Toll-like receptor cascades (Homo sapiens)

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44, 69, 71, 78, 8323, 64, 67, 7735, 4135, 41, 5213, 2443, 46, 9019, 40, 54, 88341950, 56, 61, 73, 81...35, 419, 53, 57, 7517, 48, 68, 8621, 59195915, 57, 78, 852, 23, 6111, 305, 20, 39, 667, 62, 72, 898, 12, 22, 42, 8684cytosolendosome lumenN-ter TLR9dimer:unmethylatedCpG DNATriacyl lipopeptide LPS Ligand recognized byTLR10Diacyl lipopeptide GPIN-CD14(20-345) GPIN-CD14(20-345) Major outer membrane protein P GPIN-CD14(20-345) fl-TLR9:unmethylatedCpG DNAGPIN-CD14(20-345) SFTPA oligomer Lipoteichoic acid LBP:bacterial LPSLBPDiacyl lipopeptide TLR3 TLR6/2ligand:CD14:CD36viral dsRNA GPIN-CD14(20-345) Imidazoquinoline compounds Unmethylated CpG DNAMAL:PI(4,5)P2:activated TLR2/4TLR2 Diacyl lipopeptide TIRAP DNM3 Activated TLR1:2 orTLR 2:6heterodimers orTLR4 homodimerMyD88 cascadeinitiated on plasmamembrane2xN4GlycoAsn-TLR4 TLR2 LPS 2xN4GlycoAsn-TLR4 TLR6:TLR2ITGAM 4xPalmC-CD36TLR4:LY96:LPS:CD14TLR2 FlagellinC-ter-TLR9 dimerLipoteichoic acid TLR7(?-1049) TLR10TLR5MyD88 dependentcascade initiatedon endosome2xN4GlycoAsn-LY96 Unmethylated CpG DNA CD14(20-345) 4xPalmC-CD36 Regulation of TLR byendogenous ligandITGAM 2xN4GlycoAsn-TLR4 Ligands recognizedby TLR7 and TLR8Dynamin-1/2/3SFTPA oligomer,SFTPD oligomeractivated TLR9:PI3Kclass IIIClostridial peptidoglycan CD14CD180 GPIN-CD14(20-345)CD14(20-345) TLR1:TLR2TLR6 Lipoteichoic acid TLR6 Lipoteichoic acid TLR6:TLR2 recognizedligandMyrG-p-S16-TICAM2PI(4,5)P2N-ter TLR9 dimerTIRAPClostridial peptidoglycan CD14(20-345) TLR7 orTLR8:recognizedligandGPIN-CD14(20-345) PLCG2GPIN-CD14(20-345) ITGB2 LY96 MyD88:Mal cascadeinitiated on plasmamembraneLPS:GPI-anchoredCD14CD14(20-345) GPIN-CD14(20-345)Ligand recognized by TLR10 Integrin alphaMbeta2LPS:CD14LPS GPIN-CD14(20-345) MyrG-p-S16-TICAM2 2xN4GlycoAsn-TLR4 TLR4 GPIN-CD14(20-345) LPS Unmethylated CpG DNA TLR5homodimer:bacterialflagellinEEA1:EEA1TLR1 TLR9(1-?) LY86 4xPalmC-CD36 DNM1 TLR7(?-1049) Unmethylated CpG DNA TLR1 TLR9(?-1032) GPIN-CD14(20-345) Clostridial peptidoglycan CD14(20-345) Trafficking andprocessing ofendosomal TLRTriacyl lipopeptide MAL:PI(4,5)P2SFTPA oligomer,SFTPD oligomerMajor outer membrane protein P Lipoteichoic acid LPS:CD14:CR32xN4GlycoAsn-LY96 TLR5 C-ter TLR9dimer:unmethylatedCpG DNATLR2 TLR2 Unmethylated CpG DNA Triacyl lipopeptide LPS:secreted CD14LPS TLR9(?-1032) DNM2 TLR3viral dsRNACD14(20-345) LPS TLR10 Diacyl lipopeptide TLR9TLR6 TLR9(1-?) GPIN-CD14(20-345) viral dsRNA :TLR3TRAM:TLR4:LY96:LPS:CD14LPS SFTPA oligomer PIK3C3 TLR1:TLR2:TLR1/2ligand:CD14PTPN4Major outer membrane protein P 2xN4GlycoAsn-LY96 LY96 TLR6:TLR2:ligand:CD14:CD36TLR4:LY96LPS Triacyl lipopeptide LPS4xPalmC-CD36 PI(4,5)P2 TLR1:TLR2 recognizedligandTLR9 ssRNA SFTPD oligomer CD14(20-345)LBPEEA1 Imidazoquinoline compounds MyrG-p-S16-TICAM2PIK3R4 TIRAP Flagellin TLR1 SFTPD oligomer TLR10 homodimerbound to ligandTLR6 2xN4GlycoAsn-LY96 PIK3R4 PIK3C3 ITGB2 ZFYVE20Diacyl lipopeptide Clostridial peptidoglycan TLR7 or TLR8TLR8 PI(4,5)P2 GPIN-CD14(20-345) TLR1:TLR2ligand:CD14TLR8 RP105:MD1PI3K class IIILBP 4xPalmC-CD36 LPS TLR1 MyD88-independentTLR3/TLR4 cascade TLR4:LY96:LPS:CD14TLR9 TLR2 Major outer membrane protein P ssRNA GPIN-CD14(20-345) TLR4 Triacyl lipopeptide BPILPS Major outer membrane protein P Clostridial peptidoglycan 18405910, 25, 26, 30, 36...76791, 32, 72, 85440618, 603551, 5818, 6016, 28, 33, 9144418359, 63, 73, 8218, 6029, 37, 87, 8841879597642, 6153, 7587426, 31, 35, 55, 801818, 6021, 597934, 3831, 3527, 40, 707947929, 3746520, 26, 39, 9346, 7214, 313, 594


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). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 168898
Reactome-version 
Reactome version: 61
Reactome Author 
Reactome Author: de Bono, Bernard, Gillespie, Marc E, Luo, F, Gay, Nicholas J

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Bibliography

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History

View all...
CompareRevisionActionTimeUserComment
129910view23:29, 23 May 2024EweitzModified title
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
ComplexR-HSA-181230 (Reactome)
BPIProteinP17213 (Uniprot-TrEMBL)
C-ter TLR9

dimer:unmethylated

CpG DNA
ComplexR-HSA-1679087 (Reactome)
C-ter-TLR9 dimerComplexR-HSA-1679581 (Reactome)
CD14(20-345) ProteinP08571 (Uniprot-TrEMBL)
CD14(20-345)ProteinP08571 (Uniprot-TrEMBL)
CD14ComplexR-HSA-166029 (Reactome)
CD180 ProteinQ99467 (Uniprot-TrEMBL)
Clostridial peptidoglycan MetaboliteCHEBI:8005 (ChEBI)
DNM1 ProteinQ05193 (Uniprot-TrEMBL)
DNM2 ProteinP50570 (Uniprot-TrEMBL)
DNM3 ProteinQ9UQ16 (Uniprot-TrEMBL)
Diacyl lipopeptide MetaboliteCHEBI:46896 (ChEBI)
Dynamin-1/2/3ComplexR-HSA-446847 (Reactome)
EEA1 ProteinQ15075 (Uniprot-TrEMBL)
EEA1:EEA1ComplexR-HSA-187897 (Reactome)
Flagellin ProteinP04949 (Uniprot-TrEMBL)
FlagellinProteinP04949 (Uniprot-TrEMBL)
GPIN-CD14(20-345) ProteinP08571 (Uniprot-TrEMBL)
GPIN-CD14(20-345)ProteinP08571 (Uniprot-TrEMBL)
ITGAM ProteinP11215 (Uniprot-TrEMBL)
ITGB2 ProteinP05107 (Uniprot-TrEMBL)
Imidazoquinoline compounds R-ALL-1216503 (Reactome)
Imidazoquinoline compounds R-ALL-188128 (Reactome)
Integrin alphaMbeta2ComplexR-HSA-202755 (Reactome)
LBP ProteinP18428 (Uniprot-TrEMBL)
LBP:bacterial LPSComplexR-HSA-166013 (Reactome)
LBPProteinP18428 (Uniprot-TrEMBL)
LPS MetaboliteCHEBI:16412 (ChEBI)
LPS:CD14:CR3ComplexR-HSA-2559438 (Reactome)
LPS:CD14ComplexR-HSA-166043 (Reactome)
LPS:GPI-anchored CD14ComplexR-HSA-166034 (Reactome)
LPS:secreted CD14ComplexR-HSA-166026 (Reactome)
LPSMetaboliteCHEBI:16412 (ChEBI)
LY86 ProteinO95711 (Uniprot-TrEMBL)
LY96 ProteinQ9Y6Y9 (Uniprot-TrEMBL)
Ligand recognized by TLR10R-NUL-168948 (Reactome)
Ligand recognized by TLR10 R-NUL-168948 (Reactome)
Ligands recognized by TLR7 and TLR8ComplexR-ALL-1216505 (Reactome)
Lipoteichoic acid MetaboliteCHEBI:28640 (ChEBI)
MAL:PI(4,5)P2:activated TLR2/4ComplexR-HSA-2559411 (Reactome)
MAL:PI(4,5)P2ComplexR-HSA-2559415 (Reactome)
Major outer membrane protein P ProteinP30690 (Uniprot-TrEMBL)
MyD88 cascade

initiated on plasma

membrane
PathwayR-HSA-975871 (Reactome) 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 endosome
PathwayR-HSA-975155 (Reactome) 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 TLR3/TLR4 cascade PathwayR-HSA-166166 (Reactome) 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.

MyD88:Mal cascade

initiated on plasma

membrane
PathwayR-HSA-166058 (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.
MyrG-p-S16-TICAM2 ProteinQ86XR7 (Uniprot-TrEMBL)
MyrG-p-S16-TICAM2ProteinQ86XR7 (Uniprot-TrEMBL)
N-ter TLR9

dimer:unmethylated

CpG DNA
ComplexR-HSA-1679094 (Reactome)
N-ter TLR9 dimerComplexR-HSA-1679574 (Reactome)
PI(4,5)P2 MetaboliteCHEBI:18348 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI3K class IIIComplexR-HSA-188015 (Reactome)
PIK3C3 ProteinQ8NEB9 (Uniprot-TrEMBL)
PIK3R4 ProteinQ99570 (Uniprot-TrEMBL)
PLCG2ProteinP16885 (Uniprot-TrEMBL)
PTPN4ProteinP29074 (Uniprot-TrEMBL)
RP105:MD1ComplexR-HSA-166154 (Reactome)
Regulation of TLR by endogenous ligandPathwayR-HSA-5686938 (Reactome) Diverse molecules of host-cell origin may serve as endogenous ligands of Toll-like receptors (TLRs) (Erridge C 2010; Piccinini AM & Midwood KS 2010). These molecules are known as damage-associated molecular patterns (DAMPs). DAMPs are immunologically silent in healthy tissues but become active upon tissue damage during both infectious and sterile insult. DAMPs are released from necrotic cells or secreted from activated cells in response to tissue damage to mediate tissue repair by promoting inflammatory responses. However, DAMPs have also been implicated in the pathogenesis of many inflammatory and autoimmune diseases, including rheumatoid arthritis (RA), cancer, and atherosclerosis. The mechanism underlying the switch from DAMPs that initiate controlled tissue repair, to those that mediate chronic, uncontrolled inflammation is still unclear. Recent evidence suggests that an abnormal increase in protein citrullination is involved in disease pathophysiology (Anzilotti C et al. 2010; Sanchez-Pernaute O et al. 2013; Sokolove J et al. 2011; Sharma P et al. 2012). Citrullination is a post-translational modification event mediated by peptidyl-arginine deaminase enzymes which catalyze the deimination of proteins by converting arginine residues into citrullines in the presence of calcium ions.
SFTPA oligomer R-HSA-391092 (Reactome)
SFTPA oligomer, SFTPD oligomerComplexR-HSA-391108 (Reactome)
SFTPD oligomer R-HSA-391097 (Reactome)
TIRAP ProteinP58753 (Uniprot-TrEMBL)
TIRAPProteinP58753 (Uniprot-TrEMBL)
TLR1 ProteinQ15399 (Uniprot-TrEMBL)
TLR10 ProteinQ9BXR5 (Uniprot-TrEMBL)
TLR10 homodimer bound to ligandComplexR-HSA-188116 (Reactome)
TLR10ProteinQ9BXR5 (Uniprot-TrEMBL)
TLR1:TLR2 ligand:CD14ComplexR-HSA-2559462 (Reactome)
TLR1:TLR2 recognized ligandComplexR-NME-168944 (Reactome)
TLR1:TLR2:TLR1/2 ligand:CD14ComplexR-HSA-181226 (Reactome)
TLR1:TLR2ComplexR-HSA-168946 (Reactome)
TLR2 ProteinO60603 (Uniprot-TrEMBL)
TLR3 ProteinO15455 (Uniprot-TrEMBL)
TLR3ProteinO15455 (Uniprot-TrEMBL)
TLR4 ProteinO00206 (Uniprot-TrEMBL)
TLR4:LY96:LPS:CD14ComplexR-HSA-166850 (Reactome)
TLR4:LY96:LPS:CD14ComplexR-HSA-2201299 (Reactome)
TLR4:LY96ComplexR-HSA-166050 (Reactome)
TLR5

homodimer:bacterial

flagellin
ComplexR-HSA-188027 (Reactome)
TLR5 ProteinO60602 (Uniprot-TrEMBL)
TLR5ProteinO60602 (Uniprot-TrEMBL)
TLR6 ProteinQ9Y2C9 (Uniprot-TrEMBL)
TLR6/2 ligand:CD14:CD36ComplexR-HSA-2559461 (Reactome)
TLR6:TLR2 recognized ligandComplexR-ALL-181407 (Reactome)
TLR6:TLR2:ligand:CD14:CD36ComplexR-HSA-181410 (Reactome)
TLR6:TLR2ComplexR-HSA-168949 (Reactome)
TLR7 or

TLR8:recognized

ligand
ComplexR-HSA-188132 (Reactome)
TLR7 or TLR8ComplexR-HSA-188166 (Reactome)
TLR7(?-1049) ProteinQ9NYK1 (Uniprot-TrEMBL)
TLR8 ProteinQ9NR97 (Uniprot-TrEMBL)
TLR9 ProteinQ9NR96 (Uniprot-TrEMBL)
TLR9(1-?) ProteinQ9NR96 (Uniprot-TrEMBL)
TLR9(?-1032) ProteinQ9NR96 (Uniprot-TrEMBL)
TLR9ProteinQ9NR96 (Uniprot-TrEMBL)
TRAM:TLR4:LY96:LPS:CD14ComplexR-HSA-166163 (Reactome)
Trafficking and

processing of

endosomal TLR
PathwayR-HSA-1679131 (Reactome) 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 DNA R-NUL-167913 (Reactome)
Unmethylated CpG DNAR-NUL-167913 (Reactome)
ZFYVE20ProteinQ9H1K0 (Uniprot-TrEMBL)
activated TLR9:PI3K class IIIComplexR-HSA-188017 (Reactome)
fl-TLR9:unmethylated CpG DNAComplexR-HSA-187884 (Reactome)
ssRNA R-NUL-167963 (Reactome)
ssRNA R-NUL-170292 (Reactome)
viral dsRNA R-VIR-6790593 (Reactome)
viral dsRNA :TLR3ComplexR-HSA-167985 (Reactome)
viral dsRNAR-VIR-6790593 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
4xPalmC-CD36R-HSA-2559464 (Reactome)
Activated TLR1:2 or

TLR 2:6 heterodimers or

TLR4 homodimer
R-HSA-2201316 (Reactome)
BPITBarR-HSA-166015 (Reactome)
C-ter TLR9

dimer:unmethylated

CpG DNA
ArrowR-HSA-187895 (Reactome)
C-ter TLR9

dimer:unmethylated

CpG DNA
R-HSA-188002 (Reactome)
C-ter-TLR9 dimerR-HSA-187895 (Reactome)
CD14(20-345)R-HSA-169719 (Reactome)
Dynamin-1/2/3ArrowR-HSA-2201293 (Reactome)
EEA1:EEA1ArrowR-HSA-1679098 (Reactome)
EEA1:EEA1ArrowR-HSA-187895 (Reactome)
FlagellinR-HSA-188025 (Reactome)
GPIN-CD14(20-345)R-HSA-166038 (Reactome)
GPIN-CD14(20-345)R-HSA-2559464 (Reactome)
GPIN-CD14(20-345)R-HSA-2559468 (Reactome)
Integrin alphaMbeta2R-HSA-2559439 (Reactome)
LBP:bacterial LPSArrowR-HSA-166015 (Reactome)
LBP:bacterial LPSR-HSA-166038 (Reactome)
LBP:bacterial LPSR-HSA-169719 (Reactome)
LBPArrowR-HSA-166038 (Reactome)
LBPArrowR-HSA-169719 (Reactome)
LBPR-HSA-166015 (Reactome)
LPS:CD14:CR3ArrowR-HSA-2559439 (Reactome)
LPS:CD14R-HSA-166041 (Reactome)
LPS:CD14R-HSA-2559439 (Reactome)
LPS:GPI-anchored CD14ArrowR-HSA-166038 (Reactome)
LPS:secreted CD14ArrowR-HSA-169719 (Reactome)
LPSR-HSA-166015 (Reactome)
Ligand recognized by TLR10R-HSA-168947 (Reactome)
Ligands recognized by TLR7 and TLR8R-HSA-167983 (Reactome)
MAL:PI(4,5)P2:activated TLR2/4ArrowR-HSA-2201316 (Reactome)
MAL:PI(4,5)P2ArrowR-HSA-2559456 (Reactome)
MAL:PI(4,5)P2R-HSA-2201316 (Reactome)
MyrG-p-S16-TICAM2ArrowR-HSA-2201341 (Reactome)
MyrG-p-S16-TICAM2R-HSA-166168 (Reactome)
MyrG-p-S16-TICAM2R-HSA-2201341 (Reactome)
N-ter TLR9

dimer:unmethylated

CpG DNA
ArrowR-HSA-1679098 (Reactome)
N-ter TLR9 dimerR-HSA-1679098 (Reactome)
PI(4,5)P2R-HSA-2559456 (Reactome)
PI3K class IIIR-HSA-188002 (Reactome)
PLCG2ArrowR-HSA-2201293 (Reactome)
PTPN4TBarR-HSA-2201341 (Reactome)
R-HSA-166015 (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.

R-HSA-166038 (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.



R-HSA-166041 (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 lymphocyte antigen 96 (LY96, also known as myeloid differentiation factor 2 (MD2)) form a heterodimer that specifically recognizes structurally diverse LPS molecules. A structural study of TLR4:LY96 complex revealed that LY96 (MD2) interaction with TLR4 relies on hydrogen and electrostatic bonds (Kim HM et al, 2007). LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. Both hydrophobic and hydrophilic interactions contribute to the main dimerization interaction between LY96, 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 LY96. (Park BS et al, 2009).

The activated TLR4 receptor is composed of two copies of the TLR4:LY96:LPS complex and initiates signal transduction by recruiting intracellular adaptor molecules.

R-HSA-166168 (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.
R-HSA-1679098 (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).
R-HSA-1679589 (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,).
R-HSA-167983 (Reactome) Endosomal recognition of influenza genomic RNA and imidazoquinoline compounds occurs by means of TLR7 and TLR8.
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-168947 (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.
R-HSA-168950 (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.
R-HSA-168951 (Reactome) The TLR2:TLR1 complex recognizes Neisserial PorB and Mycobacterial triacylated lipoproteins and peptides, amongst others.
R-HSA-169719 (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.



R-HSA-187895 (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.
R-HSA-188002 (Reactome) TLR9 signaling has the uncommon property of triggering PI3K-mediated cascades via Rab5.
R-HSA-188025 (Reactome) Fragments of extracelllar flagellin bind the TLR5 homodimer.
R-HSA-2201293 (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].
R-HSA-2201316 (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].
R-HSA-2201341 (Reactome) TRIF-related adapter molecule (TRAM or also known as TICAM2) is a sorting adapter which recruits TRIF to activated TLR4. Like TLR4, TRAM (TICAM2) was detected both at the plasma membrane and in the endosomal compartment. TICAM2 was reported to recruit TRIF to the plasma membrane (Tanimuro N et al. 2008). However, TICAM2 did not induce TRIF-mediated signaling from the cell surface, instead, TICAM2 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 TICAM2 and their association are required to trigger TRIF-mediated signaling, TICAM2 can target endosomes independently on its interaction with TLR4. TICAM2 cellular localization is controlled by myristoylation and phosphorylation of its N-terminal bipartite sorting signal motif (Kagan JC et al 2008).

TICAM2 has been shown to undergo phosphorylation on Ser-16 by protein kinase C (PKC) epsilon in LPS-treated human THP1 and murine embryonic fibroblasts (MEF) cells (McGettrick AF et al. 2006). The phosphorylation at Ser-16 by PKC epsilon was required for TICAM2 to be depleted from the membrane (McGettrick AF et al. 2006).

It has recently been demonstrated that phosphorylation of TICAM2 at tyrosine residue Y167 by an unknown protein tyrosine kinase is needed for TICAM2 translocation from the plasma membrane to the endosomal membrane, where it can associate with the activated TLR4 complex (Huai et al. 2015). PTPN4, a protein tyrosine phosphatase, dephosphorylates Y167 of TICAM2, thus inhibiting TICAM2 endocytosis (Huai et al. 2015).

R-HSA-2559439 (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].

R-HSA-2559456 (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].
R-HSA-2559464 (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]
R-HSA-2559468 (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]
RP105:MD1TBarR-HSA-166041 (Reactome)
SFTPA oligomer, SFTPD oligomerTBarR-HSA-166041 (Reactome)
SFTPA oligomer, SFTPD oligomerTBarR-HSA-168951 (Reactome)
TIRAPR-HSA-2559456 (Reactome)
TLR10 homodimer bound to ligandArrowR-HSA-168947 (Reactome)
TLR10R-HSA-168947 (Reactome)
TLR1:TLR2 ligand:CD14ArrowR-HSA-2559468 (Reactome)
TLR1:TLR2 ligand:CD14R-HSA-168951 (Reactome)
TLR1:TLR2 recognized ligandR-HSA-2559468 (Reactome)
TLR1:TLR2:TLR1/2 ligand:CD14ArrowR-HSA-168951 (Reactome)
TLR1:TLR2R-HSA-168951 (Reactome)
TLR3R-HSA-168092 (Reactome)
TLR4:LY96:LPS:CD14ArrowR-HSA-166041 (Reactome)
TLR4:LY96:LPS:CD14ArrowR-HSA-2201293 (Reactome)
TLR4:LY96:LPS:CD14R-HSA-166168 (Reactome)
TLR4:LY96:LPS:CD14R-HSA-2201293 (Reactome)
TLR4:LY96R-HSA-166041 (Reactome)
TLR5

homodimer:bacterial

flagellin
ArrowR-HSA-188025 (Reactome)
TLR5R-HSA-188025 (Reactome)
TLR6/2 ligand:CD14:CD36ArrowR-HSA-2559464 (Reactome)
TLR6/2 ligand:CD14:CD36R-HSA-168950 (Reactome)
TLR6:TLR2 recognized ligandR-HSA-2559464 (Reactome)
TLR6:TLR2:ligand:CD14:CD36ArrowR-HSA-168950 (Reactome)
TLR6:TLR2R-HSA-168950 (Reactome)
TLR7 or

TLR8:recognized

ligand
ArrowR-HSA-167983 (Reactome)
TLR7 or TLR8R-HSA-167983 (Reactome)
TLR9R-HSA-1679589 (Reactome)
TRAM:TLR4:LY96:LPS:CD14ArrowR-HSA-166168 (Reactome)
Unmethylated CpG DNAR-HSA-1679098 (Reactome)
Unmethylated CpG DNAR-HSA-1679589 (Reactome)
Unmethylated CpG DNAR-HSA-187895 (Reactome)
ZFYVE20ArrowR-HSA-188002 (Reactome)
activated TLR9:PI3K class IIIArrowR-HSA-188002 (Reactome)
fl-TLR9:unmethylated CpG DNAArrowR-HSA-1679589 (Reactome)
viral dsRNA :TLR3ArrowR-HSA-168092 (Reactome)
viral dsRNAR-HSA-168092 (Reactome)
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