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Details on Person Interleukin 1 (IL1) signals via Interleukin 1 receptor 1 (IL...
| Class:Id | Summation:451689 |
|---|---|
| _displayName | Interleukin 1 (IL1) signals via Interleukin 1 receptor 1 (IL... |
| _timestamp | 2017-07-24 13:25:15 |
| created | [InstanceEdit:451663] Jupe, S, 2010-01-08 |
| literatureReference | [LiteratureReference:507711] Structural basis for signal transduction by the Toll/interleukin-1 receptor domains [LiteratureReference:451666] The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress [LiteratureReference:446653] Mass spectrometric analysis of the endogenous type I interleukin-1 (IL-1) receptor signaling complex formed after IL-1 binding identifies IL-1RAcP, MyD88, and IRAK-4 as the stable components [LiteratureReference:208040] Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain [LiteratureReference:451682] The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway [LiteratureReference:450692] The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1 [LiteratureReference:450816] Kinase-active interleukin-1 receptor-associated kinases promote polyubiquitination and degradation of the Pellino family: direct evidence for PELLINO proteins being ubiquitin-protein isopeptide ligases [LiteratureReference:451409] Pellino proteins are more than scaffold proteins in TLR/IL-1R signalling: a role as novel RING E3-ubiquitin-ligases [LiteratureReference:450158] Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation [LiteratureReference:507720] Translocation of the interleukin-1 receptor-associated kinase-1 (IRAK-1) into the nucleus [LiteratureReference:507718] Interleukin-1 receptor-associated kinase (IRAK) -1-mediated NF-kappaB activation requires cytosolic and nuclear activity [LiteratureReference:9013275] Expression of interleukin-18 receptor in fibroblast-like synoviocytes [LiteratureReference:448595] IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines [LiteratureReference:9013258] IL-37 requires IL-18Rα and SIGIRR/IL-1R8 to diminish allergic airway inflammation in mice [LiteratureReference:8981647] Structural and Functional Attributes of the Interleukin-36 Receptor [LiteratureReference:8863040] IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist [LiteratureReference:9010017] Cloning and characterization of IL-1HY2, a novel interleukin-1 family member |
| modified | [InstanceEdit:451699] Jupe, S, 2010-01-08 [InstanceEdit:507710] Jupe, S, 2010-02-08 [InstanceEdit:561119] Jupe, S, 2010-03-25 [InstanceEdit:561122] Jupe, S, 2010-03-25 [InstanceEdit:744684] Jupe, S, 2010-05-17 [InstanceEdit:9013296] Duenas, Corina, 2017-07-24 |
| text | 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). 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. Interleukin-18 is another Interleukin-1 related cytokine which signals through IL18R and IL18RAP subunit receptors (which share homology with IL1R and IL1RAP in the cytokine signaling cascade). Later it follows a MYD88/IRAK1/TRAF6 cascade signaling until reach the NFKB activation (Moller et al. 2002). Interleukin 33, 36, 37 and 38 are relatively recently discovered Interleukin-1 related citokines which are also able to signal through IL1 receptor subunits or other as IL18R, IL37R (Schmitz et al. 2005, Yi et al. 2016, Lunding et al. 2015, van de Veendorck et al. 2012, Lin et al. 2001). |
| (summation) | [Pathway:9020702] Interleukin-1 signaling [Homo sapiens] |
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