Toll-like Receptor Cascades (Homo sapiens)

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8, 11, 19, 47, 6932, 5239, 45, 46, 71147, 33, 44, 55675, 8118, 29, 53, 704, 29, 382, 32, 34, 21, 34, 58, 60...20, 26, 63, 6836, 45, 48, 49, 5615, 17, 73, 864464, 76, 7844812, 3, 80cytosolendosome lumenGPIN-CD14(20-345) LY86 TLR9(1-?) TLR6 4xPalmC-CD36 CD180 TLR102xN4GlycoAsn-LY96 MyD88:MAL(TIRAP)cascade initiatedon plasma membranePIK3R4 EEA1:EEA1TLR9 TLR4:LY96ZFYVE20DNM3 Imidazoquinoline compounds TLR2 TLR10 Clostridial peptidoglycan TLR7 orTLR8:recognizedligandFlagellin GPIN-CD14(20-345) TLR5 TLR8 PTPN4Diacyl lipopeptide MyD88 cascadeinitiated on plasmamembraneRP105:MD1TLR6:TLR2Lipoteichoic acid MyrG-p-S16-TICAM2GPIN-CD14(20-345) 4xPalmC-CD36TLR7 or TLR8GPIN-CD14(20-345) activated TLR9:PI3Kclass IIILipoteichoic acid N-ter TLR9 dimerTrafficking andprocessing ofendosomal TLRLPS:secreted CD14Major outer membrane protein P TLR7(?-1049) Unmethylated CpG DNAUnmethylated CpG DNA TLR9TLR9(?-1032) CD14(20-345) DNM2 TLR6/2ligand:CD14:CD36ITGAM LPS GPIN-CD14(20-345) LPS:CD14:CR3TLR1 TLR10 homodimerbound to ligandTLR4 PIK3C3 Unmethylated CpG DNA CD14(20-345)PIK3C3 TLR2 4xPalmC-CD36 TLR6:TLR2:ligand:CD14:CD36Ligand recognized by TLR10 ssRNA TLR4:LY96:LPS:CD14LBPTriacyl lipopeptide C-ter-TLR9 dimerLigands recognizedby TLR7 and TLR8fl-TLR9:unmethylatedCpG DNAITGB2 SFTPA oligomer,SFTPD oligomerPLCG2GPIN-CD14(20-345) Clostridial peptidoglycan Integrin alphaMbeta2TLR5TLR1:TLR2 recognizedligandTLR9(?-1032) Unmethylated CpG DNA EEA1 LPS LPS TRAM:TLR4:LY96:LPS:CD14LPSLipoteichoic acid Toll Like Receptor 3(TLR3) CascadeTLR1:TLR2ITGB2 LY96 Dynamin-1/2/3LPS Major outer membrane protein P Triacyl lipopeptide SFTPD oligomer DNM1 LPS TLR1 SFTPA oligomer,SFTPD oligomerCD14(20-345) LPS:CD14Regulation of TLR byendogenous ligandMajor outer membrane protein P TLR2 2xN4GlycoAsn-TLR4 MyD88-independentTLR4 cascade GPIN-CD14(20-345) TLR9(1-?) TLR1:TLR2ligand:CD14BPITLR4:LY96:LPS:CD14GPIN-CD14(20-345)PI3K class IIITriacyl lipopeptide SFTPA oligomer Diacyl lipopeptide LBP TLR4 Diacyl lipopeptide GPIN-CD14(20-345) ssRNA TLR6:TLR2 recognizedligandTLR1:TLR2:TLR1/2ligand:CD14LBP:bacterial LPSLPS TLR2 ITGAM 2xN4GlycoAsn-TLR4 GPIN-CD14(20-345) LBPTLR9 TLR5homodimer:bacterialflagellinSFTPD oligomer MyrG-p-S16-TICAM2Ligand recognized byTLR10TLR6 2xN4GlycoAsn-LY96 TLR7(?-1049) GPIN-CD14(20-345) C-ter TLR9dimer:unmethylatedCpG DNALPS PIK3R4 Imidazoquinoline compounds N-ter TLR9dimer:unmethylatedCpG DNALPS MyrG-p-S16-TICAM2 LY96 GPIN-CD14(20-345)FlagellinMyD88 dependentcascade initiatedon endosomeSFTPA oligomer TLR8 LPS:GPI-anchoredCD14Unmethylated CpG DNA Clostridial peptidoglycan CD14(20-345) 24, 5724, 578176, 7, 625, 8130, 8184517513, 20, 63, 797267, 77241, 9, 8540432412, 23, 54, 654, 3833, 35, 41, 5125, 2810, 16, 31, 50, 61...7235, 418472723437813, 257243307242, 6422, 27, 58, 813, 25, 37, 59, 7917, 86


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: 66
Reactome Author 
Reactome Author: de Bono, Bernard, Gillespie, Marc E, Luo, F, Gay, Nicholas J

Quality Tags

Ontology Terms

 

Bibliography

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  1. Sen GC, Sarkar SN.; ''Transcriptional signaling by double-stranded RNA: role of TLR3.''; PubMed
  2. Wagner H.; ''The immunobiology of the TLR9 subfamily.''; PubMed
  3. Chockalingam A, Cameron JL, Brooks JC, Leifer CA.; ''Negative regulation of signaling by a soluble form of toll-like receptor 9.''; PubMed
  4. Aliprantis AO, Yang RB, Mark MR, Suggett S, Devaux B, Radolf JD, Klimpel GR, Godowski P, Zychlinsky A.; ''Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2.''; PubMed
  5. Manukyan M, Triantafilou K, Triantafilou M, Mackie A, Nilsen N, Espevik T, Wiesmüller KH, Ulmer AJ, Heine H.; ''Binding of lipopeptide to CD14 induces physical proximity of CD14, TLR2 and TLR1.''; PubMed
  6. Cherfils-Vicini J, Platonova S, Gillard M, Laurans L, Validire P, Caliandro R, Magdeleinat P, Mami-Chouaib F, Dieu-Nosjean MC, Fridman WH, Damotte D, Sautès-Fridman C, Cremer I.; ''Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance.''; PubMed
  7. Gangloff M, Gay NJ.; ''MD-2: the Toll 'gatekeeper' in endotoxin signalling.''; PubMed
  8. Heine H, Ulmer AJ.; ''Recognition of bacterial products by toll-like receptors.''; PubMed
  9. Carpenter S, O'Neill LA.; ''Recent insights into the structure of Toll-like receptors and post-translational modifications of their associated signalling proteins.''; PubMed
  10. Barton GM, Kagan JC, Medzhitov R.; ''Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA.''; PubMed
  11. Takeda K, Akira S.; ''Toll-like receptors in innate immunity.''; PubMed
  12. Schaefer L.; ''Complexity of danger: the diverse nature of damage-associated molecular patterns.''; PubMed
  13. Govindaraj RG, Manavalan B, Basith S, Choi S.; ''Comparative analysis of species-specific ligand recognition in Toll-like receptor 8 signaling: a hypothesis.''; PubMed
  14. Wright SD, Tobias PS, Ulevitch RJ, Ramos RA.; ''Lipopolysaccharide (LPS) binding protein opsonizes LPS-bearing particles for recognition by a novel receptor on macrophages.''; PubMed
  15. Kagan JC, Medzhitov R.; ''Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling.''; PubMed
  16. Liu L, Botos I, Wang Y, Leonard JN, Shiloach J, Segal DM, Davies DR.; ''Structural basis of toll-like receptor 3 signaling with double-stranded RNA.''; PubMed
  17. Wright SD, Levin SM, Jong MT, Chad Z, Kabbash LG.; ''CR3 (CD11b/CD18) expresses one binding site for Arg-Gly-Asp-containing peptides and a second site for bacterial lipopolysaccharide.''; PubMed
  18. McNamara N, Gallup M, Sucher A, Maltseva I, McKemy D, Basbaum C.; ''AsialoGM1 and TLR5 cooperate in flagellin-induced nucleotide signaling to activate Erk1/2.''; PubMed
  19. Akira S.; ''Toll-like receptor signaling.''; PubMed
  20. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S.; ''Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8.''; PubMed
  21. Schwandner R, Dziarski R, Wesche H, Rothe M, Kirschning CJ.; ''Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2.''; PubMed
  22. Cot M, Ray A, Gilleron M, Vercellone A, Larrouy-Maumus G, Armau E, Gauthier S, Tiraby G, Puzo G, Nigou J.; ''Lipoteichoic acid in Streptomyces hygroscopicus: structural model and immunomodulatory activities.''; PubMed
  23. Erridge C.; ''Endogenous ligands of TLR2 and TLR4: agonists or assistants?''; PubMed
  24. da Silva Correia J, Ulevitch RJ.; ''MD-2 and TLR4 N-linked glycosylations are important for a functional lipopolysaccharide receptor.''; PubMed
  25. Chen J, Nag S, Vidi PA, Irudayaraj J.; ''Single molecule in vivo analysis of toll-like receptor 9 and CpG DNA interaction.''; PubMed
  26. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S.; ''Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway.''; PubMed
  27. Takeuchi O, Kawai T, Mühlradt PF, Morr M, Radolf JD, Zychlinsky A, Takeda K, Akira S.; ''Discrimination of bacterial lipoproteins by Toll-like receptor 6.''; PubMed
  28. Latz E, Verma A, Visintin A, Gong M, Sirois CM, Klein DC, Monks BG, McKnight CJ, Lamphier MS, Duprex WP, Espevik T, Golenbock DT.; ''Ligand-induced conformational changes allosterically activate Toll-like receptor 9.''; PubMed
  29. Beutler B.; ''Inferences, questions and possibilities in Toll-like receptor signalling.''; PubMed
  30. Jin MS, Kim SE, Heo JY, Lee ME, Kim HM, Paik SG, Lee H, Lee JO.; ''Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide.''; PubMed
  31. de Bouteiller O, Merck E, Hasan UA, Hubac S, Benguigui B, Trinchieri G, Bates EE, Caux C.; ''Recognition of double-stranded RNA by human toll-like receptor 3 and downstream receptor signaling requires multimerization and an acidic pH.''; PubMed
  32. Hoarau C, Gérard B, Lescanne E, Henry D, François S, Lacapère JJ, El Benna J, Dang PM, Grandchamp B, Lebranchu Y, Gougerot-Pocidalo MA, Elbim C.; ''TLR9 activation induces normal neutrophil responses in a child with IRAK-4 deficiency: involvement of the direct PI3K pathway.''; PubMed
  33. da Silva Correia J, Soldau K, Christen U, Tobias PS, Ulevitch RJ.; ''Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex. transfer from CD14 to TLR4 and MD-2.''; PubMed
  34. Okusawa T, Fujita M, Nakamura J, Into T, Yasuda M, Yoshimura A, Hara Y, Hasebe A, Golenbock DT, Morita M, Kuroki Y, Ogawa T, Shibata K.; ''Relationship between structures and biological activities of mycoplasmal diacylated lipopeptides and their recognition by toll-like receptors 2 and 6.''; PubMed
  35. Kim HM, Park BS, Kim JI, Kim SE, Lee J, Oh SC, Enkhbayar P, Matsushima N, Lee H, Yoo OJ, Lee JO.; ''Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran.''; PubMed
  36. Husebye H, Halaas Ø, Stenmark H, Tunheim G, Sandanger Ø, Bogen B, Brech A, Latz E, Espevik T.; ''Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity.''; PubMed
  37. Chockalingam A, Brooks JC, Cameron JL, Blum LK, Leifer CA.; ''TLR9 traffics through the Golgi complex to localize to endolysosomes and respond to CpG DNA.''; PubMed
  38. Massari P, Visintin A, Gunawardana J, Halmen KA, King CA, Golenbock DT, Wetzler LM.; ''Meningococcal porin PorB binds to TLR2 and requires TLR1 for signaling.''; PubMed
  39. Huai W, Song H, Wang L, Li B, Zhao J, Han L, Gao C, Jiang G, Zhang L, Zhao W.; ''Phosphatase PTPN4 preferentially inhibits TRIF-dependent TLR4 pathway by dephosphorylating TRAM.''; PubMed
  40. Divanovic S, Trompette A, Atabani SF, Madan R, Golenbock DT, Visintin A, Finberg RW, Tarakhovsky A, Vogel SN, Belkaid Y, Kurt-Jones EA, Karp CL.; ''Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105.''; PubMed
  41. Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO.; ''The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex.''; PubMed
  42. Núñez Miguel R, Wong J, Westoll JF, Brooks HJ, O'Neill LA, Gay NJ, Bryant CE, Monie TP.; ''A dimer of the Toll-like receptor 4 cytoplasmic domain provides a specific scaffold for the recruitment of signalling adaptor proteins.''; PubMed
  43. Tao N, Wagner SJ, Lublin DM.; ''CD36 is palmitoylated on both N- and C-terminal cytoplasmic tails.''; PubMed
  44. Fenton MJ, Golenbock DT.; ''LPS-binding proteins and receptors.''; PubMed
  45. Kagan JC, Su T, Horng T, Chow A, Akira S, Medzhitov R.; ''TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta.''; PubMed
  46. McGettrick AF, Brint EK, Palsson-McDermott EM, Rowe DC, Golenbock DT, Gay NJ, Fitzgerald KA, O'Neill LA.; ''Trif-related adapter molecule is phosphorylated by PKC{epsilon} during Toll-like receptor 4 signaling.''; PubMed
  47. Kawai T, Akira S.; ''Pathogen recognition with Toll-like receptors.''; PubMed
  48. Aki D, Minoda Y, Yoshida H, Watanabe S, Yoshida R, Takaesu G, Chinen T, Inaba T, Hikida M, Kurosaki T, Saeki K, Yoshimura A.; ''Peptidoglycan and lipopolysaccharide activate PLCgamma2, leading to enhanced cytokine production in macrophages and dendritic cells.''; PubMed
  49. Chiang CY, Veckman V, Limmer K, David M.; ''Phospholipase Cγ-2 and intracellular calcium are required for lipopolysaccharide-induced Toll-like receptor 4 (TLR4) endocytosis and interferon regulatory factor 3 (IRF3) activation.''; PubMed
  50. Tokisue T, Watanabe T, Tsujita T, Nishikawa S, Hasegawa T, Seya T, Matsumoto M, Fukuda K.; ''Significance of the N-terminal histidine-rich region for the function of the human toll-like receptor 3 ectodomain.''; PubMed
  51. Akashi S, Saitoh S, Wakabayashi Y, Kikuchi T, Takamura N, Nagai Y, Kusumoto Y, Fukase K, Kusumoto S, Adachi Y, Kosugi A, Miyake K.; ''Lipopolysaccharide interaction with cell surface Toll-like receptor 4-MD-2: higher affinity than that with MD-2 or CD14.''; PubMed
  52. Takeshita F, Gursel I, Ishii KJ, Suzuki K, Gursel M, Klinman DM.; ''Signal transduction pathways mediated by the interaction of CpG DNA with Toll-like receptor 9.''; PubMed
  53. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A.; ''The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5.''; PubMed
  54. Yu L, Wang L, Chen S.; ''Endogenous toll-like receptor ligands and their biological significance.''; PubMed
  55. Elner SG, Petty HR, Elner VM, Yoshida A, Bian ZM, Yang D, Kindzelskii AL.; ''TLR4 mediates human retinal pigment epithelial endotoxin binding and cytokine expression.''; PubMed
  56. Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, Granucci F, Kagan JC.; ''CD14 controls the LPS-induced endocytosis of Toll-like receptor 4.''; PubMed
  57. Ohnishi T, Muroi M, Tanamoto K.; ''N-linked glycosylations at Asn(26) and Asn(114) of human MD-2 are required for toll-like receptor 4-mediated activation of NF-kappaB by lipopolysaccharide.''; PubMed
  58. Hajjar AM, O'Mahony DS, Ozinsky A, Underhill DM, Aderem A, Klebanoff SJ, Wilson CB.; ''Cutting edge: functional interactions between toll-like receptor (TLR) 2 and TLR1 or TLR6 in response to phenol-soluble modulin.''; PubMed
  59. Latz E, Schoenemeyer A, Visintin A, Fitzgerald KA, Monks BG, Knetter CF, Lien E, Nilsen NJ, Espevik T, Golenbock DT.; ''TLR9 signals after translocating from the ER to CpG DNA in the lysosome.''; PubMed
  60. Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, Takeda K, Akira S.; ''Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components.''; PubMed
  61. Funami K, Matsumoto M, Oshiumi H, Akazawa T, Yamamoto A, Seya T.; ''The cytoplasmic 'linker region' in Toll-like receptor 3 controls receptor localization and signaling.''; PubMed
  62. Hanten JA, Vasilakos JP, Riter CL, Neys L, Lipson KE, Alkan SS, Birmachu W.; ''Comparison of human B cell activation by TLR7 and TLR9 agonists.''; PubMed
  63. Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, Lipford G, Bauer S.; ''Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848.''; PubMed
  64. Fitzgerald KA, Rowe DC, Golenbock DT.; ''Endotoxin recognition and signal transduction by the TLR4/MD2-complex.''; PubMed
  65. Piccinini AM, Midwood KS.; ''DAMPening inflammation by modulating TLR signalling.''; PubMed
  66. Gibbard RJ, Morley PJ, Gay NJ.; ''Conserved features in the extracellular domain of human toll-like receptor 8 are essential for pH-dependent signaling.''; PubMed
  67. Hasan U, Chaffois C, Gaillard C, Saulnier V, Merck E, Tancredi S, Guiet C, Brière F, Vlach J, Lebecque S, Trinchieri G, Bates EE.; ''Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through MyD88.''; PubMed
  68. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C.; ''Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.''; PubMed
  69. Takeda K, Akira S.; ''TLR signaling pathways.''; PubMed
  70. Smith MF, Mitchell A, Li G, Ding S, Fitzmaurice AM, Ryan K, Crowe S, Goldberg JB.; ''Toll-like receptor (TLR) 2 and TLR5, but not TLR4, are required for Helicobacter pylori-induced NF-kappa B activation and chemokine expression by epithelial cells.''; PubMed
  71. Tanimura N, Saitoh S, Matsumoto F, Akashi-Takamura S, Miyake K.; ''Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling.''; PubMed
  72. Kawai T, Akira S.; ''TLR signaling.''; PubMed
  73. Troelstra A, de Graaf-Miltenburg LA, van Bommel T, Verhoef J, Van Kessel KP, Van Strijp JA.; ''Lipopolysaccharide-coated erythrocytes activate human neutrophils via CD14 while subsequent binding is through CD11b/CD18.''; PubMed
  74. Means TK, Wang S, Lien E, Yoshimura A, Golenbock DT, Fenton MJ.; ''Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis.''; PubMed
  75. Nyman T, Stenmark P, Flodin S, Johansson I, Hammarström M, Nordlund P.; ''The crystal structure of the human toll-like receptor 10 cytoplasmic domain reveals a putative signaling dimer.''; PubMed
  76. Yamamoto M, Sato S, Mori K, Hoshino K, Takeuchi O, Takeda K, Akira S.; ''Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling.''; PubMed
  77. Zhang Z, Louboutin JP, Weiner DJ, Goldberg JB, Wilson JM.; ''Human airway epithelial cells sense Pseudomonas aeruginosa infection via recognition of flagellin by Toll-like receptor 5.''; PubMed
  78. Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, Takeuchi O, Takeda K, Akira S.; ''TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway.''; PubMed
  79. Wei T, Gong J, Jamitzky F, Heckl WM, Stark RW, Rössle SC.; ''Homology modeling of human Toll-like receptors TLR7, 8, and 9 ligand-binding domains.''; PubMed
  80. Ewald SE, Lee BL, Lau L, Wickliffe KE, Shi GP, Chapman HA, Barton GM.; ''The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor.''; PubMed
  81. Triantafilou M, Gamper FG, Haston RM, Mouratis MA, Morath S, Hartung T, Triantafilou K.; ''Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 heterodimers at the cell surface determines heterotypic associations with CD36 and intracellular targeting.''; PubMed
  82. Häcker H, Mischak H, Miethke T, Liptay S, Schmid R, Sparwasser T, Heeg K, Lipford GB, Wagner H.; ''CpG-DNA-specific activation of antigen-presenting cells requires stress kinase activity and is preceded by non-specific endocytosis and endosomal maturation.''; PubMed
  83. Ewald SE, Engel A, Lee J, Wang M, Bogyo M, Barton GM.; ''Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase.''; PubMed
  84. Kishore U, Greenhough TJ, Waters P, Shrive AK, Ghai R, Kamran MF, Bernal AL, Reid KB, Madan T, Chakraborty T.; ''Surfactant proteins SP-A and SP-D: structure, function and receptors.''; PubMed
  85. Vercammen E, Staal J, Beyaert R.; ''Sensing of viral infection and activation of innate immunity by toll-like receptor 3.''; PubMed
  86. Wright SD, Jong MT.; ''Adhesion-promoting receptors on human macrophages recognize Escherichia coli by binding to lipopolysaccharide.''; PubMed

History

View all...
CompareRevisionActionTimeUserComment
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

View all...
NameTypeDatabase referenceComment
2xN4GlycoAsn-LY96 ProteinQ9Y6Y9 (Uniprot-TrEMBL)
2xN4GlycoAsn-TLR4 ProteinO00206 (Uniprot-TrEMBL)
4xPalmC-CD36 ProteinP16671 (Uniprot-TrEMBL)
4xPalmC-CD36ProteinP16671 (Uniprot-TrEMBL)
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)
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-ALL-168948 (Reactome)
Ligand recognized by TLR10 R-ALL-168948 (Reactome)
Ligands recognized by TLR7 and TLR8ComplexR-ALL-1216505 (Reactome)
Lipoteichoic acid MetaboliteCHEBI:28640 (ChEBI)
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 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(TIRAP)

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)
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)
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)
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)
Toll Like Receptor 3 (TLR3) CascadePathwayR-HSA-168164 (Reactome) 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.

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-ALL-167913 (Reactome)
Unmethylated CpG DNAR-ALL-167913 (Reactome)
ZFYVE20ProteinQ9H1K0 (Uniprot-TrEMBL)
activated TLR9:PI3K class IIIComplexR-HSA-188017 (Reactome)
fl-TLR9:unmethylated CpG DNAComplexR-HSA-187884 (Reactome)
ssRNA R-ALL-167963 (Reactome)
ssRNA R-ALL-170292 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
4xPalmC-CD36R-HSA-2559464 (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)
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)
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-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-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-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)
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)
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)
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