Toll-like Receptor Cascades (Homo sapiens)

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7, 35, 45, 63, 823, 42, 4950, 6623, 4715, 7146, 48, 68, 8114, 62, 64, 834, 24, 485, 51, 58716176, 6931, 44, 78, 7918, 38, 6018, 20, 29, 36, 522, 8, 13, 7471124, 11, 21, 22, 41...30, 31, 43, 8251, 5851, 58activated TLR9PI3K class III TLR1TLR2 fl-TLR9unmethylated CpG DNA TLR1TLR2TLR1/2 ligandCD14 TLR4MD2 TLR6TLR2 TLR6TLR2ligandCD14CD36 TLR1TLR2 ligandCD14 EEA1EEA1 TLR4MD2 PorB Homotrimer Integrin alphaMbeta2 N-ter TLR9 dimer TLR7 or TLR8recognized ligand TLR7 or TLR8 TLR1TLR2TLR1/2 ligandCD14 TLR6TLR2 recognized ligand TLR4MD2LPSCD14 TLR1TLR2 ligandCD14 C-ter TLR7 dimer MALPIC-ter-TLR9 dimer Integrin alphaMbeta2 TLR1TLR2 ligandCD14 TLR4MD2 C-ter-TLR9 dimer TLR1TLR2 recognized ligand TLR8 dimer PI3K class III endosome lumenTLR6TLR2 recognized ligand TLR4MD2LPSCD14 TLR4MD2LPSCD14 TLR4MD2 TLR6TLR2 recognized ligand MALactivated TLR2/4 TLR10 homodimer bound to ligand TLR8 dimer CD14 TLR6TLR2ligandCD14CD36 PI3K class III fl-TLR9unmethylated CpG DNA PorB Homotrimer Ligands recognized by TLR7 and TLR8 TLR10 homodimer TLR1TLR2 recognized ligand viral dsRNA TLR3 Imidazoquinoline compounds TLR6/2 ligandCD14CD36 CD14 C-ter TLR7 dimer TLR6TLR2 C-ter TLR9 dimerunmethylated CpG DNA cytosolTLR4MD2 PorB Homotrimer TLR6/2 ligandCD14CD36 TLR6TLR2 TLR1TLR2 TLR6/2 ligandCD14CD36 LPSGPI-anchored CD14 N-ter TLR9 dimer MALPITRAMTLR4MD2LPSCD14 LPSsecreted CD14 TLR1TLR2 recognized ligand TLR7 or TLR8 TLR1TLR2 N-ter TLR9 dimerunmethylated CpG DNA TLR4MD2LPSCD14 Activated TLR12 or TLR 26 heterodimers or TLR4 homodimer TLR5 homodimerbacterial flagellin LBPbacterial LPS LPSCD14CR3 RP105MD1 LPSGPI-anchored CD14 TLR1TLR2TLR1/2 ligandCD14Dynamin-1/2/3fl-TLR9unmethylated CpG DNAGPIN-CD14TLR5 GPIN-CD14N-ter TLR9 dimerunmethylated CpG DNALipoteichoic acid TIRAP TLR7 or TLR8EEA1 MyD88 cascade initiated on plasma membraneLPS CD180 TLR6 TLR6TLR2MyD88-independent cascade Flagellin TLR7TLR6TLR2 recognized ligandZFYVE202xN4GlycoAsn-LY96 LBPTrafficking and processing of endosomal TLRTLR9MyD88Mal cascade initiated on plasma membraneTLR2 Major outer membrane protein P TLR8 IMIQ TLR2 Unmethylated CpG DNALY96 TLR9TLR7 or TLR8recognized ligandviral dsRNA TLR3TLR2 CD14TLR10 homodimer bound to ligandDiacyl lipopeptide 2xN4GlycoAsn-TLR4 C-ter-TLR9 dimerTLR3 GPIN-CD14Major outer membrane protein P GPIN-CD14Clostridial peptidoglycan LY96 2xN4GlycoAsn-LY96 Flagellin4xPalmC-CD36 LPS Ligands recognized by TLR7 and TLR8TLR2 PIK3R4TLR1TLR9EEA1EEA1TLR9TRAMTLR4MD2LPSCD14PIK3R4activated TLR9PI3K class IIITLR5 homodimerbacterial flagellinTLR8 TLR2 Triacyl lipopeptide 4xPalmC-CD36 TLR1MyrG-p-S16-TICAM22xN4GlycoAsn-TLR4 Major outer membrane protein P TLR4MD2LPSCD14LPS N-ter TLR9 dimerTLR5Activated TLR12 or TLR 26 heterodimers or TLR4 homodimerPIMyrG-p-S16-TICAM2TLR6/2 ligandCD14CD36R-848 TLR6TLR2ligandCD14CD36CD14TLR10Diacyl lipopeptide Triacyl lipopeptide TIRAP PI4xPalmC-CD36Ligand recognized by TLR10LBPPI3K class IIILPSCD14MyD88 dependent cascade initiated on endosomeTLR1TLR2 recognized ligandPIK3C3 Clostridial peptidoglycan TLR6 GPIN-CD14TLR6 CD14Triacyl lipopeptide LPS MyrG-p-S16-TICAM2GPIN-CD14TLR4 2xN4GlycoAsn-LY96 4xPalmC-CD36 LPS ITGB2 LBPbacterial LPSLipoteichoic acid LPSGPI-anchored CD14CD14Diacyl lipopeptide TLR3TLR9TLR1TLR2 ligandCD14PILipoteichoic acid ITGB2 GPIN-CD14RP105MD1LPS LPSsecreted CD14TLR10 GPIN-CD14GPIN-CD14MALPITLR1Integrin alphaMbeta2LPSCD14CR3LY86 Viral dsRNA PLCG2TLR9 CD14ITGAM LPS LPS LBP TLR1TLR2GPIN-CD14TIRAPTLR7TLR4 GPIN-CD14PIK3C3 GPIN-CD14ITGAM MALactivated TLR2/42xN4GlycoAsn-TLR4 C-ter TLR9 dimerunmethylated CpG DNATLR9 Clostridial peptidoglycan LPSTLR4MD2TLR4MD2LPSCD141956, 76, 85335149, 831933, 7517, 27731934331, 6, 41, 7077, 841910, 43, 53, 83656, 8515, 39, 551933, 754, 243457, 5980159, 40, 51, 59, 616346, 6951, 5915337244, 786, 805, 16, 25, 26, 28...2, 13, 40, 6733, 75193476


Description

In human, ten members of the Toll-like receptor (TLR) family (TLR1-TLR10) have been identified (TLR11 has been found in mouse, but not in human). All TLRs have a similar Toll/IL-1 receptor (TIR) domain in their cytoplasmic region and an Ig-like domain in the extracellular region, where each is enriched with a varying number of leucine-rich repeats (LRRs). Each TLR can recognize specific microbial pathogen components. The binding pathogenic component to TLR initializes signaling pathways that lead to induction of Interferon alpha/beta and inflammatory cytokines. There are two main signaling pathways. The first is a MyD88-dependent pathway that is common to all TLRs, except TLR3; the second is a TRIF(TICAM1)-dependent pathway that is peculiar to TLR3 and TLR4. TLR4-mediated signaling pathway via TRIF requires adapter molecule TRAM (TRIF-related adapter molecule or TICAM2). TRAM is thought to bridge between the activated TLR4 complex and TRIF.(Takeda & Akira 2004; Akira 2003; Takeda & Akira 2005; Kawai 2005; Heine & Ulmer 2005). Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=168898

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Bibliography

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History

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CompareRevisionActionTimeUserComment
112684view16:07, 9 October 2020ReactomeTeamReactome version 73
101601view11:47, 1 November 2018ReactomeTeamreactome version 66
101137view21:32, 31 October 2018ReactomeTeamreactome version 65
100665view20:05, 31 October 2018ReactomeTeamreactome version 64
100215view16:51, 31 October 2018ReactomeTeamreactome version 63
99766view15:16, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99325view12:47, 31 October 2018ReactomeTeamreactome version 62
93988view13:49, 16 August 2017ReactomeTeamreactome version 61
93593view11:28, 9 August 2017ReactomeTeamreactome version 61
88400view15:21, 4 August 2016FehrhartOntology Term : 'Toll-like receptor signaling pathway' added !
88399view15:20, 4 August 2016FehrhartOntology Term : 'PW:0000003' removed !
88398view15:20, 4 August 2016FehrhartOntology Term : 'signaling pathway' added !
86700view09:24, 11 July 2016ReactomeTeamreactome version 56
83597view13:35, 27 November 2015Anweshaimproved layoutt of complex components
83400view11:07, 18 November 2015ReactomeTeamVersion54
81595view13:08, 21 August 2015ReactomeTeamVersion53
77055view08:35, 17 July 2014ReactomeTeamFixed remaining interactions
76760view12:12, 16 July 2014ReactomeTeamFixed remaining interactions
76084view10:14, 11 June 2014ReactomeTeamRe-fixing comment source
75794view11:32, 10 June 2014ReactomeTeamReactome 48 Update
75144view14:09, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74867view14:22, 3 May 2014EgonwMarked a metabolite as a DataNode type="Metabolite"...
74791view08:52, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2xN4GlycoAsn-LY96 ProteinQ9Y6Y9 (Uniprot-TrEMBL)
2xN4GlycoAsn-TLR4 ProteinO00206 (Uniprot-TrEMBL)
4xPalmC-CD36 ProteinP16671 (Uniprot-TrEMBL)
4xPalmC-CD36ProteinP16671 (Uniprot-TrEMBL)
Activated TLR1

2 or TLR 2

6 heterodimers or TLR4 homodimer		ComplexREACT_8654 (Reactome)
C-ter TLR9 dimer unmethylated CpG DNAComplexREACT_116565 (Reactome)
C-ter-TLR9 dimerComplexREACT_116183 (Reactome)
CD14ProteinP08571 (Uniprot-TrEMBL)
CD14ProteinREACT_7012 (Reactome)
CD180 ProteinQ99467 (Uniprot-TrEMBL)
Clostridial peptidoglycan MetaboliteCHEBI:8005 (ChEBI)
Diacyl lipopeptide MetaboliteCHEBI:46896 (ChEBI)
Dynamin-1/2/3ProteinREACT_22651 (Reactome)
EEA1 EEA1ComplexREACT_9336 (Reactome)
EEA1 ProteinQ15075 (Uniprot-TrEMBL)
Flagellin ProteinP04949 (Uniprot-TrEMBL)
FlagellinProteinP04949 (Uniprot-TrEMBL)
GPIN-CD14ProteinP08571 (Uniprot-TrEMBL)
IMIQ MetaboliteCHEBI:36704 (ChEBI)
ITGAM ProteinP11215 (Uniprot-TrEMBL)
ITGB2 ProteinP05107 (Uniprot-TrEMBL)
Integrin alphaMbeta2ComplexREACT_12291 (Reactome)
LBP bacterial LPSComplexREACT_7556 (Reactome)
LBP ProteinP18428 (Uniprot-TrEMBL)
LBPProteinP18428 (Uniprot-TrEMBL)
LPS

CD14

CR3		ComplexREACT_151313 (Reactome)
LPS CD14ComplexREACT_7856 (Reactome)
LPS GPI-anchored CD14ComplexREACT_7567 (Reactome)
LPS secreted CD14ComplexREACT_7211 (Reactome)
LPS MetaboliteCHEBI:16412 (ChEBI)
LPSCHEBI:16412 (ChEBI)
LY86 ProteinO95711 (Uniprot-TrEMBL)
LY96 ProteinQ9Y6Y9 (Uniprot-TrEMBL)
Ligand recognized by TLR10REACT_9270 (Reactome)
Ligands recognized by TLR7 and TLR8MetaboliteREACT_27596 (Reactome)
Lipoteichoic acid MetaboliteCHEBI:28640 (ChEBI)
MAL PIComplexREACT_151450 (Reactome)
MAL activated TLR2/4ComplexREACT_152404 (Reactome)
Major outer membrane protein P ProteinP30690 (Uniprot-TrEMBL)
MyD88 Mal cascade initiated on plasma membranePathwayREACT_6788 (Reactome) The first known downstream component of TLR4 and TLR2 signaling is the adaptor MyD88. Another adapter MyD88-adaptor-like (Mal; also known as TIR-domain-containing adaptor protein or TIRAP) has also been described for TLR4 and TLR2 signaling. MyD88 comprises an N-terminal Death Domain (DD) and a C-terminal TIR, whereas Mal lacks the DD. The TIR homotypic interactions bring adapters into contact with the activated TLRs, whereas the DD modules recruit serine/threonine kinases such as interleukin-1-receptor-associated kinase (IRAK). Recruitment of these protein kinases is accompanied by phosphorylation, which in turn results in the interaction of IRAKs with TNF-receptor-associated factor 6 (TRAF6). The oligomerization of TRAF6 activates TAK1, a member of the MAP3-kinase family, and this leads to the activation of the IkB kinases. These kinases, in turn, phosphorylate IkB, leading to its proteolytic degradation and the translocation of NF-kB to the nucleus. Concomitantly, members of the activator protein-1 (AP-1) transcription factor family, Jun and Fos, are activated, and both AP-1 transcription factors and NF-kB are required for cytokine production, which in turn produces downstream inflammatory effects.
MyD88 cascade initiated on plasma membranePathwayWP2801 (WikiPathways) Mammalian myeloid differentiation factor 88 (MyD88) is Toll/interleukin (IL)-1 (TIR)-domain containing adapter protein which plays crucial role in TLR signaling. All TLRs, with only one exception of TLR3, can initiate downstream signaling trough MyD88. In the MyD88 - dependent pathway, once the adaptor is bound to TLR it leads to recruitment of IL1 receptor associated kinase family – IRAK which is followed by activation of tumour necrosis factor receptor-associated factor 6 (TRAF6) . TRAF6 is an ubiquitin E3 ligase which in turn induces TGF-beta activating kinase 1 (TAK1) auto phosphorylation. Once activated TAK1 can ultimately mediate the induction of the transcription factor NF-kB or the mitogen-activated protein kinases (MAPK), such as JNK, p38 and ERK. This results in the translocation of the activated NF-kB and MAPKs to the nucleus and the initiation of appropriate gene transcription leading to the production of many proinflammatory cytokines and antimicrobial peptides.
MyD88 dependent cascade initiated on endosomePathwayWP2768 (WikiPathways) Upon binding of their ligands, TLR7/8 and TLR9 recruit a cytoplasmic adaptor MyD88 and IRAKs, downstream of which the signaling pathways are divided to induce either inflammatory cytokines or type I IFNs.
MyD88-independent cascade PathwayWP2752 (WikiPathways) 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.

MyrG-p-S16-TICAM2ProteinQ86XR7 (Uniprot-TrEMBL)
N-ter TLR9 dimer unmethylated CpG DNAComplexREACT_119250 (Reactome)
N-ter TLR9 dimerComplexREACT_119168 (Reactome)
PI3K class IIIComplexREACT_9166 (Reactome)
PIMetaboliteCHEBI:18348 (ChEBI)
PIK3C3 ProteinQ8NEB9 (Uniprot-TrEMBL)
PIK3R4ProteinQ99570 (Uniprot-TrEMBL)
PLCG2ProteinP16885 (Uniprot-TrEMBL)
R-848 MetaboliteCHEBI:36706 (ChEBI)
RP105 MD1ComplexREACT_7670 (Reactome)
TIRAP ProteinP58753 (Uniprot-TrEMBL)
TIRAPProteinP58753 (Uniprot-TrEMBL)
TLR1

TLR2 TLR1/2 ligand

CD14		ComplexREACT_8364 (Reactome)
TLR1

TLR2 ligand

CD14		ComplexREACT_152304 (Reactome)
TLR1 TLR2 recognized ligandREACT_8189 (Reactome)
TLR1 TLR2ComplexREACT_8486 (Reactome)
TLR10 ProteinQ9BXR5 (Uniprot-TrEMBL)
TLR10 homodimer bound to ligandComplexREACT_9231 (Reactome)
TLR10ProteinQ9BXR5 (Uniprot-TrEMBL)
TLR1ProteinQ5FWG5 (Uniprot-TrEMBL)
TLR2 ProteinO60603 (Uniprot-TrEMBL)
TLR3 ProteinO15455 (Uniprot-TrEMBL)
TLR3ProteinO15455 (Uniprot-TrEMBL)
TLR4

MD2 LPS

CD14		ComplexREACT_124771 (Reactome)
TLR4

MD2 LPS

CD14		ComplexREACT_7465 (Reactome)
TLR4 MD2ComplexREACT_7105 (Reactome)
TLR4 ProteinO00206 (Uniprot-TrEMBL)
TLR5 ProteinO60602 (Uniprot-TrEMBL)
TLR5 homodimer bacterial flagellinComplexREACT_9374 (Reactome)
TLR5ProteinO60602 (Uniprot-TrEMBL)
TLR6

TLR2 ligand CD14

CD36		ComplexREACT_8969 (Reactome)
TLR6 TLR2 recognized ligandREACT_8552 (Reactome)
TLR6 TLR2ComplexREACT_8554 (Reactome)
TLR6 ProteinQ9Y2C9 (Uniprot-TrEMBL)
TLR6/2 ligand

CD14

CD36		ComplexREACT_150804 (Reactome)
TLR7 or TLR8 recognized ligandComplexREACT_9279 (Reactome)
TLR7 or TLR8ComplexREACT_9168 (Reactome)
TLR7ProteinQ9NYK1 (Uniprot-TrEMBL)
TLR8 ProteinQ9NR97 (Uniprot-TrEMBL)
TLR9 ProteinQ9NR96 (Uniprot-TrEMBL)
TLR9ProteinQ9NR96 (Uniprot-TrEMBL)
TRAM

TLR4 MD2 LPS

CD14		ComplexREACT_7083 (Reactome)
Trafficking and processing of endosomal TLRPathwayWP2709 (WikiPathways) Mammalian TLR3, TLR7, TLR8, TLR9 are endosomal receptors that sense nucleic acids that have been released from endocytosed/phagocytosed bacteria, viruses or parasites. These TLRs have a ligand-recognition domain that faces the lumen of the endosome (which is topologically equivalent to the outside of the cell), a transmembrane domain, and a signaling domain that faces the cytosol.

Under normal conditions, self nucleic acids are not recognized by TLRs due to multiple levels of regulation including receptor compartmentalization, trafficking and proteolytic processing (Barton GM et al 2006, Ewald SE et al 2008). At steady state TLR3, TLR7, TLR8, TLR9 reside primarily in the endoplasmic reticulum (ER), however, their activation by specific ligands only occurs within acidified endolysosomal compartments (Hacker H et al 1998, Funami K et al 2004, Gibbard RJ et al 2006). Several chaperon proteins associate with TLRs in the ER to provide efficient translocation to endolysosome. Upon reaching endolysosomal compartments the ectodomains of TLR7 and TLR9 are proteolytically cleaved by cysteine endoproteases. Both full-length and cleaved C-terminus of TLR9 bind CpG-oligodeoxynucleotides, however it has been proposed that only the processed receptor is functional.

Although similar cleavage of TLR3 has been reported by Ewald et al 2011, other studies demonstrated that the N-terminal region of TLR3 ectodomain was implicated in ligand binding, thus TLR3 may function as a full-length receptor (Liu L et al 2008, Tokisue T et al 2008).

There are no data on TLR8 processing, although the cell biology of TLR8 is probably similar to TLR9 and TLR7 (Gibbard RJ et al 2006, Wei T et al 2009).

Triacyl lipopeptide MetaboliteCHEBI:60192 (ChEBI)
Unmethylated CpG DNAREACT_9187 (Reactome)
Viral dsRNA REACT_21871 (Reactome)
ZFYVE20ProteinQ9H1K0 (Uniprot-TrEMBL)
activated TLR9 PI3K class IIIComplexREACT_9357 (Reactome)
fl-TLR9 unmethylated CpG DNAComplexREACT_9181 (Reactome)
viral dsRNA TLR3ComplexREACT_7159 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
4xPalmC-CD36REACT_150409 (Reactome)
Activated TLR1

2 or TLR 2

6 heterodimers or TLR4 homodimer		REACT_121383 (Reactome)
C-ter TLR9 dimer unmethylated CpG DNAREACT_9041 (Reactome)
C-ter-TLR9 dimerREACT_8991 (Reactome)
CD14REACT_6843 (Reactome)
Dynamin-1/2/3ArrowREACT_121112 (Reactome)
EEA1 EEA1ArrowREACT_118564 (Reactome)
EEA1 EEA1ArrowREACT_8991 (Reactome)
FlagellinREACT_9059 (Reactome)
GPIN-CD14REACT_150261 (Reactome)
GPIN-CD14REACT_150409 (Reactome)
GPIN-CD14REACT_6902 (Reactome)
Integrin alphaMbeta2REACT_150423 (Reactome)
LBP bacterial LPSREACT_6843 (Reactome)
LBP bacterial LPSREACT_6902 (Reactome)
LBPArrowREACT_6843 (Reactome)
LBPArrowREACT_6902 (Reactome)
LBPREACT_6834 (Reactome)
LPS CD14REACT_150423 (Reactome)
LPS CD14REACT_6795 (Reactome)
LPS GPI-anchored CD14ArrowREACT_6902 (Reactome)
LPS secreted CD14ArrowREACT_6843 (Reactome)
LPSREACT_6834 (Reactome)
Ligand recognized by TLR10REACT_9052 (Reactome)
Ligands recognized by TLR7 and TLR8REACT_9012 (Reactome)
MAL PIREACT_121383 (Reactome)
MyrG-p-S16-TICAM2REACT_6808 (Reactome)
N-ter TLR9 dimerREACT_118564 (Reactome)
PI3K class IIIREACT_9041 (Reactome)
PIREACT_150399 (Reactome)
PLCG2ArrowREACT_121112 (Reactome)
REACT_118564 (Reactome) TLR9 traffics to an endosomal vesicle where it is processed by cathepsin S at neural pH to generate an N-terminal product (TLR9 N-ter, aa 1-723). The N-terminal fragment of TLR9 also binds ligand, but in contrast to the C-terminal fragment it inhibits TLR9 signaling. Thus, a proper balance between the two proteolytic events probably regulates TLR9-mediated host responses. (Chockalingam A et al 2011).
REACT_118633 (Reactome) Both the full-length receptor and cleaved fragment corresponding to the C-terminal part of TLR9 were capable to bind ligand, however only processed form (TLR9 C-ter, aa 471-1032) was shown to bind MyD88 and induce signaling in different mouse cells (Ewald SE et al 2008,).
REACT_121112 (Reactome) Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta [Tanimuro N et al 2008; Kagan JC et al 2008]. While TLR4 translocation to endosomes is governed by known regulators of general endocytic processes such as dynamins and clathrin, other proteins that specifically regulate LPS-stimulated TLR4 endocytosis have been also identified [Husebye et al 2006; Kagan JC et al 2008; Zanoni I et al 2011]. Thus, CD14 has been implicated both in transporting LPS to TLR4 and in delivering TLR4 to an endosomal compartment. TLR4 translocation activated by CD14 appears to be Syk-mediated, and requires its downstream effector phospholipase C gamma 2 (PLCgamma2), which in turn induces a drop in the concentration of PIP2 required for endosomal sealing [Zanoni I et al 2011]. It has also been shown that PLCgamma2 induces inositol 1,4,5-trisphosphate (IP(3)) production and subsequent calcium (Ca2+) release. Released intracellular Ca2+ was reported to mediate TLR4 trafficking and subsequent activation of IRF3. [Aki D et al 2008; Chiang CY et al 2012].
REACT_121217 (Reactome) TRIF-related adapter molecule (TRAM or also known as TICAM2) is a sorting adapter which recruits TRIF to activated TLR4. Like TLR4, TRAM was detected both at the plasma membrane and in the endosomal compartment. TRAM was reported to recruit TRIF to the plasma membrane [Tanimuro N et al 2008]. However, TRAM did not induce TRIF-mediated signaling from the cell surface, instead, TRAM endocytosis was required for activation of IRF3 and induction of IFN-beta [Tanimuro N et al 2008; Kagan JC et al 2008]. Although, endocytosis of both TLR4 and TRAM and their association are required to trigger TRIF-mediated signaling, TRAM can target endosomes independently on its interaction with TLR4. TRAM cellular localization is controlled by myristoylation and phosphorylation of its N-terminal bipartite sorting signal motif [Kagan JC et al 2008].

TRAM has been shown to undergo phosphorylation on Ser-16 by protein kinase C epsilon in LPS-treated human THP1 and murine embryonic fibroblasts (MEF) cells [McGettrick AF et al 2006].

REACT_121383 (Reactome) TIRAP/Mal-deficient mice showed normal responses to the TLR3, TLR5, TLR7, and TLR9 ligands, but were defective in TLR4 and TLR2 ligand-induced proinflammatory cytokine production (Horng et al. 2002,Yamamoto et al. 2002). In contrast, TLR4 ligand-induced activation of IRF-3 and expression of IFN-inducible genes were not impaired in TIRAP/Mal knockout macrophages or in mice lacking both MyD88 and TIRAP/Mal (Horng et al. 2002,Yamamoto et al. 2002). Thus, TIRAP/Mal is an essential adapter that is involved in the MyD88-dependent pathway via TLR4 and TLR2, but not in the MyD88-independent pathway. Mal contains a phosphatidylinositol 4,5-bisphosphate-binding domain required for retention in the plasma membrane. The intracellular TIR domains of TLR2 or 4 associate with Mal at the cytoplasmic side of the plasma membrane, which in turn facilitates the binding of MyD88 to the activated TLR, leading to NF-kB and MAPK activation [Nunez Miguel et al 2007].
REACT_150261 (Reactome) CD14, a GPI-anchored molecule found on the cell surface of human phagocytes, has been identified as a co-receptor that interacts with LPS. CD14 has been also implicated in TLR-2 signalling [Hajishengallis G et al 2006; Zivkovic A et al 2011]. Studies have demonstrated that CD14 can bind to triacylated lipoproteins and mediate the activation of the innate immune system trough TLR2:TLR1 complex [Nakata T et al 2006; Manukyan M et al 2005; Triantafilou M et al 2006]
REACT_150399 (Reactome) Upon LPS stimulation, Mal(TIRAP) was shown to bind to PIP2-rich regions on the cell surface trough its phosphatidylinositol 4,5-bisphosphate-binding domain [Kagan JC and Medzithov R 2007]. TLR2 or 4 associates with Mal(TIRAP) on the cell surface, which in turn facilitates the binding of MyD88 to the activated TLR, leading to NF-kB and MAPK activation [Nunez Miguel R et al 2007, Nagpal K et al 2009].
REACT_150409 (Reactome) Scavenger receptor CD36 has been reported to function as an essential co-receptor involved in recognition of LTA and certain diacylated lipoproteins and presenting them to the TLR2:TLR6 heterodimer at the cell surface. CD14, a GPI-anchored molecule found on the cell surface of human phagocytes, has been also implicated in TLR2:TLR6 signaling [Stuart L et al 2005; Hoebe KP et al 2005; Triantafilou M et al 2006; Nilsen NJ et al 2008]
REACT_150423 (Reactome) Upon LPS stimulation, CD14, in addition to promote endotoxin transfer to TLR4, also triggers complement receptor 3 (CR3) activation [Troelstra A et al 1999; Kagan JC and Medzithov R 2007]. LPS-mediated CR3 upregulation results in induction of PIP5K-dependent de novo synthesis of PIP2 in the lipid rafts through the phosphorylation of PI(4)P. Mal(TIRAP) is then recruited at the site of the newly generated PIP2 where it binds TLR4 via the TIR domain. Finally, MyD88 is recruited to the activated TLR4-CD14 complex via the TIRAP molecule and initiates a signaling cascade leading to a first wave of NF-kB activation from the plasma membrane [Kagan JC and Medzithov R 2007].

CR3 (CD11b/CD18) is a member of CD18 receptor family of cell surface glycoproteins, which are expressed in human phagocytes. Each of the three receptors (CR3, lymphocyte function-associated antigen LFA-1, and p150-95) is a heterodimer composed of a beta-chain (CD18) that is identical in all three receptors and a noncovalently associated alpha chain (CD11) that is unique to each molecule [ . CR3 is known as a receptor for the surface-bound complement protein C3bi, but it has been also reported to recognize several other ligands, including bacterial patterns such as LPS and lipid A. Two distinct binding sites on CR3 have been described: 1) a protein-binding-site that binds C3bi, fibrinogen, and Leishmania glycoprotein 63, and 2) a lipid- binding-site involved in the binding of LPS, lipid A [Wright SD et al 1989; Van Strijp J.A.G et al 1993].

CR3, LFA-1 and p150-95 have been reported to mediate not only LPS interaction but also promote the binding of Escherichia coli to human macrophages [Wright SD and Jong MTC 1986].

REACT_6753 (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.
REACT_6795 (Reactome) The Toll-like receptor 4 (TLR4) is a membrane-spanning protein distantly related to the IL1 receptor. Both CD14 and members of the Toll family contain multiple leucine-rich repeats. In addition, the latter possess a Toll-homology domain in the cytoplasmic tail, which is important in the generation of a transmembrane signal linked to LPS-induced cell activation. Of all Toll family members, TLR4 is probably the exclusive receptor for LPS from most Gram negative organisms.

Toll-like receptor 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that specifically recognizes structurally diverse LPS molecules. A structural study of TLR4:MD-2 complex revealed that MD-2 interaction with TLR4 relies on hydrogen and electrostatic bonds (Kim HM et al, 2007). LPS binds to the hydrophobic pocket of MD-2 and directly mediates the dimerization of the two TLR4:MD-2 complexes in a symmetrical manner. Both hydrophobic and hydrophilic interactions contribute to the main dimerization interaction between MD-2, LPS and TLR4 multimer components. The phosphate groups of LPS also contribute to the receptor multimerization by forming ionic interactions with positively charged residues of TLR4 and MD-2. (Park BS et al, 2009).

The activated TLR4 receptor is composed of two copies of the TLR4-MD2-LPS complex and initiates signal transduction by recruiting intracellular adaptor molecules.

REACT_6808 (Reactome) TRIF-related adapter molecule (TRAM, also called TIRP or TICAM2) is 235 amino acids in length, and its TIR domain is most closely related to TRIF (and hence its name). Notably, both human and mouse TRAM contain a cysteine (C117 in humans) at the position where other adapters and TLRs have a conserved proline, although an adjacent proline (P116) is present. TRAM associates with TLR4 and TRIF, as well as the non-canonical NFkB kinases, IKK epsilon, and TBK1, which phosphorylate IRF3. TRAM provides specificity for the MyD88-independent component of TLR4 signaling.
REACT_6834 (Reactome) Lipopolysaccharide-binding protein (LBP) is a ~60-kDa serum glycoprotein which transfers LPS to both membrane-bound and soluble CD14. The LPS binding site of LBP consists of basic residues that bind the phosphorylated head of the bacterial lipid A.

LBP is an acute-phase opsonin that binds gram-negative bacteria and bacterial fragments and promote the interaction of coated bacteria with phagocytes.

REACT_6843 (Reactome) At the beginning of this reaction, 1 molecule of 'Secreted form of CD14', and 1 molecule of 'LBP complexed with bacterial LPS' are present. At the end of this reaction, 1 molecule of 'LBP', and 1 molecule of 'LPS complexed with secreted CD14' are present.



REACT_6902 (Reactome) At the beginning of this reaction, 1 molecule of 'GPI-anchored form of CD14', and 1 molecule of 'LBP complexed with bacterial LPS' are present. At the end of this reaction, 1 molecule of 'LPS complexed with GPI-anchored CD14', and 1 molecule of 'LBP' are present.



REACT_7951 (Reactome) The TLR2:TLR1 complex recognizes Neisserial PorB and Mycobacterial triacylated lipoproteins and peptides, amongst others.
REACT_7984 (Reactome) TLR2 - in combination with TLR6 - plays a major role in recognizing lipoteichoic acid (LTA) and peptidoglycan wall products from Gram-positive bacteria, as well as Mycobacterial diacylated lipopeptides.
REACT_8991 (Reactome) Synthetic oligodeoxynucleotides (ODN) expressing non-methylated CpG motifs patterned after those present in bacterial DNA have characteristic immunomodulatory effects. CpG DNA is recognized as a pathogen-associated molecular pattern by TLR9, and triggers a rapid innate immune response.
REACT_9012 (Reactome) Endosomal recognition of influenza genomic RNA and imidazoquinoline compounds occurs by means of TLR7 and TLR8.
REACT_9041 (Reactome) TLR9 signaling has the uncommon property of triggering PI3K-mediated cascades via Rab5.
REACT_9052 (Reactome) Microbal stimulation was shown to alter mRNA expression of TLR10 in human granulocytes, monocytes[Zarember KA and Godowski P 2002] and B cells[Bourke ED et al 2003]. However the natural ligand of TLR10 remains unknown.
REACT_9059 (Reactome) Fragments of extracelllar flagellin bind the TLR5 homodimer.
RP105 MD1TBarREACT_6795 (Reactome)
TIRAPREACT_150399 (Reactome)
TLR1

TLR2 ligand

CD14		REACT_7951 (Reactome)
TLR1 TLR2 recognized ligandREACT_150261 (Reactome)
TLR1 TLR2REACT_7951 (Reactome)
TLR10REACT_9052 (Reactome)
TLR3REACT_6753 (Reactome)
TLR4

MD2 LPS

CD14		REACT_6808 (Reactome)
TLR4 MD2REACT_6795 (Reactome)
TLR5REACT_9059 (Reactome)
TLR6 TLR2 recognized ligandREACT_150409 (Reactome)
TLR6 TLR2REACT_7984 (Reactome)
TLR6/2 ligand

CD14

CD36		REACT_7984 (Reactome)
TLR7 or TLR8REACT_9012 (Reactome)
TLR9REACT_118633 (Reactome)
Unmethylated CpG DNAREACT_118564 (Reactome)
Unmethylated CpG DNAREACT_118633 (Reactome)
Unmethylated CpG DNAREACT_8991 (Reactome)
Viral dsRNA REACT_6753 (Reactome)
ZFYVE20ArrowREACT_9041 (Reactome)
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