Figure 1.

TLR4 plasma membrane and endosome signaling. A) LPB protein extracts LPS from the bacterial cell wall and transfers it to CD14. In the presence of LPS, CD14 allows the translocation of the TLR4‐MD‐2 complex to lipid rafts, where it dimerizes. Then the formation of the “myddosome” complex (containing TIRAP, MyD88, and IRAKs) occurs. IRAKs recruit TRAF6, which interacts with TAB1/2/3 and TAK1 for the activation of NF‐κB and AP‐1. CD14 binds directly to LPS and induces a signal that leads to the activation of NFAT transcription factors. B) The LPS receptor complex is internalized through a CD14‐dependent mechanism, involving ITAM‐bearing molecules, Syk tyrosine kinase, and PLCγ2. Calcium mobilization from the extracellular space via TRPM7 is also required, at least in part. In the endosome, TRAM‐TRIF adaptor molecules bind to TRAF3, which interacts with TANK to recruit IKKs and TBK1, which activate IRF3