Figure 2

Canonical activation of NFkB by Toll-like receptor and IL-1 receptor. The family of Toll-like receptors (TLRs) comprises 13 members, of which TLR4, TLR5, TLR7 and TLR9 are the most important. All TLRs have leucine-rich repeat motifs in their extracellular domain, which recognize distinct microbial patterns such as lipopolysaccharide, flaggellin, viral double-stranded RNA and unmethylated CpG motifs. The IL-1 receptor subfamily is characterized by immunoglobin-like structures in their extracellular binding domain. Generally, binding of the ligand to the TLR or to IL-1 receptor (IL-1R) activates the receptor and leads to the recruitment of adaptor proteins like myeloid differentiation primary response gene 88 (MyD88). Next, MyD88 recruits downstream adaptor molecules like IL-1 receptor-associated kinase 1 and 4 (IRAK1 and IRAK4). IRAK4 is autophosphorylated and phosphorylates IRAK1. Activation of IRAK1 allows binding of TNF receptor-associated factor 6 (TRAF6) to the complex. Further, the conformation of the complex changes, which leads to release of the IRAK1-TRAF6 complex from the receptor complex and the association with another membrane-associated complex, composed of transforming growth factor-beta activated kinase-1 (TAK1), TAK1-binding protein 1 (TAB1) and TAB2. Subsequently, TAB2 and TAK1 are phosphorylated and, together with TRAF6 and TAB1, these two units are translocated into the cytosol. IRAK1 is poly-ubiquitinated and degraded by the proteasome. In the cytoplasm, TRAF6 associates with Ubc13/Uev1A, which is an E2 ubiquitin-conjugating enzyme complex. K63-linked poly-ubiquitination of TRAF6 is necessary for binding to and activation of TAK1, which in turn phosphorylates and activates inhibitor of NFκB kinases (IKK) and stimulates a c-Jun NH2-terminal kinase (JNK). Inhibitor of NF B a-protein (IκBα) is degraded and NFκB is free to translocate to the nucleus. As such, NFκB is able to regulate gene transcription. MAP, mitogen-activated protein; P, phosphogroup; Ub, ubiquitin.