we know very little about microbial systems for directly targeting non-cytoplasmic portions of TLR signaling pathways, that is, the ligand interacting portions of the receptor itself. In this review, we compare and contrast strategies by which bacteria and viruses antagonize TLR signaling networks to identify potential areas for future research. Copyright © 2015. Published by Elsevier Ltd.Current Opinion in Immunology. 02/2015; 32.
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ABSTRACT: ACE2 and Ang-(1-7) have important roles in preventing acute lung injury. However, it is not clear whether upregulation of the ACE2/Ang-(1-7)/Mas axis prevents LPS-induced injury in pulmonary microvascular endothelial cells (PMVECs) by inhibiting the MAPKs/NF-κB pathways. Primary cultured rat PMVECs were transduced with lentiviral-borne Ace2 or shRNA-Ace2, and then treated or not with Mas receptor blocker (A779) before exposure to LPS. LPS stimulation resulted in the higher levels of AngII, Ang-(1-7), cytokine secretion, and apoptosis rates, and the lower ACE2/ACE ratio. Ace2 reversed the ACE2/ACE imbalance and increased Ang-(1-7) levels, thus reducing LPS-induced apoptosis and inflammation, while inhibition of Ace2 reversed all these effects. A779 abolished these protective effects of Ace2. LPS treatment was associated with activation of the ERK, p38, JNK, and NF-κB pathways, which were aggravated by A779. Pretreatment with A779 prevented the Ace2-induced blockade of p38, JNK, and NF-κB phosphorylation. However, only JNK inhibitor markedly reduced apoptosis and cytokine secretion in PMVECs with Ace2 deletion and A779 pretreatment. These results suggest that the ACE2/Ang-(1-7)/Mas axis has a crucial role in preventing LPS-induced apoptosis and inflammation of PMVECs, by inhibiting the JNK/NF-κB pathways.Scientific Reports 02/2015; 5:8209. · 5.08 Impact Factor