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).
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Reactome Author: de Bono, Bernard, Gillespie, Marc E, Luo, F, Gay, Nicholas J
Carpenter S, O'Neill LA.; ''Recent insights into the structure of Toll-like receptors and post-translational modifications of their associated signalling proteins.''; PubMedEurope PMCScholia
Bas S, Neff L, Vuillet M, Spenato U, Seya T, Matsumoto M, Gabay C.; ''The proinflammatory cytokine response to Chlamydia trachomatis elementary bodies in human macrophages is partly mediated by a lipoprotein, the macrophage infectivity potentiator, through TLR2/TLR1/TLR6 and CD14.''; PubMedEurope PMCScholia
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da Silva Correia J, Ulevitch RJ.; ''MD-2 and TLR4 N-linked glycosylations are important for a functional lipopolysaccharide receptor.''; PubMedEurope PMCScholia
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Vercammen E, Staal J, Beyaert R.; ''Sensing of viral infection and activation of innate immunity by toll-like receptor 3.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Wright SD, Jong MT.; ''Adhesion-promoting receptors on human macrophages recognize Escherichia coli by binding to lipopolysaccharide.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Yu L, Wang L, Chen S.; ''Endogenous toll-like receptor ligands and their biological significance.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Fitzgerald KA, Rowe DC, Golenbock DT.; ''Endotoxin recognition and signal transduction by the TLR4/MD2-complex.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Means TK, Wang S, Lien E, Yoshimura A, Golenbock DT, Fenton MJ.; ''Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Gangloff M, Gay NJ.; ''MD-2: the Toll 'gatekeeper' in endotoxin signalling.''; PubMedEurope PMCScholia
Sen GC, Sarkar SN.; ''Transcriptional signaling by double-stranded RNA: role of TLR3.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Barton GM, Kagan JC, Medzhitov R.; ''Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Chen J, Nag S, Vidi PA, Irudayaraj J.; ''Single molecule in vivo analysis of toll-like receptor 9 and CpG DNA interaction.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Tao N, Wagner SJ, Lublin DM.; ''CD36 is palmitoylated on both N- and C-terminal cytoplasmic tails.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Chockalingam A, Cameron JL, Brooks JC, Leifer CA.; ''Negative regulation of signaling by a soluble form of toll-like receptor 9.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Beutler B.; ''Inferences, questions and possibilities in Toll-like receptor signalling.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO.; ''The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Wright SD, Tobias PS, Ulevitch RJ, Ramos RA.; ''Lipopolysaccharide (LPS) binding protein opsonizes LPS-bearing particles for recognition by a novel receptor on macrophages.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Govindaraj RG, Manavalan B, Basith S, Choi S.; ''Comparative analysis of species-specific ligand recognition in Toll-like receptor 8 signaling: a hypothesis.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Schaefer L.; ''Complexity of danger: the diverse nature of damage-associated molecular patterns.''; PubMedEurope PMCScholia
Li Y, Chen M, Cao H, Zhu Y, Zheng J, Zhou H.; ''Extraordinary GU-rich single-strand RNA identified from SARS coronavirus contributes an excessive innate immune response.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.
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 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.
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.
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.
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.
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).
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.
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.
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.
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.
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).
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,).
Endosomal recognition of viral single stranded (ss) RNA and imidazoquinoline compounds occurs by means of TLR7 and TLR8. Structural analyses have revealed that both TLR7 and TLR8 possess two binding sites which do not share the same specificities (Zhang Z et al. 2016). The binding site 1 is highly conserved between TLR7 and TLR8 and binds nucleosides (guanosine (G) for TLR7 and uridine (U) for TLR8) or base analogs. Binding site 2 of TLR7 and TLR8 is less conserved and binds ssRNA with U(U) and U(G) motifs. TLR7 acts as a dual receptor for G and U-containing ssRNAs. Binding of ssRNA to the site 2 of TLR7 strongly enhances the interaction of TLR7 and G at the first site leading to subsequent receptor dimerization. Conversely, chemical ligands are adequately potent to induce TLR7 dimerization by binding to the first site alone (Zhang Z et al. 2016, 2018). Further, upon ligand stimulation, the TLR8 dimer was reorganized such that the two C termini were brought into proximity (Tanji H et al. 2013). The loop between leucine-rich repeat 14 (LRR14) and LRR15 was cleaved; however, the N- and C-terminal halves remained associated and contributed to ligand recognition and dimerization, which enables downstream signaling processes (Tanji H et al. 2013, 2016).
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.
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.
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.
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.
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].
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).
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].
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]
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]
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dimer:unmethylated
CpG DNAinitiated on plasma
membranecascade initiated
on endosomeTRIF recruitment to TLR complex stimulates distinct pathways leading to production of type 1 interferons (IFNs), pro-inflammatory cytokines and induction of programmed cell death.
cascade initiated
on plasma membranedimer:unmethylated
CpG DNAhomodimer:bacterial
flagellinTLR8:recognized
ligandMammalian 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.
processing of
endosomal TLRUnder 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).
Annotated Interactions
dimer:unmethylated
CpG DNAdimer:unmethylated
CpG DNAdimer:unmethylated
CpG DNALBP is an acute-phase opsonin that binds gram-negative bacteria and bacterial fragments and promote the interaction of coated bacteria with phagocytes.
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.
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).
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].
homodimer:bacterial
flagellinTLR8:recognized
ligand