MyD88-independent TLR4 cascade (Homo sapiens)

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491, 25, 27138, 45, 561, 4231, 37, 5913, 20, 21, 26, 29...19, 261, 3, 171613, 20, 26, 29, 33...7, 12, 164, 353718, 34, 4138, 45, 5523, 577, 26, 30, 36, 5413, 20, 26, 3928, 4117, 25, 38, 44, 5210, 11, 32, 615TLR4MD2LPSCD14 IKKAIKKBNEMO TRIFTRAMTLR4MD2LPSCD14 TRIFactivated TLR3/TLR4 active caspase-8 activated TLR4/TLR3TRIFK63-pUb-RIP1 viral dsRNATLR3TRIF TLR4MD2LPSCD14 TRAMTLR4MD2LPSCD14 TLR4MD2 TRAMTLR4MD2LPSCD14 TRIFTRAMTLR4MD2LPSCD14 TAB2/3 TLR4MD2 TRIFTRAMTLR4MD2LPSCD14 TLR4MD2LPSCD14 TAB2/3 TRIFTRAMTLR4MD2LPSCD14 TAB1TAB2/TAB3TAK1 TLR4MD2LPSCD14 TRIFTRAMTLR4MD2LPSCD14 viral dsRNA TLR3 TRAMTLR4MD2LPSCD14 viral dsRNA TLR3 activated TLR4/TLR3TRIFK63-pUb-RIP1 pUb-TRAF6TAB1TAB2/TAB3free polyubiquitin chain phospho-TAK1 TLR4MD2 cytosolviral dsRNATLR3TRIF TRAMTLR4MD2LPSCD14 viral dsRNATLR3TRIF TAB2/3 activated TLR4/TLR3TRIFK63-pUb-TRAF6free K63-linked pUbTAK1complex viral dsRNATLR3TRIF viral dsRNATLR3TRIF activated TLR3/4TRIFK63-poly-Ub-TRAF3p-TBK1/p-IKKEIRF3/IRF7 SARMTRIFactivated TLR3/TLR4 viral dsRNATLR3TRIF TRIFactivated TLR3/TLR4 TLR4MD2LPSCD14 viral dsRNA TLR3 TRAMTLR4MD2LPSCD14 TRAMTLR4MD2LPSCD14 TRIFTRAMTLR4MD2LPSCD14 TRIFactivated TLR3/TLR4 TLR4MD2 TRAMTLR4MD2LPSCD14 TRIFTRAMTLR4MD2LPSCD14 viral dsRNA TLR3 Caspase-8 dimer TRIFactivated TLR3/TLR4 K63-poly-Ub-TRAF3TRIFactivated TLR3/TLR4 TLR4MD2LPSCD14 activated TBK1/IKK epsilon p-2S-IRF7p-2S-IRF7 activated TLR4/TLR3TRIFTRAF6 TLR4MD2 TRIFTRAMTLR4MD2LPSCD14 TLR4MD2 TRAMTLR4MD2LPSCD14 viral dsRNATLR3TRIF TRAMTLR4MD2LPSCD14 TLR4MD2LPSCD14 TLR4MD2LPSCD14 TRIFactivated TLR3/TLR4 IRF3/ IRF7 TRIFTRAMTLR4MD2LPSCD14 viral dsRNA TLR3 TRIFTRAMTLR4MD2LPSCD14 TLR4MD2 TRAMTLR4MD2LPSCD14 TLR4MD2 K63-poly-Ub-TRAF3TRIFactivated TLR3/TLR4 phosphorylated IRF3 and/or IRF7 dimer TRIFTRAMTLR4MD2LPSCD14 TRAMTLR4MD2LPSCD14 TRIFTRAMTLR4MD2LPSCD14 viral dsRNATLR3TRIF TRIFTRAMTLR4MD2LPSCD14 activated TBK1/IKK epsilon viral dsRNA TLR3 activated TLR3/TLR4TRIFRIP1FADD viral dsRNA TLR3 TRIFactivated TLR3/TLR4 TLR4MD2 viral dsRNATLR3TRIF activated TLR4/TLR3TRIFK63-pUb-TRAF6 activated TLR3/4TRIFK63-poly-Ub-TRAF3p-TBK1/p-IKK epsilon activated TLR4/TLR3TRIFK63-pUb-TRAF6 TLR4MD2LPSCD14 viral dsRNA TLR3 TLR4MD2 viral dsRNA TLR3 TRIFactivated TLR3/TLR4 viral dsRNATLR3TRIF p-2S-IRF7p-2S-IRF7 TRIFTRAMTLR4MD2LPSCD14 TLR4MD2LPSCD14 viral dsRNA TLR3 TLR4MD2 activated TLR4/TLR3TRIFK63-pUb-RIP1IKKcomplex TLR4MD2LPSCD14 TRIFactivated TLR3/TLR4 TAB2/3 nucleoplasmactivated TLR4/TLR3TRIFK63-pUb-TRAF6free K63-linked pUbactivated TAK1 complex viral dsRNA TLR3 TLR4MD2 viral dsRNATLR3TRIF K63-poly-Ub-TRAF3TRIFactivated TLR3/TLR4 endosome lumenRIP1TRIFactivated TLR3/TLR4 IKKAIKKBNEMO TLR4MD2 TRIFactivated TLR3/TLR4 viral dsRNATLR3TRIF viral dsRNA TLR3 TRIFTRAMTLR4MD2LPSCD14 TLR4MD2 TRIFactivated TLR3/TLR4 viral dsRNA TLR3 viral dsRNA TLR3 TRAMTLR4MD2LPSCD14 viral dsRNATLR3TRIF activated TLR4/TLR3TRIFK63-pUb-TRAF6 TRIFTRAMTLR4MD2LPSCD14 activated TLR3/4TRIFK63-poly-Ub-TRAF3p-TBK1/p-IKK epsilon TRAMTLR4MD2LPSCD14 TRAF3TRIFactivated TLR3/TLR4 viral dsRNA TLR3 TLR4MD2 TRIFactivated TLR3/TLR4 TRIFactivated TLR3/TLR4 TRIFactivated TLR3/TLR4 viral dsRNATLR3TRIF TRAMTLR4MD2LPSCD14 p-T,4S-IRF3p-T,4S-IRF3 phosphorylated IRF3 and/or IRF7 dimer TLR4MD2LPSCD14 TRIFactivated TLR3/TLR4 TAB1TAB2/TAB3TAK1 TRAMTLR4MD2LPSCD14 TLR4MD2LPSCD14 viral dsRNATLR3TRIF TLR4MD2LPSCD14 viral dsRNA TLR3 activated TLR3/TLR4TRIFRIP1FADDpro-caspase-8 TRAMTLR4MD2LPSCD14 p-T,4S-IRF3p-T,4S-IRF3 TLR4MD2 viral dsRNATLR3TRIF TRAMTLR4MD2LPSCD14 TLR4MD2 TLR4MD2LPSCD14 TRIFactivated TLR3/TLR4 TLR4MD2LPSCD14 TLR4MD2LPSCD14 viral dsRNA TLR3 MyrG-p-S16-TICAM2GPIN-CD14p-T184,T187-MAP3K7 RIPK1GPIN-CD14PTPN11TRIFactivated TLR3/TLR4LY96 p-S172-IKBKE LPS GPIN-CD14GPIN-CD14LY96 CASP8activated TLR3/TLR4TRIFRIP1FADDpro-caspase-8TICAM1 MyrG-p-S16-TICAM2LPS IKBKG TLR3 MyrG-p-S16-TICAM2RIP3TRIFactivated TLR3/TLR4TRAF6 LPS TRAF6TLR3 IKBKG TLR4 activated TLR4/TLR3TRIFK63-pUb-TRAF6TRAF3activated TLR4/TLR3TRIFK63-pUb-RIP1TLR4 MAP3K7 MyrG-p-S16-TICAM2viral dsRNA TLR3LY96 TLR3 TLR3 IKBKB TAB1TAB2/TAB3TAK1TLR4 TICAM1 GPIN-CD14TRAMTLR4MD2LPSCD14TAK1 activates NFkB by phosphorylation and activation of IKKs complexTLR3 TAB3ADPMyrG-p-S16-TICAM2TLR3 TICAM1 TICAM1 TLR4 TLR4 TICAM1 GPIN-CD14UbLY96 TLR4 GPIN-CD14ATPactivated TLR4/TLR3TRIFTRAF6LY96 TICAM1 p-S477,S479-IRF7 TICAM1 IRF7 GPIN-CD14SARM-1 LPS MyrG-p-S16-TICAM2LY96 CHUK LY96 LY96 LPS TLR3 TLR4 GPIN-CD14TICAM1 TLR4 MyrG-p-S16-TICAM2MyrG-p-S16-TICAM2TLR4 TICAM1TICAM1 active caspase-8LY96 activated TLR3/TLR4TRIFRIP1FADDactivated TLR4/TLR3TRIFK63-pUb-TRAF6free K63-linked pUbactivated TAK1 complexTLR3 SARMTRIFactivated TLR3/TLR4LY96 TAB3MyrG-p-S16-TICAM2LPS p-T184,T187-MAP3K7 activated TLR3/4TRIFK63-poly-Ub-TRAF3p-TBK1/p-IKK epsilonTAB1 GPIN-CD14MAP kinase activation in TLR cascadeK63polyUb TRAF6 TICAM1 TRAF3 MyrG-p-S16-TICAM2TAB2 K63polyUbTLR3 TRIFactivated TLR3/TLR4ADPTRAF3TRIFactivated TLR3/TLR4pUb-TRAF6TAB1TAB2/TAB3free polyubiquitin chain phospho-TAK1RIP1 ubiqutin ligasesp-S477,S479-IRF7 TICAM1 TICAM1 viral dsRNATLR3TRIFTICAM1 TICAM1 LPS GPIN-CD14TLR4 UbTLR4 MyrG-p-S16-TICAM2TICAM1 K63polyUb-TRAF3 MyrG-p-S16-TICAM2TICAM1 TLR4 TICAM1 TICAM1 CASP8TLR3 MyrG-p-S16-TICAM2LPS TICAM1 ADPK63polyUb-TRAF3 TLR3 LPS TLR4 TICAM1 K63polyUbTICAM1 SARM-1p-S172-IKBKE TAB3LY96 TICAM1 TICAM1 GPIN-CD14MAP3K7 ATPLPS TLR3 LPS IRF3/ IRF7TLR3 TAB2 TICAM1 TICAM1 TAB1 p-S172-TBK1 RIPK3phosphorylated IRF3/IRF7K63polyUb-TRAF3 RIPK1 MyrG-p-S16-TICAM2TLR3 TRAF6LY96 LY96 LPS activated TLR4/TLR3TRIFK63-pUb-RIP1IKKcomplexGPIN-CD14TRIFTRAMTLR4MD2LPSCD14RIPK1 IRF3 CASP8TICAM1 IKBKB K63polyUb-RIPK1 TLR3 TICAM1 p-4S,T404-IRF3 MyrG-p-S16-TICAM2CASP8LPS activated TLR3/4TRIFK63-poly-Ub-TRAF3p-TBK1/p-IKKEIRF3/IRF7CHUK RIPK1 LPS K63polyUb TRAF6 phosphorylated IRF3 and/or IRF7 dimerTICAM1 TICAM1 K63-poly-Ub-TRAF3TRIFactivated TLR3/TLR4FADDRIP1TRIFactivated TLR3/TLR4TLR4 TICAM1 phosphorylated IRF3 and/or IRF7 dimerp-4S,T404-IRF3 ATPTLR4 TLR4 IKKAIKKBNEMOTICAM1 FADD LY96 K63polyUb TRAF6 TLR3 TAB1 LY96 TAB2 activated TLR4/TLR3TRIFK63-pUb-TRAF6free K63-linked pUbTAK1complexp-S172-TBK1 IKK related kinases TBK1/IKK epsilonK63polyUb TRAF6 MyrG-p-S16-TICAM2TAB1 K63polyUb-RIPK1 TICAM1 MyrG-p-S16-TICAM2LY96 TLR3 TAB3GPIN-CD14FADD TAB2 TLR4 GPIN-CD14GPIN-CD14LY96 LPS LPS LPS GPIN-CD147, 1219, 26, 3419, 26, 345340, 6358, 4838, 577, 125234119, 26, 3419, 357, 14, 19, 26, 4713, 19, 26, 2922, 436, 6241535352, 9, 15, 4613, 26512, 14, 24, 5724, 33, 3847


Description

MyD88-independent signaling pathway is shared by TLR3 and TLR4 cascades. TIR-domain-containing adapter-inducing interferon-beta (TRIF or TICAM1) is a key adapter molecule in transducing signals from TLR3 and TLR4 in a MyD88-independent manner (Yamamoto M et al. 2003a). TRIF is recruited to ligand-stimulated TLR3 or 4 complex via its TIR domain. TLR3 directly binds TRIF (Oshiumi H et al 2003). In contrast, TLR4-mediated signaling pathway requires two adapter molecules, TRAM (TRIF-related adapter molecule or TICAM2) and TRIF. TRAM(TICAM2) is thought to bridge between the activated TLR4 complex and TRIF (Yamamoto M et al. 2003b, Tanimura N et al. 2008, Kagan LC et al. 2008).

TRIF recruitment to TLR complex stimulates distinct pathways leading to production of type 1 interferons (IFNs), pro-inflammatory cytokines and induction of programmed cell death. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=166166</div>

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114711view16:19, 25 January 2021ReactomeTeamReactome version 75
113156view11:22, 2 November 2020ReactomeTeamReactome version 74
112384view15:31, 9 October 2020ReactomeTeamReactome version 73
101287view11:17, 1 November 2018ReactomeTeamreactome version 66
100824view20:48, 31 October 2018ReactomeTeamreactome version 65
100365view19:23, 31 October 2018ReactomeTeamreactome version 64
99911view16:06, 31 October 2018ReactomeTeamreactome version 63
99467view14:39, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99122view12:40, 31 October 2018ReactomeTeamreactome version 62
94000view13:50, 16 August 2017ReactomeTeamreactome version 61
93610view11:28, 9 August 2017ReactomeTeamreactome version 61
88020view13:30, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86718view09:24, 11 July 2016ReactomeTeamreactome version 56
83098view09:58, 18 November 2015ReactomeTeamVersion54
81768view10:14, 26 August 2015ReactomeTeamVersion53
76995view08:28, 17 July 2014ReactomeTeamFixed remaining interactions
76700view12:06, 16 July 2014ReactomeTeamFixed remaining interactions
76026view10:08, 11 June 2014ReactomeTeamRe-fixing comment source
75735view11:21, 10 June 2014ReactomeTeamReactome 48 Update
75085view14:04, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74732view08:48, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CASP8ProteinQ14790 (Uniprot-TrEMBL)
CHUK ProteinO15111 (Uniprot-TrEMBL)
FADD ProteinQ13158 (Uniprot-TrEMBL)
FADDProteinQ13158 (Uniprot-TrEMBL)
GPIN-CD14ProteinP08571 (Uniprot-TrEMBL)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKK related kinases TBK1/IKK epsilonProteinREACT_21591 (Reactome)
IKKA

IKKB

NEMO		ComplexREACT_7693 (Reactome)
IRF3 ProteinQ14653 (Uniprot-TrEMBL)
IRF3/ IRF7ProteinREACT_21735 (Reactome)
IRF7 ProteinQ92985 (Uniprot-TrEMBL)
K63-poly-Ub-TRAF3

TRIF

activated TLR3/TLR4		ComplexREACT_124855 (Reactome)
K63polyUb TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
K63polyUb-RIPK1 ProteinQ13546 (Uniprot-TrEMBL)
K63polyUb-TRAF3 ProteinQ13114 (Uniprot-TrEMBL)
K63polyUbREACT_21645 (Reactome)
LPS MetaboliteCHEBI:16412 (ChEBI)
LY96 ProteinQ9Y6Y9 (Uniprot-TrEMBL)
MAP kinase activation in TLR cascadePathwayWP2792 (WikiPathways) The mitogen activated protein kinase (MAPK) cascade, one of the most ancient and evolutionarily conserved signaling pathways, is involved in many processes of immune responses. The MAP kinases cascade transduces signals from the cell membrane to the nucleus in response to a wide range of stimuli (Chang and Karin, 2001; Johnson et al, 2002).

There are three major groups of MAP kinases

  • the extracellular signal-regulated protein kinases ERK1/2,
  • the p38 MAP kinase
  • and the c-Jun NH-terminal kinases JNK.

ERK1 and ERK2 are activated in response to growth stimuli. Both JNKs and p38-MAPK are activated in response to a variety of cellular and environmental stresses. The MAP kinases are activated by dual phosphorylation of Thr and Tyr within the tripeptide motif Thr-Xaa-Tyr. The sequence of this tripeptide motif is different in each group of MAP kinases: ERK (Thr-Glu-Tyr); p38 (Thr-Gly-Tyr); and JNK (Thr-Pro-Tyr).

MAPK activation is mediated by signal transduction in the conserved three-tiered kinase cascade: MAPKKKK (MAP4K or MKKKK or MAPKKK Kinase) activates the MAPKKK. The MAPKKKs then phosphorylates a dual-specificity protein kinase MAPKK, which in turn phosphorylates the MAPK.

The dual specificity MAP kinase kinases (MAPKK or MKK) differ for each group of MAPK. The ERK MAP kinases are activated by the MKK1 and MKK2; the p38 MAP kinases are activated by MKK3, MKK4, and MKK6; and the JNK pathway is activated by MKK4 and MKK7. The ability of MAP kinase kinases (MKKs, or MEKs) to recognize their cognate MAPKs is facilitated by a short docking motif (the D-site) in the MKK N-terminus, which binds to a complementary region on the MAPK. MAPKs then recognize many of their targets using the same strategy, because many MAPK substrates also contain D-sites.

The upstream signaling events in the TLR cascade that initiate and mediate the ERK signaling pathway remain unclear.

MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
MyrG-p-S16-TICAM2ProteinQ86XR7 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
RIP1

TRIF

activated TLR3/TLR4		ComplexREACT_7698 (Reactome)
RIP1 ubiqutin ligasesComplexREACT_151711 (Reactome)
RIP3

TRIF

activated TLR3/TLR4		ComplexREACT_150814 (Reactome)
RIPK1 ProteinQ13546 (Uniprot-TrEMBL)
RIPK1ProteinQ13546 (Uniprot-TrEMBL)
RIPK3ProteinQ9Y572 (Uniprot-TrEMBL)
SARM

TRIF

activated TLR3/TLR4		ComplexREACT_151758 (Reactome)
SARM-1 ProteinQ6SZW1-1 (Uniprot-TrEMBL)
SARM-1ProteinQ6SZW1-1 (Uniprot-TrEMBL)
TAB1

TAB2/TAB3

TAK1		ComplexREACT_21619 (Reactome)
TAB1 ProteinQ15750 (Uniprot-TrEMBL)
TAB2 ProteinQ9NYJ8 (Uniprot-TrEMBL)
TAB3ProteinQ8N5C8 (Uniprot-TrEMBL)
TAK1 activates NFkB by phosphorylation and activation of IKKs complexPathwayWP2656 (WikiPathways) NF-kappaB is sequestered in the cytoplasm in a complex with inhibitor of NF-kappaB (IkB). Almost all NF-kappaB activation pathways are mediated by IkB kinase (IKK), which phosphorylates IkB resulting in dissociation of NF-kappaB from the complex. This allows translocation of NF-kappaB to the nucleus where it regulates gene expression.
TICAM1 ProteinQ8IUC6 (Uniprot-TrEMBL)
TICAM1ProteinQ8IUC6 (Uniprot-TrEMBL)
TLR3 ProteinO15455 (Uniprot-TrEMBL)
TLR4 ProteinO00206 (Uniprot-TrEMBL)
TRAF3

TRIF

activated TLR3/TLR4		ComplexREACT_124037 (Reactome)
TRAF3 ProteinQ13114 (Uniprot-TrEMBL)
TRAF3ProteinQ13114 (Uniprot-TrEMBL)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRAF6ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRAM

TLR4 MD2 LPS

CD14		ComplexREACT_7083 (Reactome)
TRIF

TRAM TLR4 MD2 LPS

CD14		ComplexREACT_7861 (Reactome)
TRIF activated TLR3/TLR4ComplexREACT_124095 (Reactome)
TRIF activated TLR3/TLR4ComplexREACT_151807 (Reactome)
UbProteinREACT_3316 (Reactome)
activated TLR3/4

TRIF K63-poly-Ub-TRAF3

p-TBK1/p-IKK epsilon		ComplexREACT_26959 (Reactome)
activated TLR3/4

TRIF K63-poly-Ub-TRAF3 p-TBK1/p-IKKE

IRF3/IRF7		ComplexREACT_27000 (Reactome)
activated TLR3/TLR4

TRIF RIP1 FADD

pro-caspase-8		ComplexREACT_152273 (Reactome)
activated TLR3/TLR4

TRIF RIP1

FADD		ComplexREACT_150943 (Reactome)
activated TLR4/TLR3

TRIF K63-pUb-RIP1

IKKcomplex		ComplexREACT_26016 (Reactome)
activated TLR4/TLR3

TRIF

K63-pUb-RIP1		ComplexREACT_25755 (Reactome)
activated TLR4/TLR3

TRIF K63-pUb-TRAF6 free K63-linked pUb

TAK1complex		ComplexREACT_26036 (Reactome)
activated TLR4/TLR3

TRIF K63-pUb-TRAF6 free K63-linked pUb

activated TAK1 complex		ComplexREACT_26039 (Reactome)
activated TLR4/TLR3

TRIF

K63-pUb-TRAF6		ComplexREACT_25867 (Reactome)
activated TLR4/TLR3

TRIF

TRAF6		ComplexREACT_25948 (Reactome)
active caspase-8ComplexREACT_151128 (Reactome)
p-4S,T404-IRF3 ProteinQ14653 (Uniprot-TrEMBL)
p-S172-IKBKE ProteinQ14164 (Uniprot-TrEMBL)
p-S172-TBK1 ProteinQ9UHD2 (Uniprot-TrEMBL)
p-S477,S479-IRF7 ProteinQ92985 (Uniprot-TrEMBL)
p-T184,T187-MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
pUb-TRAF6

TAB1 TAB2/TAB3 free polyubiquitin chain

phospho-TAK1		ComplexREACT_23131 (Reactome)
phosphorylated IRF3 and/or IRF7 dimerComplexREACT_21500 (Reactome)
phosphorylated IRF3 and/or IRF7 dimerComplexREACT_21689 (Reactome)
phosphorylated IRF3/IRF7ProteinREACT_21760 (Reactome)
viral dsRNA

TLR3

TRIF		ComplexREACT_7381 (Reactome)
viral dsRNA TLR3ComplexREACT_7159 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowREACT_25081 (Reactome)
ADPArrowREACT_25288 (Reactome)
ADPArrowREACT_6728 (Reactome)
ATPREACT_25081 (Reactome)
ATPREACT_25288 (Reactome)
ATPREACT_6728 (Reactome)
CASP8REACT_150447 (Reactome)
FADDREACT_150447 (Reactome)
IKK related kinases TBK1/IKK epsilonREACT_25081 (Reactome)
IKKA

IKKB

NEMO		REACT_25373 (Reactome)
IRF3/ IRF7REACT_6917 (Reactome)
K63-poly-Ub-TRAF3

TRIF

activated TLR3/TLR4		REACT_25081 (Reactome)
K63polyUbREACT_25261 (Reactome)
K63polyUbREACT_6884 (Reactome)
PTPN11TBarREACT_6917 (Reactome)
REACT_120820 (Reactome) TRIF signaling activates TRAF3 self-mediated polyubiquitination trough Lys-63 of ubiquitin. The ubiquitinated TRAF3 in turn activates the interferon response [Tseng PH et al 2010].
REACT_121070 (Reactome) TRAF3 is a ubiquitin ligase recruited to both MYD88- and TRIF-assembled signalling complexes [Hacker H et al 2006]. However, TRAF3 controls the production of interferon and proinflammatory cytokines in different ways [Tseng PH et al 2010]. Positive or negative type of regulation is dictated by TRAF3 subcellular distribution and its mode of ubiquitination. Thus, TRIF-mediated signaling initiated on endosomes triggers TRAF3 self-ubiquitination through noncanonical (K63-linked) polyubiquitination, which is essential for activation of IRF3/7 and the interferon response. In contrast, during MyD88-dependent signaling initiated from plasma membrane TRAF3 functions as a negative regulator of inflammatory cytokines and mitogen-activated protein kinases (MAPKs), unless it undergoes degradative (K48-linked) polyubiquitination mediated by TRAF6 and a pair of the ubiquitin ligases cIAP1 and cIAP2. The degradation of TRAF3 is essential for MAPK activation via TAK1 and MEKK1 [Tseng PH et al 2010].
REACT_150310 (Reactome) SARM (sterile alpha-and armadillo-motif-containing protein) is a TIR-domain-containing adaptor, which functions as a negative regulator of TRIF(TICAM1)-dependent Toll-like receptor signaling in humans. LPS treatment led to a rapid increase of the SARM expression in peripheral blood mononuclear cells (PBMCs) and as a result an increased association between SARM and TRIF. SARM expression was also shown to inhibit poly(I:C)-induced TRIF-dependent NF-kB activaion, RANTES production and IRF activation in human embryonic kidney HEK293 cells [Carty M et al 2006]. Moreover, suppression of endogenous SARM expression by siRNA led to enhanced TLR3- and TLR4-dependent gene induction in both transformed HEK293 and primary PBMC cells, while endotoxin-tolerant human monocytes showed increased expression of SARM and decreased activation of TRIF-dependent cytokines [Carty M et al 2006; Piao W et al 2009]. Thus, SARM inhibits TLR4 and TLR3 signaling by targeting TRIF. The complex of TRIF:SARM is thought to inhibit downstream TRIF signaling by preventing the recruitment of TRIF effector proteins [Carty M et al 2006].
REACT_150365 (Reactome) TLR3 and TLR4 -directed programmed necrosis (necroptosis) is mediated by the TRIF-RIP3 pathway in mouse macrophages [He S e al 2011]. RIP3 was shown to be essential mediator in TLR3-induced necroptotic cell death in human epithelial cell lines. Knockdown of RIP3 in human keratinocyte HaCaT cells blocked TLR3-mediated necroptosis without affecting the apoptotic response. Moreover, overexpression of RIP3 in human epithelial carcinoma cell line HeLa led to increased caspase-independent TLR3-induced cell death in the absence of IAPs [Feoktistova M et al 2011]. In addition, in caspase-8- or FADD-deficient human Jurkat cells dsRNA induced programmed necrosis, instead of apoptosis [Kalai M et al 2002]. Thus, when caspase-dependent apoptosis is inhibited or absent, the alternative RIP3-mediated programmed cell death is induced.
REACT_150381 (Reactome) TLR3/4 signaling component were shown to mediate apoptosis in various human cell lines in the FADD:caspasse-8-dependent manner [Kalai M et al 2002; Kaiser WJ and Offermann MK 2005; Estornes Y et al 2012]. Caspase-8 zymogens (procaspase-8) are present in the cells as inactive monomers, containing a large N-terminal prodomain with two death effector domains (DED), and a C-terminal catalytic subunit composed of small and a large domains separated by a smaller linker region [Donepudi M et al 2003; Keller N et al 2009]. Dimerization is required for caspase-8 activation [Donepudi M et al 2003]. The dimerization event occurs at the receptor signaling complex. Once dimerized, caspase-8 zymogen undergoes a series of autoproteolytic cleavage events at aspartic acid residues in their interdomain linker regions. A second cleavage event between the the N-terminal prodomain and the catalytic domain releases the active caspase from the activation complex into the cytosol. The resulting fully active enzyme is a homodimer of catalytic domains, where each domain is compsed of a large p18 and a small p10 subunit [Keller N et al 2009; Oberst A et al 2010].
REACT_150447 (Reactome) TRIF was repored to efficiently induce apoptosis when overexpressed in human HEK293T cells. TRIF-induced apoptosis occurred through activation of the FADD-caspase-8 axis [Kaiser WJ and Offermann MK 2005; Kalai M et al 2002; Estornes Y et al 2012]. C-terminus of TRIF was shown to form complexes with both RIP1 and RIP3, and disruption of these interactions by mutating the RHIM eliminated the ability of TRIF to induce apoptosis [Kaiser WJ and Offermann MK 2005].

Prevention of RIP1 ubiquitination leads to a strong association of RIP1 and caspase-8 [Feoktistova M et al 2011, Tenev et al 2011].

REACT_24952 (Reactome) TRAF6 is recruited to the N-terminal domain of TICAM1 and this event is followed by auto polyubiquitination and oligomerization of TRAF6.
REACT_25081 (Reactome) The mechanism of TBK1 or IKKi{epsilon} activation by TICAM1 is unclear. It was suggested that these protein kinases undergo autophosphorylation. The most recent studies showed that phosphorylation and the activation of TBK1/ IKKi are catalyzed by a distinct protein kinase (Clark et al. 2009). Other studies demonstrated an essential role of TRAF3 in the activation of TBK1 (Hacker et al 2006).

It was also shown that the ubiquitin like domain (ULD) of TBK1 and IKK-i, a regulatory component, is involved in the control of kinase activation, substrate presentation and downstream signaling.

REACT_25183 (Reactome) Phosphorylated TAK1 complexed with TRAF6-TAB1-TAB2/TAB3 leaves the activated TLR4 complex and translocates to the cytosol
REACT_25261 (Reactome) TAK1-binding protein 2 (TAB2) and/or TAB3, as part of a complex that also contains TAK1 and TAB1, binds polyubiquitinated TRAF6. The TAB2 and TAB3 regulatory subunits of the TAK1 complex contain C-terminal Npl4 zinc finger (NZF) motifs that recognize with Lys63-pUb chains (Kanayama et al. 2004). The recognition mechanism is specific for Lys63-linked ubiquitin chains [Kulathu Y et al 2009]. TAK1 can be activated by unattached Lys63-polyubiquitinated chains when TRAF6 has no detectable polyubiquitination (Xia et al. 2009) and thus the synthesis of these chains by TRAF6 may be the signal transduction mechanism.
REACT_25288 (Reactome) The TAK1 complex consists of the transforming growth factor-? (TGF-beta)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Sakurai H et al 2000; Shibuya H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Sakurai H et al 2000 ; Kishimoyo K et al 2000). The TAK1 complex is regulated by polyubiquitination. The TAK1 complex consists of the transforming growth factor-? (TGF- ?)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya H et al 1996; Sakurai H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Brown K et al 2005; Ono K et al 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes onto the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that leads to the activation of TAK1. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004).
REACT_25318 (Reactome) TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex.
REACT_25362 (Reactome) Polyubiquitinated TRAF6 (as E3 ubiquitin ligase) generates free K63 -linked polyubiquitin chains that non-covalently associate with ubiquitin receptors of TAB2/TAB3 regulatory proteins of the TAK1 complex, leading to the activation of the TAK1 kinase.
REACT_25373 (Reactome) Structural studies showed that NEMO binds both Lys-63- and linear polyubiquitin chains,both critical for NF-kB activation.
REACT_6713 (Reactome) RIP1 is recruited to the activated TLR receptor by binding to TICAM1(TRIF) via its RHIM motif, followed by its polyubiquitination. Polyubiquitination is possibly mediated by TRAF6 that is also recruited to the TICAM1 [Cusson-Hermance N et al 2005]. Other E3-ubiquitin ligases - cIAP1 and cIAP2 - have been reported to promote polyubiquitination of RIP proteins [Bertrand MJM et al 2011].

RIP3 was shown to inhibit TRIF-induced NF-kB activation in dose-dependent manner when overexpressed in HEK293T cells by competing with TRIF to bind RIP1 [Meylan E et al 2004].

REACT_6728 (Reactome) Human IRF-3 is activated through a two step phosphorylation in the C-terminal domain mediated by TBK1 and/or IKK-i. It requires Ser386 and/or Ser385 (site 1) and a cluster of serine/threonine residues between Ser396 and Ser405 (site 2) [Panne et al 2007]. Phosphorylated residues at site 2 alleviate autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitate phosphorylation at site 1. Phosphorylation at site 1 is required for IRF-3 dimerization.

IRF-3 and IRF-7 transcription factors possess distinct structural characteristics; IRF-7 is phosphorylated on Ser477 and Ser479 residues [Lin R et al 2000]. TRAF6 mediated ubiquitination of IRF7 is also required and essential for IRF7 phosphorylation and activation. The K-63 linked ubiquitination occurs on the last three C-terminal lysine sites (positions 444, 446, and 452) of human IRF7 independently of its C-terminal functional phosphorylation sites.[Ning et al 2008].

REACT_6793 (Reactome) Phosphorylation results in IRF-3 dimerization and removal of an autoinhibitory structure to allow interaction with the coactivators CBP/p300.
REACT_6799 (Reactome) TRIF (TICAM1) mediates the MyD88-independent pathway from TLR4.
REACT_6864 (Reactome) IRF3-P:IRF3-P' is translocated from cytosol to nucleoplasm.
REACT_6884 (Reactome) RIP1 polyubiquitination was induced upon TNF- or poly(I-C) treatment of the macrophage cell line RAW264.7 and the U373 astrocytoma line (Cusson-Hermance et al 2005). These workers have suggested that RIP1 may use similar mechanisms to induce NF-kB in the TNFR1- and Trif-dependent TLR pathways.

RIP1 modification with Lys-63 polyubiquitin chains was shown to be essential for TNF-induced activation of NF-kB (Ea et al. 2006). It is thought that TRAF family members mediate this Lys63-linked ubiquitination of RIP1 (Wertz et al. 2004, Tada et al 2001, Vallabhapurapu and Karin 2009), which may facilitate recruitment of the TAK1 complex and thus activation of NF-kB. Binding of NEMO to Lys63-linked polyubiquitinated RIP1 is also required in the signaling cascade from the activated receptor to the IKK-mediated NF-kB activation (Wu et al. 2006).

REACT_6917 (Reactome)
  • Two members of the interferon regulatory factor (IRF) family IRF-3 and IRF-7 are the major modulators of IFN gene expression. Activation of IRF-3 and IRF-7, which is mediated by TBK1/IKK protein kinases, promotes IFN gene expression and the production of IFN developing an effective antiviral immune response.

    Irf-3 deficient mice were found to be more vulnerable to virus infection. Mouse cells defective in IRF-3 and IRF-7 expression totally fail to induce IFN genes in response to viral infection. It was shown on mice and mouse cells that both IRF-3 and IRF-7 have non redundant and distinct roles. IRF-3 is expressed at a basal level in normally growing cells and is a major factor in the early induction phase of IFN-alpha/beta production, while the IRF-7 gene expression is induced upon IFNs stimulation and IRF-7 is involved in the late induction phase.

  • SH2-containing protein tyrosine phosphatase 2 (SHP-2) has been shown to inhibit the TRIF-dependent production of proin?ammatory cytokines and type I interferon in LPS or poly(I-C)-stimulated mouse peritoneal macrophages. SHP-2 overexpression also inhibited TRIF-induced IFN-? luciferase reporter gene expression in human embryonic kidney HEK293 cells. Experiments with truncated SHP-2 or truncated TBK1 mutants revealed that C-terminal domain of SHP-2 associates with N-terminal domain of TBK1 when coexpressed in HEK293 cells. Furthermore, SHP-2 is thought to prevent TBK1-mediated downstream substrate phosphorylation in tyrosine phosphatase activity independent manner by binding to kinase domain of TBK1 [An H et al 2006].
REACT_6919 (Reactome) TIR-domain-containing adaptor inducing interferon-beta (TRIF or TICAM1) was shown to play an essential role in TLR3 signaling. All poly(I:C)-induced pathways leading to NFkB and IRF3 activation were abolished in TRIF-/- mice [Yamamoto et al. 2003].
RIP1

TRIF

activated TLR3/TLR4		REACT_150447 (Reactome)
RIP1

TRIF

activated TLR3/TLR4		REACT_6884 (Reactome)
RIP1 ubiqutin ligasesREACT_6884 (Reactome)
RIPK1REACT_6713 (Reactome)
RIPK3REACT_150365 (Reactome)
RIPK3TBarREACT_6713 (Reactome)
SARM

TRIF

activated TLR3/TLR4		TBarREACT_121070 (Reactome)
SARM

TRIF

activated TLR3/TLR4		TBarREACT_24952 (Reactome)
SARM

TRIF

activated TLR3/TLR4		TBarREACT_6713 (Reactome)
SARM-1REACT_150310 (Reactome)
TAB1

TAB2/TAB3

TAK1		REACT_25261 (Reactome)
TICAM1REACT_6799 (Reactome)
TICAM1REACT_6919 (Reactome)
TRAF3

TRIF

activated TLR3/TLR4		REACT_120820 (Reactome)
TRAF3REACT_121070 (Reactome)
TRAF6REACT_24952 (Reactome)
TRAF6REACT_25362 (Reactome)
TRAM

TLR4 MD2 LPS

CD14		REACT_6799 (Reactome)
TRIF activated TLR3/TLR4ArrowREACT_25183 (Reactome)
TRIF activated TLR3/TLR4REACT_121070 (Reactome)
TRIF activated TLR3/TLR4REACT_150310 (Reactome)
TRIF activated TLR3/TLR4REACT_150365 (Reactome)
TRIF activated TLR3/TLR4REACT_24952 (Reactome)
TRIF activated TLR3/TLR4REACT_6713 (Reactome)
UbREACT_120820 (Reactome)
UbREACT_25318 (Reactome)
activated TLR3/4

TRIF K63-poly-Ub-TRAF3

p-TBK1/p-IKK epsilon		ArrowREACT_25081 (Reactome)
activated TLR3/4

TRIF K63-poly-Ub-TRAF3

p-TBK1/p-IKK epsilon		ArrowREACT_6728 (Reactome)
activated TLR3/4

TRIF K63-poly-Ub-TRAF3

p-TBK1/p-IKK epsilon		REACT_6917 (Reactome)
activated TLR3/4

TRIF K63-poly-Ub-TRAF3 p-TBK1/p-IKKE

IRF3/IRF7		REACT_6728 (Reactome)
activated TLR3/TLR4

TRIF RIP1 FADD

pro-caspase-8		REACT_150381 (Reactome)
activated TLR3/TLR4

TRIF RIP1

FADD		ArrowREACT_150381 (Reactome)
activated TLR4/TLR3

TRIF

K63-pUb-RIP1		REACT_25373 (Reactome)
activated TLR4/TLR3

TRIF K63-pUb-TRAF6 free K63-linked pUb

TAK1complex		REACT_25288 (Reactome)
activated TLR4/TLR3

TRIF K63-pUb-TRAF6 free K63-linked pUb

activated TAK1 complex		ArrowREACT_25288 (Reactome)
activated TLR4/TLR3

TRIF

K63-pUb-TRAF6		REACT_25261 (Reactome)
activated TLR4/TLR3

TRIF

TRAF6		REACT_25318 (Reactome)
active caspase-8ArrowREACT_150381 (Reactome)
pUb-TRAF6

TAB1 TAB2/TAB3 free polyubiquitin chain

phospho-TAK1		ArrowREACT_25183 (Reactome)
phosphorylated IRF3/IRF7ArrowREACT_6728 (Reactome)
viral dsRNA TLR3REACT_6919 (Reactome)

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