Interleukin-1 family signaling (Homo sapiens)

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1, 29, 1020235, 63441731-33181624-2836-38211915243126, 2930334, 35358, 98, 13112214127cytosolIL1 receptor complex:TOLLIPTPL2p62:MEKK3TAK1 complexIL1R1ATPIRAK-MTOLLIPIL1R2p62:MEKK3:TRAF6Poly-K6-Ub-hp-IRAK1IL1 receptor complex- activated IRAK4:TOLLIP:p-IRAK1ATPNFkB p105IKK complexp-Pellino-1,2,(3)ADPhp-IRAK1:p-Pellino, IRAK4:p-PellinoATPIL1:IL1R1:IL1RAP:MYD88 homodimerhp-IRAK1:K6-poly-Ub oligo-TRAF6:TAK1 complexPellino 1,2,3Interleukin-1 receptor type 1:Interleukin-1p-IRAK2ATPInterleukin 1 receptors:IL1RNADPADPATPATPPoly-K6-Ub-hp-IRAK1:IKK complexADPATPActivated IRAK4Ubc13/Uev1A complexIRAK4Interleukin-1hp-IRAK1: p-Pellino-1,2,(3)IL1RNMEK1, SEK1IL1 receptor complex-activated IRAK4:TOLLIP:hp-IRAK:TRAF6hp-IRAK1:Pellino, IRAK4:PellinoMKK6IRAK2Phospho MKK6Ub-p-NFkB1 p105TRAF6IL1 receptor complex- activated IRAK4:TOLLIP:hp-IRAK1mIL1RAPhp-IRAK1:oligo-TRAF6Phospho-MEK1, phospho-SEK1NFKB p105:TPL2:ABIN2hp-IRAK1:TRAF6IL1 receptor complexp-NFkB p105K63-polyubiquitinMYD88 homodimerhp-IRAK1, IRAK4ABIN2ADPATPADPIL1 receptor complex - activated IRAK4:TOLLIPIRAK1hp-IRAK1:K6 poly-Ub oligo-TRAF6IL1BActivated TAK complexesIL1 receptor complex-activated IRAK4:TOLLIP:IRAK1SCF beta-TrCP complexSCF betaTrCP complex:p-NFKB p105Interleukin 1 receptor type 2:interleukin 1Interleukin 1 receptorsActivated IKK ComplexIL1R1:IL1:IL1RAPhp-IRAK1:K6-poly-Ub oligo-TRAF6:Activated TAK1 complexADPADP


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.

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  95. Heissmeyer V, Krappmann D, Hatada EN, Scheidereit C.; ''Shared pathways of IkappaB kinase-induced SCF(betaTrCP)-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and IkappaBalpha.''; PubMed Europe PMC Scholia
  96. Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV.; ''TRAF6 is a signal transducer for interleukin-1.''; PubMed Europe PMC Scholia
  97. Lang V, Janzen J, Fischer GZ, Soneji Y, Beinke S, Salmeron A, Allen H, Hay RT, Ben-Neriah Y, Ley SC.; ''betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932.''; PubMed Europe PMC Scholia
  98. Khan JA, Brint EK, O'Neill LA, Tong L.; ''Crystal structure of the Toll/interleukin-1 receptor domain of human IL-1RAPL.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
114671view16:14, 25 January 2021ReactomeTeamReactome version 75
113118view11:18, 2 November 2020ReactomeTeamReactome version 74
112352view15:28, 9 October 2020ReactomeTeamReactome version 73
101253view11:14, 1 November 2018ReactomeTeamreactome version 66
100792view20:42, 31 October 2018ReactomeTeamreactome version 65
100334view19:19, 31 October 2018ReactomeTeamreactome version 64
99879view16:02, 31 October 2018ReactomeTeamreactome version 63
99436view14:37, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99023view13:07, 24 October 2018DeSlOntology Term : 'signaling pathway' added !
99022view13:06, 24 October 2018DeSlOntology Term : 'kinase mediated signaling pathway' added !
94504view09:20, 14 September 2017Mkutmonreactome version 61
86604view09:22, 11 July 2016ReactomeTeamreactome version 56
83129view10:03, 18 November 2015ReactomeTeamVersion54
81471view13:00, 21 August 2015ReactomeTeamVersion53
76943view08:21, 17 July 2014ReactomeTeamFixed remaining interactions
76648view12:02, 16 July 2014ReactomeTeamFixed remaining interactions
75978view10:03, 11 June 2014ReactomeTeamRe-fixing comment source
75681view11:01, 10 June 2014ReactomeTeamReactome 48 Update
75036view13:54, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74838view10:06, 30 April 2014ReactomeTeamReactome46
74680view08:45, 30 April 2014ReactomeTeamReactome46
44873view10:01, 6 October 2011MartijnVanIerselOntology Term : 'interleukin-1 signaling pathway' added !
44872view10:00, 6 October 2011MartijnVanIerselOntology Term : 'PW:0000512' removed !
44869view09:59, 6 October 2011MartijnVanIerselOntology Term : 'Interleukin mediated signaling pathway' added !
42058view21:53, 4 March 2011MaintBotAutomatic update
39865view05:53, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ABIN2 ProteinQ8NFZ5 (UniProt)
ADP Metabolite16761 (ChEBI)
ATP Metabolite15422 (ChEBI)
Activated IKK

Complex

ComplexREACT_7826 (Reactome)
Activated IRAK4 ProteinQ9NWZ3 (UniProt)
Activated TAK

complexes

ComplexREACT_23279 (Reactome)
IKK complex ComplexREACT_7693 (Reactome)
IL1 receptor

complex

ComplexREACT_23029 (Reactome)
IL1 receptor

complex- activated IRAK4:TOLLIP:hp- IRAK1

ComplexREACT_23332 (Reactome)
IL1 receptor

complex- activated IRAK4:TOLLIP:p- IRAK1

ComplexREACT_23087 (Reactome)
IL1 receptor

complex-activated IRAK4:TOLLIP:IRAK1

ComplexREACT_22771 (Reactome)
IL1 receptor

complex-activated IRAK4:TOLLIP:hp- IRAK:TRAF6

ComplexREACT_22757 (Reactome)
IL1 receptor

complex:TOLLIP

ComplexREACT_23348 (Reactome)
IL1 receptor complex

- activated IRAK4: TOLLIP

ComplexREACT_23002 (Reactome)
IL1:IL1R1:IL1RAP:

MYD88 homodimer

ComplexREACT_23167 (Reactome)
IL1B ProteinP01584 (UniProt)
IL1R1 ProteinP14778 (UniProt)
IL1R1:IL1:IL1RAP ComplexREACT_22656 (Reactome)
IL1R2 ProteinP27930 (UniProt)
IL1RN ProteinP18510 (UniProt)
IRAK-M ProteinQ9Y616 (UniProt)
IRAK1 ProteinP51617 (UniProt)
IRAK2 ProteinO43187 (UniProt)
IRAK4 ProteinQ9NWZ3 (UniProt)
Interleukin 1

receptor type 2: interleukin 1

ComplexREACT_22786 (Reactome)
Interleukin 1

receptors

ProteinREACT_23342 (Reactome)
Interleukin 1

receptors:IL1RN

ComplexREACT_22878 (Reactome)
Interleukin-1 ProteinREACT_22576 (Reactome)
Interleukin-1

receptor type 1: Interleukin-1

ComplexREACT_23118 (Reactome)
K63-polyubiquitin UnknownREACT_21645 (Reactome)
MEK1, SEK1 ProteinREACT_22657 (Reactome)
MKK6 ProteinP52564 (UniProt)
MYD88 homodimer ComplexREACT_14253 (Reactome)
NFKB p105:TPL2:

ABIN2

ComplexREACT_22747 (Reactome)
NFkB p105 ProteinP19838 (UniProt)
Pellino 1,2,3 ProteinREACT_22780 (Reactome)
Phospho MKK6 ProteinP52564 (UniProt)
Phospho-MEK1,

phospho-SEK1

ProteinREACT_22945 (Reactome)
Poly-K6-Ub-

hp-IRAK1

ComplexREACT_23323 (Reactome)
Poly-K6-Ub-hp-

IRAK1:IKK complex

ComplexREACT_22624 (Reactome)
SCF beta-TrCP

complex

ComplexREACT_22981 (Reactome)
SCF betaTrCP

complex:p-NFKB p105

ComplexREACT_22646 (Reactome)
TAK1 complex ComplexREACT_22633 (Reactome)
TOLLIP ProteinQ9H0E2 (UniProt)
TPL2 ProteinP41279 (UniProt)
TRAF6 ProteinQ9Y4K3 (UniProt)
Ub-p-NFkB1 p105 ProteinP19838 (UniProt)
Ubc13/Uev1A

complex

ComplexREACT_12995 (Reactome)
hp-IRAK1, IRAK4 ProteinREACT_23241 (Reactome)
hp-IRAK1: p-Pellino-

1,2,(3)

ComplexREACT_22866 (Reactome)
hp-IRAK1:K6 poly-

Ub oligo-TRAF6

ComplexREACT_23272 (Reactome)
hp-IRAK1:K6-poly-

Ub oligo-TRAF6: Activated TAK1 complex

ComplexREACT_23314 (Reactome)
hp-IRAK1:K6-poly-

Ub oligo-TRAF6: TAK1 complex

ComplexREACT_22797 (Reactome)
hp-IRAK1:Pellino,

IRAK4:Pellino

ComplexREACT_23330 (Reactome)
hp-IRAK1:TRAF6 ComplexREACT_22529 (Reactome)
hp-IRAK1:oligo-

TRAF6

ComplexREACT_22793 (Reactome)
hp-IRAK1:p-Pellino,

IRAK4:p-Pellino

ComplexREACT_22769 (Reactome)
mIL1RAP ProteinQ9NPH3-1 (UniProt)
p-IRAK2 ProteinO43187 (UniProt)
p-NFkB p105 ProteinP19838 (UniProt)
p-Pellino-1,2,(3) ProteinREACT_22733 (Reactome)
p62:MEKK3 ComplexREACT_23211 (Reactome)
p62:MEKK3:TRAF6 ComplexREACT_23141 (Reactome)

Annotated Interactions

No annotated interactions

Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP1839"
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