Interleukin-1 family signaling (Homo sapiens)
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Description
IL1B and IL18, are produced as biologically inactive propeptides that are cleaved to produce the mature, active interleukin peptide.
The IL1 receptor (IL1R) family comprises 10 members: Interleukin-1 receptor type 1 (IL1R1, IL1RA), Interleukin-1 receptor type 2 (IL1R2, IL1RB), Interleukin-1 receptor accessory protein (IL1RAP, IL1RAcP, IL1R3), Interleukin-18 receptor 1 (IL18R1, IL18RA) , Interleukin-18 receptor accessory protein (IL18RAP, IL18RB), Interleukin-1 receptor-like 1 (IL1RL1, ST2, IL33R), Interleukin-1 receptor-like 2 (IL1RL2, IL36R), Single Ig IL-1-related receptor (SIGIRR, TIR8), Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1, TIGGIR2) and X-linked interleukin-1 receptor accessory protein-like 2 (IL1RAPL2, TIGGIR1). Most of the genes encoding these receptors are on chromosome 2. IL1 family receptors heterodimerize upon cytokine binding. IL1, IL33 and IL36 bind specific receptors, IL1R1, IL1RL1, and IL1RL2 respectively. All use IL1RAP as a co-receptor. IL18 binds IL18R1 and uses IL18RAP as co-receptor.
The complexes formed by IL1 family cytokines and their heterodimeric receptors recruit intracellular signaling molecules, including Myeloid differentiation primary response protein MyD88 (MYD88), members of he IL1R-associated kinase (IRAK) family, and TNF receptor-associated factor 6 (TRAF6), activating Nuclear factor NF-kappa-B (NFκB), as well as Mitogen-activated protein kinase 14 (MAPK14, p38), c-Jun N-terminal kinases (JNKs), extracellular signal-regulated kinases (ERKs) and other Mitogen-activated protein kinases (MAPKs).
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by phosphorylation and activation of
IKKs complexoligo-TRAF6:TAK1
complexAnnotated Interactions
This 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.
After IL33:IL1RL1 ligand binding, IL1RL1 undergoes a conformational change, which allows the recruitment of IL1RAP-1 (Lingel et al. 2009, Liu et al. 2013).
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).
A20-binding inhibitor of NFkappaB2 (ABIN-2 ot TNIP2) interacts with Tpl2 and p105 but preferentially forms a ternary complex with both proteins. As ABIN2 is a polyubiquitin binding protein, it has been suggested that it may facilitate recruitment of the p105/Tpl2 complex to the activated IKK complex, allowing IKK2 induced p105 phosphorylation and consequent Tpl2 activation.
Positions of phosphorylations represented here are inferred from general experimental data (Zheng & Guan, 1994).
The catalytic subunit of MAP3K8 (TPL2) was reported to undergo phosphorylation at Thr290 in human embryonic kidney 293 (HEK293) cells transfected with MAP3K8 (Luciano BS et al. 2004; Cho J et al. 2005; Stafford MJ et al. 2006). Mutation of this residue to alanine prevented the LPS-stimulated activation of MAP3K8 in mouse macrophages (Cho J et al. 2005). Experiments with a small-molecule inhibitor of MAP3K8 have suggested that Thr290 is autophosphosphorylated after IL-1 beta stimulation of IL-1R-expressing HEK293T cells (Handoyo H et al. 2009). However, a catalytically inactive mutant of MAP3K8 (Tpl2-K167M) was reported to become phosphorylated at Thr290 in transfected HEK-293 cells, suggesting that Thr290 phosphorylation did not occur as a result of autophosphorylation (Cho J et al. 2005) In addition, the phosphorylation at Thr290 was also reported to be catalysed by IKBKB, based on small interfering RNA(siRNA)-knockdown studies and the use of high concentrations of the IKBKB inhibitor PS1145 (Cho J et al. 2005). However, the other work showed that lower concentrations of PS1145, but nevertheless sufficient to completely inhibit IKBKB, did not affect the IL-1-stimulated phosphorylation of transfected MAP3K8 at Thr290, suggesting that the IL-1 beta stimulated phosphorylation of Thr290 is catalysed by a protein kinase distinct from IKBKB. (Stafford MJ et al. 2006). Thus, phosphorylation at Thr290 is required for the physiological activation of MAP3K8 by external signals, although the mode of the modification remains to be clarified.
Activation of MAP3K8 may also occur trough phosphorylation on Ser62 and Ser400 (Stafford MJ et al. 2006; Roget K et al. 2012).
This is a black box event because the mechanism of gene regulation is not fully defined.
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