TAK1 also phosphorylates and activates the IκB kinase (IKK) complex, which is composed of three proteins: IKKα, IKKβ, and IKKγ (also known as NEMO, for NFκB essential modifier). NEMO functions by binding to polyubiquitin chains, which brings the IKK complex into proximity with TAK1. TAK1
Pattern recognition by cells of the innate immune system.
NF˜B NF˜B p50 p65 I˜B I˜B I˜B degradation cytokine genes TRAF-6 UBC13, Uve1A MyD88 MAL nucleus TAK1 TAK1 TAB1/2 TAB1/2 IRAK4IRAK1 (E3 ligase) (E2 ligase) ubiquitin polyubiquitin chain IKK° IKK˛IKK˝ (NEMO) IKK˝ IKK°/˛ IKK I˜B is degraded, releasing NF˜B into the nucleus to induce expression of cytokine genes TAK1 associates with IKK and phosphorylates IKK°, which phosphorylates I˜B TRAF-6 is polyubiquitinated, creating a scaffold for activation of TAK1 Dimerized TLRs recruit IRAK1 and IRAK4, activating the E3 ubiquitin ligase TRAF-6
Fig. 3.15 TLR signaling can activate the transcription factor NFκB, which induces the expression of pro-inflammatory cytokines. First panel: TLRs signal via their cytoplasmic TIR domains, which are brought into proximity to each other by ligand-induced dimerization of their ectodomains. Some TLRs use the adaptor protein MyD88, and others use the MyD88/MAL pair to initiate signaling. The MyD88 death domain recruits the serine–threonine kinases IRAK1 and IRAK4, in association with the ubiquitin E3 ligase TRAF-6. IRAK undergoes autoactivation and phosphorylates TRAF-6, activating its E3 ligase activity. Second panel: TRAF-6 cooperates with an E2 ligase (UBC13) and a cofactor (Uve1A) to generate polyubiquitin scaffolds (yellow triangles) by attachment of ubiquitin through its lysine 63 (K63). This scaffold recruits a complex of proteins composed of the kinase TAK1 (transforming growth factor-β-activated kinase 1) and two adaptor proteins, TAB1 (TAK1-binding protein 1) and TAB2. TAB1 and TAB2 function to bind to polyubiquitin, bringing TAK1 into proximity with IRAK to become phosphorylated (red dot). Third panel: activated TAK1 activates IKK, the IκB kinase complex. First, the IKKγ subunit (NEMO) binds to the polyubiquitin scaffold and brings the IKK complex into proximity to TAK1. TAK1 then phosphorylates and activates IKKβ. IKKβ then phosphorylates IκB, the cytoplasmic inhibitor of NFκB. Fourth panel: phosphorylated IκB is targeted by a process of ubiquitination (not shown) that leads to its degradation. This releases NFκB, which is composed of two subunits, p50 and p65, into the nucleus, driving the transcription of many genes including those encoding inflammatory cytokines. TAK1 also stimulates activation of the mitogen-activated protein kinases (MAPKs) JNK and p38, which phosphorylate and activate AP-1 transcription factors (not shown).