Interleukin-1 family signaling (Homo sapiens)
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Description
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. View original pathway at:Reactome.
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. View original pathway at:Reactome.
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DataNodes
receptor complex- activated
IRAK4:TOLLIP:hp-IRAK1receptor complex- activated
IRAK4:TOLLIP:p-IRAK1receptor complex-activated
IRAK4:TOLLIP:hp-IRAK:TRAF6complex-activated
IRAK4:TOLLIP:IRAK1- activated
IRAK4:TOLLIPreceptor type
2:interleukin 1receptor type
1:Interleukin-1(TPL2)-dependent
MAPK1/3 activationIn the absence of extra-cellular signals, cytosolic MAP3K8 (TPL2) is held inactive in the complex with ABIN2 (TNIP2) and NFkB p105 (NFKB1) (Beinke S et al., 2003; Waterfield MR et al., 2003; Lang V et al., 2004). This interaction stabilizes MAP3K8 (TPL2) but also prevents MAP3K8 and NFkB from activating their downstream signaling cascades by inhibiting the kinase activity of MAP3K8 and the proteolysis of NFkB precursor protein p105. Upon activation of MAP3K8 by various stimuli (such as LPS, TNF-alpha, and IL-1 beta), IKBKB phosphorylates NFkB p105 (NFKB1) at Ser927 and Ser932, which trigger p105 proteasomal degradation and releases MAP3K8 from the complex (Beinke S et al., 2003, 2004; Roget K et al., 2012). Simultaneously, MAP3K8 is activated by auto- and/or transphosphorylation (Gantke T et al. 2011; Yang HT et al. 2012). The released active MAP3K8 phosphorylates its substrates, MAP2Ks. The free MAP3K8, however, is also unstable and is targeted for proteasome-mediated degradation, thus restricting prolonged activation of MAP3K8 (TPL2) and its downstream signaling pathways (Waterfield MR et al. 2003; Cho J et al., 2005). Furthermore, partially degraded NFkB p105 (NFKB1) into p50 can dimerize with other NFkB family members to regulate the transcription of target genes.
MAP3K8 activity is thought to regulate the dynamics of transcription factors that control an expression of diverse genes involved in growth, differentiation, and inflammation. Suppressing the MAP3K8 kinase activity with selective inhibitors, such as C8-chloronaphthyridine-3-carbonitrile, caused a significant reduction in TNFalpha production in LPS- and IL-1beta-induced both primary human monocytes and human blood (Hall JP et al. 2007). Similar results have been reported for mouse LPS-stimulated RAW264.7 cells (Hirata K et al. 2010). Moreover, LPS-stimulated macrophages derived from Map3k8 knockout mice secreted lower levels of pro-inflammatory cytokines such as TNFalpha, Cox2, Pge2 and CXCL1 (Dumitru CD et al. 2000; Eliopoulos AG et al. 2002). Additionally, bone marrow-derived dendritic cells (BMDCs) and macrophages from Map3k8 knockout mice showed significantly lower expression of IL-1beta in response to LPS, poly IC and LPS/MDP (Mielke et al., 2009). However, several other studies seem to contradict these findings and Map3k8 deficiency in mice has been also reported to enhance pro-inflammatory profiles. Map3k8 deficiency in LPS-stimulated macrophages was associated with an increase in nitric oxide synthase 2 (NOS2) expression (López-Peláez et al., 2011). Similarly, expression of IRAK-M, whose function is to compete with IL-1R-associated kinase (IRAK) family of kinases, was decreased in Map3k8-/- macrophages while levels of TNF and IL6 were elevated (Zacharioudaki et al., 2009). Moreover, significantly higher inflammation level was observed in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated Map3k8-/- mouse skin compared to WT skin (DeCicco-Skinner K. et al., 2011). Additionally, MAP3K8 activity is associated with NFkB inflammatory pathway. High levels of active p65 NFkB were observed in the nucleus of Map3k8 -/- mouse keratinocytes that dramatically increased within 15-30 minutes of TPA treatment. Similarly, increased p65 NFkB was observed in Map3k8-deficient BMDC both basally and after stimulation with LPS when compared to wild type controls (Mielke et al., 2009). The data opposes the findings that Map3k8-deficient mouse embryo fibroblasts and human Jurkat T cells with kinase domain-deficient protein have a reduction in NFkB activation but only when certain stimuli are administered (Lin et al., 1999; Das S et al., 2005). Thus, it is possible that whether MAP3K8 serves more of a pro-inflammatory or anti-inflammatory role may depend on cell- or tissue type and on stimuli (LPS vs. TPA, etc.) (Mielke et al., 2009; DeCicco-Skinner K. et al., 2012).
MAP3K8 has been also studied in the context of carcinogenesis, however the physiological role of MAP3K8 in the etiology of human cancers is also convoluted (Vougioukalaki M et al., 2011; DeCicco-Skinner K. et al., 2012).
IKBA:SCF beta-TrCP
complexoligo-TRAF6:TAK1
complexAnnotated Interactions
receptor complex- activated
IRAK4:TOLLIP:hp-IRAK1receptor complex- activated
IRAK4:TOLLIP:hp-IRAK1receptor complex- activated
IRAK4:TOLLIP:p-IRAK1receptor complex- activated
IRAK4:TOLLIP:p-IRAK1receptor complex- activated
IRAK4:TOLLIP:p-IRAK1receptor complex-activated
IRAK4:TOLLIP:hp-IRAK:TRAF6receptor complex-activated
IRAK4:TOLLIP:hp-IRAK:TRAF6complex-activated
IRAK4:TOLLIP:IRAK1complex-activated
IRAK4:TOLLIP:IRAK1complex-activated
IRAK4:TOLLIP:IRAK1- activated
IRAK4:TOLLIP- activated
IRAK4:TOLLIP- activated
IRAK4:TOLLIPreceptor type
2:interleukin 1receptor type
1:Interleukin-1receptor type
1:Interleukin-1IKBA:SCF beta-TrCP
complexIKBA:SCF beta-TrCP
complexThis basic trimolecular complex is referred to as the IKK complex. Each catalytic IKK subunit has an N-terminal kinase domain and leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-terminal NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs.
IKK beta is the major IKK catalytic subunit for NF-kB activation. Phosphorylation in the activation loop of IKK beta requires Ser177 and Ser181 and thus activates the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.
Though not clearly demonstrated and therefore not shown here, the current models of IRAK1 involvement suggest it would be within a complex including TRAF6.
Though not shown here, the current models of IRAK1 involvement suggest it is part of a complex that includes TRAF6.
Pellino1-3 possess E3 ligase activity and are believed to directly catalyse polyubiquitylation of IRAK1 (Xiao et al. 2008; Butler et al. 2007; Ordureau et al. 2008). They are capable of catalysing the formation of K63- and K48-linked polyubiquitin chains; the type of linkage is controlled by the collaborating E2 enzyme. All the Pellino proteins can combine with the E2 heterodimer UBE2N:UBE2V1 (Ubc13:Uev1a) to catalyze K63-linked ubiquitylation (Ordureau et al. 2008).
Pellino1-3 possess E3 ligase activity and are believed to directly catalyse polyubiquitylation of IRAK1 (Xiao et al. 2008; Butler et al. 2007; Ordureau et al. 2008). They are capable of catalysing the formation of K63- and K48-linked polyubiquitin chains; the type of linkage is controlled by the collaborating E2 enzyme. All the Pellino proteins can combine with the E2 heterodimer UBE2N:UBE2V1 (Ubc13:Uev1a) to catalyze K63-linked ubiquitylation (Ordureau et al. 2008).
IRAK1 polyubiquitination was originally thought to tag IRAK1 for proteolysis by the proteasome, but more recently has been shown to involve K63-linked, not K48-linked polyubiquitination (Windheim et al. 2008; Conze et al. 2008), which is believed to have a scaffoling function. IRAK1 is ubiquitinated on K134 and K180; mutation of these sites impairs IL1R-mediated ubiquitination of IRAK1 (Conze et al. 2008). Some authors have proposed a role for TRAF6 as the E3 ubiquitin ligase that catalyzes polyubiquitination of IRAK1 (Conze et al. 2008) but this view has been refuted (Windheim et al. 2008, Xiao et al. 2008). The current consensus is that Pellino proteins are the physiologically-relevant IRAK1 E3 ubiquitin ligases.oligo-TRAF6:TAK1
complexoligo-TRAF6:TAK1
complex