Toll Like Receptor 3 (TLR3) Cascade (Homo sapiens)

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13, 42, 5425, 50535068, 866514, 50, 6128, 34, 52, 7324, 566414, 32, 44, 7218, 21, 221, 62, 65, 7827, 8828, 34, 35, 37, 48...23, 875, 9, 112268, 79, 8729, 50, 72, 88881, 39, 45, 46, 781, 8010, 49, 5728, 34, 47, 73, 76...cytosolendosomenucleoplasmTICAM1:activatedTLR3 complexesHBV dsRNA intermediate form UBC(609-684) UBC(381-456) TICAM1 UBC(77-152) activatedTLR3:TICAM1:K63pUb-RIP1K63polyUb-TRAF6 Rotavirus dsRNA Influenza A dsRNA intermediate form HCV dsRNA intermediate form RIP3:TICAM1:activated TLR3HCV dsRNA intermediate form TRAF6 viral dsRNA :TLR3K63polyUb HCV dsRNA intermediate form TLR3 HBV dsRNA intermediate form HSV1 dsRNA intermediate form TICAM1 TLR3 p-4S,T404-IRF3 HBV dsRNA intermediate form HCV dsRNA intermediate form TRAF6 K63pUb-TRAF6:TAB1:TAB2,TAB3:free pUb:p-T-TAK1IRF7 TLR3 TAB1 K63polyUb-TRAF6 TICAM1 UBB(153-228) TICAM1 HCV dsRNA intermediate form TICAM1 ADPUBC(533-608) UbFADD TAB1 Rotavirus dsRNA ApoptosisTICAM1 RIPK1Rotavirus dsRNA TAB3 SARM-1 K63polyUb-TRAF3 Influenza A dsRNA intermediate form Rotavirus dsRNA K63polyUb-TRAF3 K63polyUb-TRAF6 Influenza A dsRNA intermediate form p-S172-IKBKE TICAM1 TLR3 HBV dsRNA intermediate form UBC(153-228) Influenza A dsRNA intermediate form p-S477,S479-IRF7 viraldsRNA:TLR3:TRIF:pUb-TRAF6:TAB1:TAB2,TAB3:free polyUb: p-TAK1RIP1 ubiqutinligasesHSV1 dsRNA intermediate form MAP3K7 ATPTAB1 K63polyUb HSV1 dsRNA intermediate form TLR3 activatedTLR3:TRIF:RIP1:FADD:pro-caspase-8UBC(533-608) UBB(1-76) HCV dsRNA intermediate form HCV dsRNA intermediate form TLR3RPS27A(1-76) ADPTLR3 HBV dsRNA intermediate form TAB2 Rotavirus dsRNA HCV dsRNA intermediate form SARM:TICAM1:viraldsRNA:TLR3K63polyUb-RIPK1 CASP8(385-479) TICAM1 Influenza A dsRNA intermediate form Influenza A dsRNA intermediate form Rotavirus dsRNA HBV dsRNA intermediate form p-S172-IKBKE Influenza A dsRNA intermediate form HBV dsRNA intermediate form viraldsRNA:TLR3:TICAM1:K63pUb-RIP1:CHUK:IKBKB:IKBKGHBV dsRNA intermediate form HSV1 dsRNA intermediate form UBB(1-76) HCV dsRNA intermediate form TLR3 ligandTLR3 UBC(77-152) UBB(77-152) RIPK3HSV1 dsRNA intermediate form IKBKE p-S477,S479-IRF7 TLR3 viraldsRNA:TLR3:TICAM1:K63pUb-TRAF6UBC(153-228) ATPIRF3 TLR3 p-4S,T404-IRF3,p-S477,S479-IRF7HCV dsRNA intermediate form TANK TAB2 HSV1 dsRNA intermediate form HBV dsRNA intermediate form RIPK1 TICAM1 UBC(457-532) Rotavirus dsRNA Influenza A dsRNA intermediate form RIPK1 HCV dsRNA intermediate form K63polyUb-TANK K63polyUb-TRAF3 K63-linked polyUbTRAF6 complexesHCV dsRNA intermediate form K63polyUb-RIPK1 HBV dsRNA intermediate form UBC(457-532) TLR3 TAB3 phosphorylated IRF3and/or IRF7 dimerHSV1 dsRNA intermediate form UBC(229-304) HBV dsRNA intermediate form TLR3 UBE2V1 RIPK1 HBV dsRNA intermediate form p-4S,T404-IRF3 FADDCHUK UBC(229-304) K63polyUb-TANK HSV1 dsRNA intermediate form TLR3 RIPK3 RIPK1 K63polyUb-TANK IRF7 UBC(1-76) K63polyUbRotavirus dsRNA Rotavirus dsRNA Regulated NecrosisHSV1 dsRNA intermediate form Influenza A dsRNA intermediate form HSV1 dsRNA intermediate form HSV1 dsRNA intermediate form p-T184,T187-MAP3K7 GPIN-CD14(20-345) HBV dsRNA intermediate form BIRC2 K63polyUb-TRAF3 TLR3 HSV1 dsRNA intermediate form UBC(457-532) UBA52(1-76) HCV dsRNA intermediate form Influenza A dsRNA intermediate form CASP8(1-479) UBC(533-608) Influenza A dsRNA intermediate form HBV dsRNA intermediate form HCV dsRNA intermediate form BIRC3 TICAM1 HBV dsRNA intermediate form IRF3 viraldsRNA:TLR3:TICAM1:RIPK1HCV dsRNA intermediate form HBV dsRNA intermediate form TLR3 Rotavirus dsRNA TBK1 UBC(153-228) Rotavirus dsRNA IRF3,IRF7HSV1 dsRNA intermediate form TAB2 MyrG-p-S16-TICAM2 HBV dsRNA intermediate form FADD Rotavirus dsRNA UBE2D2 HBV dsRNA intermediate form TRAF3Rotavirus dsRNA UBE2D1 TAB2 TAB3 Influenza A dsRNA intermediate form TRAF6HSV1 dsRNA intermediate form Influenza A dsRNA intermediate form CHUK:IKBKB:IKBKGRotavirus dsRNA HCV dsRNA intermediate form RPS27A(1-76) CASP8(1-479)active caspase-8Rotavirus dsRNA UBE2N K63pUb-TANK:K63pUb-TRAF3:TICAM1:TLR3:viral dsRNAK63polyUb TANKactivatedTLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7TICAM1 HCV dsRNA intermediate form HCV dsRNA intermediate form IKK related kinasesTBK1/IKK epsilonUBB(153-228) ATPp-4S,T404-IRF3 Rotavirus dsRNA p-S172-TBK1 Influenza A dsRNA intermediate form HSV1 dsRNA intermediate form TANK:K63-poly-Ub-TRAF3:TICAM1:viral dsRNA:TLR3UBC(1-76) UBB(153-228) UBC(77-152) Influenza A dsRNA intermediate form TICAM1 CASP8(217-374) UbUBC(305-380) UBB(77-152) HSV1 dsRNA intermediate form Rotavirus dsRNA Influenza A dsRNA intermediate form Rotavirus dsRNA UBC(305-380) TICAM1 K63polyUbRotavirus dsRNA K63polyUb-TRAF3:TICAM1:activated TLR3TLR3 viraldsRNA:TLR3:TRIF:TRAF6TAB1:TAB2,TAB3:TAK1Rotavirus dsRNA Influenza A dsRNA intermediate form UBB(77-152) TLR3 K63polyUb-TRAF6 TAB1 TLR3 TICAM1 MAP kinaseactivationHCV dsRNA intermediate form LPS TLR3 viraldsRNA:TLR3:TICAM1phosphorylated IRF3and/or IRF7 dimerTLR3 TLR3 TICAM1 TICAM1 TICAM1 Rotavirus dsRNA IKBKG SARM-1viraldsRNA:TLR3:TRIF:polyUb-TRAF6:TAK1:TAB1:TAB2/TAB3: free polyUb chainp-S477,S479-IRF7 HSV1 dsRNA intermediate form Influenza A dsRNA intermediate form Influenza A dsRNA intermediate form K63polyUb-TRAF6 RPS27A(1-76) UBC(229-304) K63polyUb-TRAF6 TICAM1 Influenza A dsRNA intermediate form TRAF3 LY96 UBA52(1-76) ADPactivatedTLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKiactivatedTLR3:TRIF:RIP1:FADDRotavirus dsRNA TLR3 UBB(1-76) TICAM1RIPK1 MAP3K7 IKBKB HSV1 dsRNA intermediate form UBC(381-456) TICAM1 CHUK UBE2D3 p-T184,T187-MAP3K7 HSV1 dsRNA intermediate form K63polyUb-TRAF3 TLR4 HBV dsRNA intermediate form UBC(1-76) HBV dsRNA intermediate form UBC(609-684) IKBKG HSV1 dsRNA intermediate form HSV1 dsRNA intermediate form TRAF3:TICAM1:viraldsRNA:TLR3HCV dsRNA intermediate form UBC(381-456) HBV dsRNA intermediate form HCV dsRNA intermediate form HBV dsRNA intermediate form HSV1 dsRNA intermediate form UBA52(1-76) TAB3 HCV dsRNA intermediate form TAK1 activates NFkBby phosphorylationand activation ofIKKs complexUBC(305-380) UBC(609-684) Influenza A dsRNA intermediate form TICAM1 Influenza A dsRNA intermediate form IKBKB p-IRAK2 TICAM1 p-S172-TBK1 67, 747123, 73, 8764715171717171716423, 73, 8751713, 8, 20, 33, 40...71637, 16, 55537112, 26, 36, 4315, 21, 23, 4968716423, 28, 73, 8268647151712, 6, 19, 38, 58...28, 7371157130, 754, 59717118, 2123, 73, 8718, 2117, 77, 8471717171643118, 60, 63711, 2364


Toll-like receptor 3 (TLR3) as was shown for mammals is expressed on myeloid dendritic cells, respiratory epithelium, macrophages, and appears to play a central role in mediating the antiviral and inflammatory responses of the innate immunity in combating viral infections.

Mammalian TLR3 recognizes dsRNA, and that triggers the receptor to induce the activation of NF-kappaB and the production of type I interferons (IFNs). dsRNA-stimulated phosphorylation of two specific TLR3 tyrosine residues (Tyr759 and Tyr858) is essential for initiating TLR3 signaling pathways. View original pathway at:Reactome.</div>


Pathway is converted from Reactome ID: 168164
Reactome version: 66
Reactome Author 
Reactome Author: Luo, F

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  88. Häcker H, Karin M.; ''Regulation and function of IKK and IKK-related kinases.''; PubMed Europe PMC
  89. Li K, Li NL, Wei D, Pfeffer SR, Fan M, Pfeffer LM.; ''Activation of chemokine and inflammatory cytokine response in hepatitis C virus-infected hepatocytes depends on Toll-like receptor 3 sensing of hepatitis C virus double-stranded RNA intermediates.''; PubMed Europe PMC


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101378view11:26, 1 November 2018ReactomeTeamreactome version 66
100916view21:01, 31 October 2018ReactomeTeamreactome version 65
100457view19:36, 31 October 2018ReactomeTeamreactome version 64
100004view16:20, 31 October 2018ReactomeTeamreactome version 63
99557view14:53, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99186view12:42, 31 October 2018ReactomeTeamreactome version 62
93762view13:34, 16 August 2017ReactomeTeamreactome version 61
93286view11:19, 9 August 2017ReactomeTeamreactome version 61
88401view15:21, 4 August 2016FehrhartOntology Term : 'Toll-like receptor signaling pathway' added !
86370view09:16, 11 July 2016ReactomeTeamreactome version 56
83334view10:49, 18 November 2015ReactomeTeamVersion54
81488view13:01, 21 August 2015ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
ApoptosisPathwayR-HSA-109581 (Reactome) Apoptosis is a distinct form of cell death that is functionally and morphologically different from necrosis. Nuclear chromatin condensation, cytoplasmic shrinking, dilated endoplasmic reticulum, and membrane blebbing characterize apoptosis in general. Mitochondria remain morphologically unchanged. In 1972 Kerr et al introduced the concept of apoptosis as a distinct form of "cell-death", and the mechanisms of various apoptotic pathways are still being revealed today.
The two principal pathways of apoptosis are (1) the Bcl-2 inhibitable or intrinsic pathway induced by various forms of stress like intracellular damage, developmental cues, and external stimuli and (2) the caspase 8/10 dependent or extrinsic pathway initiated by the engagement of death receptors
The caspase 8/10 dependent or extrinsic pathway is a death receptor mediated mechanism that results in the activation of caspase-8 and caspase-10. Activation of death receptors like Fas/CD95, TNFR1, and the TRAIL receptor is promoted by the TNF family of ligands including FASL (APO1L OR CD95L), TNF, LT-alpha, LT-beta, CD40L, LIGHT, RANKL, BLYS/BAFF, and APO2L/TRAIL. These ligands are released in response to microbial infection, or as part of the cellular, humoral immunity responses during the formation of lymphoid organs, activation of dendritic cells, stimulation or survival of T, B, and natural killer (NK) cells, cytotoxic response to viral infection or oncogenic transformation.
The Bcl-2 inhibitable or intrinsic pathway of apoptosis is a stress-inducible process, and acts through the activation of caspase-9 via Apaf-1 and cytochrome c. The rupture of the mitochondrial membrane, a rapid process involving some of the Bcl-2 family proteins, releases these molecules into the cytoplasm. Examples of cellular processes that may induce the intrinsic pathway in response to various damage signals include: auto reactivity in lymphocytes, cytokine deprivation, calcium flux or cellular damage by cytotoxic drugs like taxol, deprivation of nutrients like glucose and growth factors like EGF, anoikis, transactivation of target genes by tumor suppressors including p53.
In many non-immune cells, death signals initiated by the extrinsic pathway are amplified by connections to the intrinsic pathway. The connecting link appears to be the truncated BID (tBID) protein a proteolytic cleavage product mediated by caspase-8 or other enzymes.
BIRC2 ProteinQ13490 (Uniprot-TrEMBL)
BIRC3 ProteinQ13489 (Uniprot-TrEMBL)
CASP8(1-479) ProteinQ14790 (Uniprot-TrEMBL)
CASP8(1-479)ProteinQ14790 (Uniprot-TrEMBL)
CASP8(217-374) ProteinQ14790 (Uniprot-TrEMBL)
CASP8(385-479) ProteinQ14790 (Uniprot-TrEMBL)
CHUK ProteinO15111 (Uniprot-TrEMBL)
CHUK:IKBKB:IKBKGComplexR-HSA-168113 (Reactome) Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS & Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.
FADD ProteinQ13158 (Uniprot-TrEMBL)
FADDProteinQ13158 (Uniprot-TrEMBL)
GPIN-CD14(20-345) ProteinP08571 (Uniprot-TrEMBL)
HBV dsRNA intermediate form R-HBV-8982481 (Reactome)
HCV dsRNA intermediate form R-HCV-8982462 (Reactome)
HSV1 dsRNA intermediate form R-HER-6791257 (Reactome)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKE ProteinQ14164 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKK related kinases TBK1/IKK epsilonComplexR-HSA-450329 (Reactome)
IRF3 ProteinQ14653 (Uniprot-TrEMBL)
IRF3,IRF7ComplexR-HSA-450317 (Reactome)
IRF7 ProteinQ92985 (Uniprot-TrEMBL)
Influenza A dsRNA intermediate form R-FLU-9028895 (Reactome)
K63-linked polyUb TRAF6 complexesComplexR-HSA-975153 (Reactome)
K63pUb-TANK:K63pUb-TRAF3:TICAM1:TLR3:viral dsRNAComplexR-HSA-9013976 (Reactome)
K63pUb-TRAF6:TAB1:TAB2,TAB3:free pUb:p-T-TAK1ComplexR-HSA-847073 (Reactome)
K63polyUb R-HSA-450152 (Reactome)
K63polyUb R-HSA-450271 (Reactome)
K63polyUb-RIPK1 ProteinQ13546 (Uniprot-TrEMBL)
K63polyUb-TANK ProteinQ92844 (Uniprot-TrEMBL)
K63polyUb-TRAF3 ProteinQ13114 (Uniprot-TrEMBL)
K63polyUb-TRAF3:TICAM1:activated TLR3ComplexR-HSA-9013989 (Reactome)
K63polyUb-TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
K63polyUbR-HSA-450152 (Reactome)
LPS MetaboliteCHEBI:16412 (ChEBI)
LY96 ProteinQ9Y6Y9 (Uniprot-TrEMBL)
MAP kinase activationPathwayR-HSA-450294 (Reactome) 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-TICAM2 ProteinQ86XR7 (Uniprot-TrEMBL)
RIP1 ubiqutin ligasesComplexR-HSA-2569050 (Reactome)
RIP3:TICAM1:activated TLR3ComplexR-HSA-9013956 (Reactome)
RIPK1 ProteinQ13546 (Uniprot-TrEMBL)
RIPK1ProteinQ13546 (Uniprot-TrEMBL)
RIPK3 ProteinQ9Y572 (Uniprot-TrEMBL)
RIPK3ProteinQ9Y572 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
Regulated NecrosisPathwayR-HSA-5218859 (Reactome) Necrosis has traditionally been considered as a passive, unregulated cell death. However, accumulating evidence suggests that necrosis, like apoptosis, can be executed by genetically controlled and highly regulated cellular process that is morphologically characterized by a loss of cell membrane integrity, intracellular organelles and/or the entire cell swelling (oncosis) (Rello S et al. 2005; Galluzzi L et al. 2007; Berghe TV et al. 2014). The morphological hallmarks of the nectotic death have been associated with different forms of programmed cell death including (but not limited to) parthanatos, necroptosis, glutamate-induced oxytosis, ferroptosis, inflammasome-mediated necrosis etc. Each of them can be triggered under certain pathophysiological conditions. For example UV, ROS or alkylating agents may induce poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation (parthanatos), while tumor necrosis factor (TNF) or toll like receptor ligands (LPS and dsRNA) can trigger necrosome-mediated necroptosis. The initiation events, e.g., PARP1 hyperactivation, necrosome formation, activation of NADPH oxidases, in turn trigger one or several common intracellular signals such as NAD+ and ATP-depletion, enhanced Ca2+ influx, dysregulation of the redox status, increased production of reactive oxygen species (ROS) and the activity of phospholipases. These signals affect cellular organelles and membranes leading to osmotic swelling, massive energy depletion, lipid peroxidation and the loss of lysosomal membrane integrity. Regulated or programmed necrosis eventually leads to cell lysis and release of cytoplasmic content into the extracellular region that is often associated with a tissue damage resulting in an intense inflammatory response.

The Reactome module describes necroptosis as the most characterized form of regulated necrosis. The molecular mechanisms behind the other types of regulated necrosis as well as interconnectivity among them need further studies.

Rotavirus dsRNA R-ROT-8982440 (Reactome)
SARM-1 ProteinQ6SZW1-1 (Uniprot-TrEMBL)
SARM-1ProteinQ6SZW1-1 (Uniprot-TrEMBL)
SARM:TICAM1:viral dsRNA:TLR3ComplexR-HSA-9014322 (Reactome)
TAB1 ProteinQ15750 (Uniprot-TrEMBL)
TAB1:TAB2,TAB3:TAK1ComplexR-HSA-450277 (Reactome)
TAB2 ProteinQ9NYJ8 (Uniprot-TrEMBL)
TAB3 ProteinQ8N5C8 (Uniprot-TrEMBL)
TAK1 activates NFkB

by phosphorylation and activation of

IKKs complex
PathwayR-HSA-445989 (Reactome) 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.
TANK ProteinQ92844 (Uniprot-TrEMBL)
TANK:K63-poly-Ub-TRAF3:TICAM1:viral dsRNA:TLR3ComplexR-HSA-9013980 (Reactome)
TANKProteinQ92844 (Uniprot-TrEMBL)
TBK1 ProteinQ9UHD2 (Uniprot-TrEMBL)
TICAM1 ProteinQ8IUC6 (Uniprot-TrEMBL)
TICAM1:activated TLR3 complexesComplexR-HSA-9013962 (Reactome)
TICAM1ProteinQ8IUC6 (Uniprot-TrEMBL)
TLR3 ProteinO15455 (Uniprot-TrEMBL)
TLR3 ligandComplexR-NUL-9038432 (Reactome)
TLR3ProteinO15455 (Uniprot-TrEMBL)
TLR4 ProteinO00206 (Uniprot-TrEMBL)
TRAF3 ProteinQ13114 (Uniprot-TrEMBL)
TRAF3:TICAM1:viral dsRNA:TLR3ComplexR-HSA-9013984 (Reactome)
TRAF3ProteinQ13114 (Uniprot-TrEMBL)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRAF6ProteinQ9Y4K3 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UBE2D1 ProteinP51668 (Uniprot-TrEMBL)
UBE2D2 ProteinP62837 (Uniprot-TrEMBL)
UBE2D3 ProteinP61077 (Uniprot-TrEMBL)
UBE2N ProteinP61088 (Uniprot-TrEMBL)
UBE2V1 ProteinQ13404 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
activated TLR3:TICAM1:K63pUb-RIP1ComplexR-HSA-9014344 (Reactome)
activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7ComplexR-HSA-9013981 (Reactome)
activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKiComplexR-HSA-9013982 (Reactome)
activated TLR3:TRIF:RIP1:FADD:pro-caspase-8ComplexR-HSA-9013891 (Reactome)
activated TLR3:TRIF:RIP1:FADDComplexR-HSA-9013893 (Reactome)
active caspase-8ComplexR-HSA-2562550 (Reactome)
p-4S,T404-IRF3 ProteinQ14653 (Uniprot-TrEMBL)
p-4S,T404-IRF3,p-S477,S479-IRF7ComplexR-HSA-450240 (Reactome)
p-IRAK2 ProteinO43187 (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)
phosphorylated IRF3 and/or IRF7 dimerComplexR-HSA-450256 (Reactome)
phosphorylated IRF3 and/or IRF7 dimerComplexR-HSA-450349 (Reactome)
viral dsRNA:TLR3:TICAM1:K63pUb-RIP1:CHUK:IKBKB:IKBKGComplexR-HSA-9014341 (Reactome)
viral dsRNA:TLR3:TICAM1:K63pUb-TRAF6ComplexR-HSA-450309 (Reactome)
viral dsRNA:TLR3:TICAM1:RIPK1ComplexR-HSA-177649 (Reactome)
viral dsRNA:TLR3:TICAM1ComplexR-HSA-168907 (Reactome)
viral dsRNA:TLR3:TRIF:TRAF6ComplexR-HSA-177693 (Reactome)
viral dsRNA:TLR3:TRIF:pUb-TRAF6:TAB1:TAB2,TAB3:free polyUb: p-TAK1ComplexR-HSA-177691 (Reactome)
viral dsRNA:TLR3:TRIF:polyUb-TRAF6:TAK1:TAB1:TAB2/TAB3: free polyUb chainComplexR-HSA-177689 (Reactome)
viral dsRNA :TLR3ComplexR-HSA-167985 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-177692 (Reactome)
ADPArrowR-HSA-9013978 (Reactome)
ADPArrowR-HSA-9013986 (Reactome)
ATPR-HSA-177692 (Reactome)
ATPR-HSA-9013978 (Reactome)
ATPR-HSA-9013986 (Reactome)
CASP8(1-479)R-HSA-9013889 (Reactome)
CHUK:IKBKB:IKBKGR-HSA-9014343 (Reactome)
FADDR-HSA-9013889 (Reactome)
IKK related kinases TBK1/IKK epsilonR-HSA-9013986 (Reactome)
IRF3,IRF7R-HSA-9013979 (Reactome)
K63-linked polyUb TRAF6 complexesmim-catalysisR-HSA-450358 (Reactome)
K63pUb-TANK:K63pUb-TRAF3:TICAM1:TLR3:viral dsRNAArrowR-HSA-9013990 (Reactome)
K63pUb-TANK:K63pUb-TRAF3:TICAM1:TLR3:viral dsRNAR-HSA-9013986 (Reactome)
K63pUb-TRAF6:TAB1:TAB2,TAB3:free pUb:p-T-TAK1ArrowR-HSA-847070 (Reactome)
K63polyUb-TRAF3:TICAM1:activated TLR3ArrowR-HSA-9013974 (Reactome)
K63polyUb-TRAF3:TICAM1:activated TLR3R-HSA-9013985 (Reactome)
K63polyUbArrowR-HSA-450358 (Reactome)
K63polyUbR-HSA-177690 (Reactome)
K63polyUbR-HSA-9014342 (Reactome)
R-HSA-168092 (Reactome) Viral dsRNA triggers an antiviral pathway mediated by toll like receptor 3. TLR3 dimerization occurs upon ligand binding to positivly charged residues on the ectodomain termini of TLR3 wich are responsible for the interaction with sugar-phosphate groups of dsRNA.
R-HSA-168929 (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].
R-HSA-168930 (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 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 NFkB activation in dose-dependent manner when overexpressed in HEK293T cells by competing with TRIF to bind RIP1 (Meylan E et al. 2004).

R-HSA-168933 (Reactome) Phosphorylation results in IRF-3 dimerization and removal of an autoinhibitory structure to allow interaction with the coactivators CBP/p300.
R-HSA-177671 (Reactome) IRF3-P:IRF3-P' is translocated from cytosol to nucleoplasm.
R-HSA-177690 (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.This binding leads to autophosphorylation and activation of TAK1.
R-HSA-177692 (Reactome) TAK1 complex consists of transforming growth factor-beta (TGFB)-activated kinase (TAK1) and TAK1-binding protein 1 (TAB1), TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya et al. 1996, Sakurai et al. 2000). TAB1 promotes TAK1 autophosphorylation at the kinase activation lobe, probably through an allosteric mechanism (Brown et al. 2005, Ono 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 to 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 lead to TAK1 activation. 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).
R-HSA-177694 (Reactome) TRAF6 is recruited to the N-terminal domain of TICAM1 and this event is followed by auto polyubiquitination and oligomerization of TRAF6.
R-HSA-450259 (Reactome) TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination. 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.
R-HSA-450358 (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.
R-HSA-847070 (Reactome) Phosphorylated TAK1 complexed with TRAF6-TAB1-TAB2/TAB3 leaves the activated TLR4 complex and translocates to the cytosol
R-HSA-9013889 (Reactome) TRIF (also known as TICAM1) 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).

R-HSA-9013895 (Reactome) TLR3 and TLR4 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).
R-HSA-9013963 (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.
R-HSA-9013974 (Reactome) TRIF(TICAM1) 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).
R-HSA-9013978 (Reactome) Human IRF3 is activated through a two step phosphorylation in the C-terminal domain mediated by TBK1 and/or IKKi. 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 IRF3 dimerization.

IRF3 and IRF7 transcription factors possess distinct structural characteristics; IRF7 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).

R-HSA-9013979 (Reactome) SH2-containing protein tyrosine phosphatase 2 (SHP-2) has been shown to inhibit the TRIF-dependent production of proinflammatory 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).
R-HSA-9013985 (Reactome) TRAF family member-associated NFkB activator (TANK or ITRAF) is a TRAF-binding protein that has been implicated in RLR, TNFR and IL-1R/TLR signaling pathways in mammals (Rothe M et a.l 1996; Pomerantz JL and Baltimore D 1999; Li C et al. 2002; Guo B and Cheng G 2007; Konno H 2009). TANK was shown to interact with TBK1, IKK epsilon, IPS-1, TRIF (TICAM1), IRF3 and is thought to be a part of the TRAF3-containing complex (Pomerantz JL and Baltimore D 1999; Guo B and Cheng G 2007; Gatot JC et al. 2007). Upon microbe stimulation TANK is believed to induce IRF-dependent type I IFN production in mammalian cells by linking kinase TBK1 or IKK epsilon with upstream mediators TRAF3/6 (Guo B and Cheng G 2007; Gatot JC et al. 2007). In addition, TANK is thought to act synergistically with IKK epsilon or TBK1 to link them to IKK complex via interaction with NEMO (IKK gamma), where TBK1/IKK epsilon may modulate NFkB activation (Chariot A et al. 2002). TANK influence on NFkB activation was found to occur via either positive or negative regulation (Guo B and Cheng G 2007, Konno H et al. 2009; Pomerantz JL and Baltimore D 1999; Kawagoe T et al. 2009).

Two other adaptor proteins NAK-associated protein 1 (NAP1) and SINTBAD (not shown here) have been implicated in TBK1/IKKepsilon-mediated activation of IRF3 (Sasai M et al. 2005; Ryzhakov G and Randow F 2007). Structural and functional studies showed that TANK, NAP1 and SINTBAD share a common region which mediates association with the coiled-coil 2 in TBK1 (Ryzhakov G and Randow F 2007; Goncalves A et al. 2011; Larabi A et al. 2013; Tu D et al. 2013). TANK, NAP1 and SINTBAD were found to compete for TBK1 binding (Ryzhakov G and Randow F 2007; Goncalves A et al. 2011), TBK1 is thought to form alternative complexes with each adaptor TANK, NAP1 or SINTBAD, rather than a single large multiprotein complex containing all three adaptors (Goncalves A et al. 2011; Larabi A et al. 2013).

R-HSA-9013986 (Reactome) Upon stimulation by pathogen-associated inflammatory signals, TANK-binding kinase 1 (TBK1) and inhibitor of kappaB kinase epsilon (IKKi) induce type I interferon expression and modulate nuclear factor kappa B (NFkB) signaling (Fitzgerald KA et al. 2003; Hemmi H et al. 2004). The structural studies of TBK1 revealed a dimeric assembly which is mediated by several interfaces involving kinase domain (KD), a ubiquitin-like domain (ULD), and an alpha-helical scaffold dimerization domain (SDD) of TBK1 (Larabi A et al. 2013; Tu D et al. 2013). ULD of TBK1 and IKKi was involved in the control of kinase activation, substrate presentation and downstream signaling (Ikeda F et al 2007; Tu D et al. 2013). An intact TBK1 dimer was a subject to K63-linked polyubiquitination on lysines 30 and 401 (Tu D et al. 2013). Activation of TBK1 rearranged the KD into an active conformation while maintaining the overall dimer conformation (Larabi A et al. 2013). The ubiquitination sites and dimer contacts are conserved in the close homolog IKKi (Tu D et al. 2013). The activation of TBK1 and IKKi may occur through autophosphorylation or via activity of 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). TBK1 and IKKi were found to interact with scaffold proteins TANK (TRAF family member associated NFkB activator), NAP1 (NAK-associated protein 1), SINTBAD (similar to NAP1 TBK1 adaptor) which connect TBK1/IKKi to pathogen-activated signaling cascades (Pomerantz JL and Baltimore D 1999; Guo B and Cheng G 2007; Gatot JC et al. 2007; Ryzhakov G and Randow F 2007; Goncalves A et al. 2011).
R-HSA-9013990 (Reactome) Upon stimulation by pathogen-associated inflammatory signals TANK associates with TRAF3 which may result in K63-linked ubiquitination of TANK (Gatot JC et al. 2007). How the ubiquitination of TANK contributes to the activation of TBK1 and/or IKKepsilon remains unclear.
R-HSA-9013992 (Reactome) Tumor necrosis factor (TNF) receptor associated factor 3 (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].
R-HSA-9014320 (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. A pairwise yeast two-hybrid assay demonstrated that SARM is capable of binding directly to TICAM1 (Carty M et al. 2006). GST pulldown studies suggest that protein-protein interactions occur between the TIR domains of SARM and TICAM1 (Carlsson E et al. 2016). The complex of TICAM1:SARM is thought to inhibit downstream TRIF signaling by preventing the recruitment of TRIF effector proteins (Carty M et al. 2006).

SARM expression was shown to inhibit poly(I:C)-induced TICAM1-dependent NFkappaB 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 (Carty M et al. 2006), Thus, SARM associates with TICAM1 via its TIR and sterile-alpha motif (SAM) domains to block the induction of proinflammatory genes downstream TLR3.

R-HSA-9014342 (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).

R-HSA-9014343 (Reactome) Structural studies showed that NEMO binds both Lys-63- and linear polyubiquitin chains,both critical for NF-kB activation.
RIP1 ubiqutin ligasesmim-catalysisR-HSA-9014342 (Reactome)
RIP3:TICAM1:activated TLR3ArrowR-HSA-9013963 (Reactome)
RIPK1R-HSA-168930 (Reactome)
RIPK3R-HSA-9013963 (Reactome)
RIPK3TBarR-HSA-168930 (Reactome)
SARM-1R-HSA-9014320 (Reactome)
SARM:TICAM1:viral dsRNA:TLR3ArrowR-HSA-9014320 (Reactome)
TAB1:TAB2,TAB3:TAK1R-HSA-177690 (Reactome)
TANK:K63-poly-Ub-TRAF3:TICAM1:viral dsRNA:TLR3ArrowR-HSA-9013985 (Reactome)
TANK:K63-poly-Ub-TRAF3:TICAM1:viral dsRNA:TLR3R-HSA-9013990 (Reactome)
TANKR-HSA-9013985 (Reactome)
TICAM1:activated TLR3 complexesR-HSA-9013963 (Reactome)
TICAM1R-HSA-168929 (Reactome)
TLR3 ligandR-HSA-168092 (Reactome)
TLR3R-HSA-168092 (Reactome)
TRAF3:TICAM1:viral dsRNA:TLR3ArrowR-HSA-9013992 (Reactome)
TRAF3:TICAM1:viral dsRNA:TLR3R-HSA-9013974 (Reactome)
TRAF3:TICAM1:viral dsRNA:TLR3mim-catalysisR-HSA-9013974 (Reactome)
TRAF3R-HSA-9013992 (Reactome)
TRAF6R-HSA-177694 (Reactome)
UbR-HSA-450259 (Reactome)
UbR-HSA-450358 (Reactome)
UbR-HSA-9013974 (Reactome)
UbR-HSA-9013990 (Reactome)
activated TLR3:TICAM1:K63pUb-RIP1ArrowR-HSA-9014342 (Reactome)
activated TLR3:TICAM1:K63pUb-RIP1R-HSA-9014343 (Reactome)
activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7ArrowR-HSA-9013979 (Reactome)
activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7R-HSA-9013978 (Reactome)
activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKE:IRF3/IRF7mim-catalysisR-HSA-9013978 (Reactome)
activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKiArrowR-HSA-9013978 (Reactome)
activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKiArrowR-HSA-9013986 (Reactome)
activated TLR3:TRIF:K63polyUb-TRAF3:K63polyUb-TANK:p-TBK1/p-IKKiR-HSA-9013979 (Reactome)
activated TLR3:TRIF:RIP1:FADD:pro-caspase-8ArrowR-HSA-9013889 (Reactome)
activated TLR3:TRIF:RIP1:FADD:pro-caspase-8R-HSA-9013895 (Reactome)
activated TLR3:TRIF:RIP1:FADD:pro-caspase-8mim-catalysisR-HSA-9013895 (Reactome)
activated TLR3:TRIF:RIP1:FADDArrowR-HSA-9013895 (Reactome)
active caspase-8ArrowR-HSA-9013895 (Reactome)
p-4S,T404-IRF3,p-S477,S479-IRF7ArrowR-HSA-9013978 (Reactome)
p-4S,T404-IRF3,p-S477,S479-IRF7R-HSA-168933 (Reactome)
phosphorylated IRF3 and/or IRF7 dimerArrowR-HSA-168933 (Reactome)
phosphorylated IRF3 and/or IRF7 dimerArrowR-HSA-177671 (Reactome)
phosphorylated IRF3 and/or IRF7 dimerR-HSA-177671 (Reactome)
viral dsRNA:TLR3:TICAM1:K63pUb-RIP1:CHUK:IKBKB:IKBKGArrowR-HSA-9014343 (Reactome)
viral dsRNA:TLR3:TICAM1:K63pUb-TRAF6ArrowR-HSA-450259 (Reactome)
viral dsRNA:TLR3:TICAM1:K63pUb-TRAF6R-HSA-177690 (Reactome)
viral dsRNA:TLR3:TICAM1:RIPK1ArrowR-HSA-168930 (Reactome)
viral dsRNA:TLR3:TICAM1:RIPK1R-HSA-9013889 (Reactome)
viral dsRNA:TLR3:TICAM1:RIPK1R-HSA-9014342 (Reactome)
viral dsRNA:TLR3:TICAM1ArrowR-HSA-168929 (Reactome)
viral dsRNA:TLR3:TICAM1ArrowR-HSA-847070 (Reactome)
viral dsRNA:TLR3:TICAM1R-HSA-168930 (Reactome)
viral dsRNA:TLR3:TICAM1R-HSA-177694 (Reactome)
viral dsRNA:TLR3:TICAM1R-HSA-9013992 (Reactome)
viral dsRNA:TLR3:TICAM1R-HSA-9014320 (Reactome)
viral dsRNA:TLR3:TRIF:TRAF6ArrowR-HSA-177694 (Reactome)
viral dsRNA:TLR3:TRIF:TRAF6R-HSA-450259 (Reactome)
viral dsRNA:TLR3:TRIF:pUb-TRAF6:TAB1:TAB2,TAB3:free polyUb: p-TAK1ArrowR-HSA-177692 (Reactome)
viral dsRNA:TLR3:TRIF:pUb-TRAF6:TAB1:TAB2,TAB3:free polyUb: p-TAK1R-HSA-847070 (Reactome)
viral dsRNA:TLR3:TRIF:polyUb-TRAF6:TAK1:TAB1:TAB2/TAB3: free polyUb chainArrowR-HSA-177690 (Reactome)
viral dsRNA:TLR3:TRIF:polyUb-TRAF6:TAK1:TAB1:TAB2/TAB3: free polyUb chainR-HSA-177692 (Reactome)
viral dsRNA:TLR3:TRIF:polyUb-TRAF6:TAK1:TAB1:TAB2/TAB3: free polyUb chainmim-catalysisR-HSA-177692 (Reactome)
viral dsRNA :TLR3ArrowR-HSA-168092 (Reactome)
viral dsRNA :TLR3R-HSA-168929 (Reactome)

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