Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4 - PubMed (original) (raw)

Figure 1

Simplified model of lipopolysaccharide (LPS) signalling (the abbreviations used are defined at the end of the figure legend). Circulating LBP recognizes LPS in the plasma and brings it to CD14. This aids the loading of LPS onto the LPS receptor complex, which is composed of dimerized TLR4 receptors and two molecules of the extracellular adapter MD-2. Subsequent signals activated by TLR4 can be subdivided into those dependent on MyD88 (and Mal), which occur early (represented by the events illustrated on the right hand side of the diagram), and those independent of MyD88, which occur later and use the adapters TRIF and TRAM (depicted on the left). LPS signalling leads to the early activation of NF-κB, IRF3 and MAPK kinase pathways, which is mediated by the adapters MyD88 and Mal. After the subsequent activation and phosphorylation of IRAK, TRAF6 becomes activated, which gives rise to the expression of numerous pro-inflammatory genes. As a later response to LPS, TLR4 gives rise to the activation of TRAF6 and TBK1, an event mediated by the adapters TRIF and TRAM. Details of these interactions are given in the text. ST2, SIGIRR, MyD88s, IRAK-M, Tollip, IRAK2c and IRAK2d are negative regulators and are shown in red. Abbreviations: IFN, interferon; ΙΚΚ, ΙκB kinase; IRAK, interleukin-1 receptor-associated kinase; IRF, interferon response factor; ISRE, interferon-sensitive response element; LPS, lipopolysaccharide; LBP, LPS-binding protein; Mal, MyD88 adapter like; MAPK, mitogen-activated protein kinase; MKK, mitogen-activated protein kinase kinase; MyD88, myeloid differentiation marker; NF-κB, nuclear factor-κB; RIP, receptor interacting protein; SIGIRR, single immunoglobulin interleukin-1 receptor-related molecule; TBK, TANK-binding kinase; TLR, Toll-like receptor; ΤRΑF6, tumour necrosis factor receptor-associated factor; TRIF, TIR-containing adapter molecule; TRAM, TRIF-related adapter molecule; Tollip, TAB, TAK-1 binding protein; TAK, transforming growth factor-β-activated kinase. Uev1a/Ubc13 are TRAF6 ubiquitin ligases.