p62:MEKK3 binds to TRAF6 IRAK4-activated IRAK1 autophosphorylates IRAK4 phosphorylates IRAK1 Hyperphosphorylated IRAK1 associates with TRAF6 IRAK2 is phosphorylated downstream of IRAK4 following IL1 receptor activation The Interleukin 1 receptor complex binds Tollip IL1R1:IL1:IL1RAP:MYD88 homodimer binds IRAK4 IRAK1 binds to MYD88 within the IL1R complex IRAK4 is activated by autophosphorylation IL1R1:IL1:IL1RAP binds MYD88 homodimer IL1 receptor antagonist protein binds Interleukin 1 receptors Interleukin-1 receptor type 1: Interleukin 1 binds Interleukin-1 receptor accessory protein, membrane associated isoform Interleukin-1 receptor type 2 binds Interleukin 1 Interleukin-1 receptor type 1 binds Interleukin 1 TPL2 phosphorylates MEK1, SEK1 The SCF betaTrCP complex binds p-NFkB p105 NFKB p105, TPL2 (COT) and ABIN2 form a stable complex Beta-TrCP ubiquitinates then dissociates from p-NFKB p105 IRAK1 and 4 interact with Pellino1,2 and 3 TAK1 is activated within the TAK1 complex Polyubiquitinated TRAF6 interacts with TAK1 complex TRAF6 auto-ubiquitinates with Lys63-linked polyubiquitin chains The IKKB complex phosphorylates NFkB p105 NEMO binds polyubiquitinated IRAK1 Pellino ubiquitinates IRAK1 IRAK1 and 4 can phosphorylate Pellino-1 and 2. IRAK1 induces oligomerisation of TRAF6 TRAF6 binding leads to IRAK1:TRAF6 release TAK1 phosphorylates MKK6 PathwayStep6877 PathwayStep7107 PathwayStep7108 PathwayStep7109 PathwayStep7115 PathwayStep7114 PathwayStep7117 PathwayStep7116 PathwayStep7111 PathwayStep7110 PathwayStep7113 PathwayStep7112 PathwayStep7106 PathwayStep7105 PathwayStep7104 PathwayStep7129 PathwayStep7131 PathwayStep7130 PathwayStep7118 PathwayStep7119 PathwayStep7124 PathwayStep7123 PathwayStep7122 PathwayStep7121 PathwayStep7128 PathwayStep7127 PathwayStep7126 PathwayStep7125 PathwayStep7120 Interleukin-1 signaling Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-05-17 Interleukin 1 (IL1) signals via Interleukin 1 receptor 1 (IL1R1), the only signaling-capable IL1 receptor. This is a single chain type 1 transmembrane protein comprising an extracellular ligand binding domain and an intracellular region called the Toll/Interleukin-1 receptor (TIR) domain that is structurally conserved and shared by other members of the two families of receptors (Xu et al. 2000). This domain is also shared by the downstream adapter molecule MyD88. IL1 binding to IL1R1 leads to the recruitment of a second receptor chain termed the IL1 receptor accessory protein (IL1RAP or IL1RAcP) enabling the formation of a high-affinity ligand-receptor complex that is capable of signal transduction. Intracellular signaling is initiated by the recruitment of MyD88 to the IL-1R1/IL1RAP complex. IL1RAP is only recruited to IL1R1 when IL1 is present; it is believed that a TIR domain signaling complex is formed between the receptor and the adapter TIR domains. The recruitment of MyD88 leads to the recruitment of Interleukin-1 receptor-associated kinase (IRAK)-1 and -4, probably via their death domains. IRAK4 then activates IRAK1, allowing IRAK1 to autophosphorylate. Both IRAK1 and IRAK4 then dissociate from MyD88 (Brikos et al. 2007) which remains stably complexed with IL-1R1 and IL1RAP. They in turn interact with Tumor Necrosis Factor Receptor (TNFR)-Associated Factor 6 (TRAF6), which is an E3 ubiquitin ligase (Deng et al. 2000). TRAF6 is then thought to auto-ubiquinate, attaching K63-polyubiquitin to itself with the assistance of the E2 conjugating complex Ubc13/Uev1a. K63-pUb-TRAF6 recruits Transforming Growth Factor (TGF) beta-activated protein kinase 1 (TAK1) in a complex with TAK1-binding protein 2 (TAB2) and TAB3, which both contain nuclear zinc finger motifs that interact with K63-polyubiquitin chains (Ninomiya-Tsuji et al. 1999). This activates TAK1, which then activates inhibitor of NF-kappaB (IkappaB) kinase 2 (IKK2 or IKKB) within the IKK complex, the kinase responsible for phosphorylation of IkappaB. The IKK complex also contains the scaffold protein NF-kappa B essential modulator (NEMO). TAK1 also couples to the upstream kinases for p38 and c-jun N-terminal kinase (JNK). IRAK1 undergoes K63-linked polyubiquination; Pellino E3 ligases are important in this process. (Butler et al. 2007; Ordureau et al. 2008). The activity of these proteins is greatly enhanced by IRAK phosphorylation (Schauvliege et al. 2006), leading to K63-linked polyubiquitination of IRAK1. This recruits NEMO to IRAK1, with NEMO binding to polyubiquitin (Conze et al. 2008).<br><br>TAK1 activates IKKB (and IKK), resulting in phosphorylation of the inhibitory IkB proteins and enabling translocation of NFkB to the nucleus; IKKB also phosphorylates NFkB p105, leading to its degradation and the subsequent release of active TPL2 that triggers the extracellular-signal regulated kinase (ERK)1/2 MAPK cascade. TAK1 can also trigger the p38 and JNK MAPK pathways via activating the upstream MKKs3, 4 and 6. The MAPK pathways activate a number of downstream kinases and transcription factors that co-operate with NFkB to induce the expression of a range of TLR/IL-1R-responsive genes. There are reports suggesting that IL1 stimulation increases nuclear localization of IRAK1 (Bol et al. 2000) and that nuclear IRAK1 binds to the promoter of NFkB-regulated gene and IkBa, enhancing binding of the NFkB p65 subunit to NFkB responsive elements within the IkBa promoter. IRAK1 is required for IL1-induced Ser-10 phosphorylation of histone H3 in vivo (Liu et al. 2008). However, details of this aspect of IRAK1 signaling mechanisms remain unclear. Pubmed10094049 Pubmed10899313 Pubmed11057907 Pubmed11081518 Pubmed16884718 Pubmed17507369 Pubmed17675297 Pubmed17997719 Pubmed18276832 Pubmed18347055 Pubmed19022706 Pubmed19161412 Pubmed19302047 Reactome Database ID Release 43446652 Reactome, http://www.reactome.org ReactomeREACT_22442 Reviewed: Pinteaux, E, 2010-05-17 PathwayStep3436 Activated TAK1 mediates phosphorylation of the IKK Complex