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Toll-Like Receptors (TLR)

Toll-Like Receptors (TLR)

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Toll-Like Receptors (TLR)

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  1. Toll-Like Receptors (TLR)

  2. Toll-Like Receptor Signaling • Toll receptor initially discovered in Drosophila as important receptor in dorso-ventral embryonic pattern • Toll mutants refers to the fact that these mutants could not establish a proper dorsal-ventral axis • Toll in German means ‘great’, apparently this was one of the words describing the scientists’ enthusiasm after observing the mutant flies • Hoffman and colleagues showed that Toll-mutant flies susceptible to fungal infections • Mammalian homologues discovered and designated as Toll-Like Receptors (TLR) • TLRs recognize specific patterns in pathogens which are not observed in mammals

  3. Toll-Like Receptors

  4. Toll-Like Receptors

  5. LipoPolySaccharides (LPS) • Large molecules found in outer membrane of Gram- negative bacteria • Comprised of a lipid and saccharide component • Highly immunogenic • Recognized by TLR4 • Can cause septic shock and lead to death • Often referred to as Endotoxin since it is not secreted but is a byproduct of bacterial lysis • Great variability among different bacterial strains

  6. Viral Nucleic Acids • TLR3, TLR7 and TLR8 detect viral nucleic acids • Found in intracellular membranes since viral nucleic acids are endogenously generated • Note the TIR domains of these TLRs face the cytosol of the cell • Poly I:C is an agonist for TLR3 that mimics binding of dsRNA to TLR3

  7. Cytoplasmic TIR domain TLRs and TIR Domain • Cytoplasmic tails of TLRs show similarities to IL-1 receptor (TIR) • Common adaptor to TLRs is MyD88 • Crucial proline residue in all TLR TIR domains, except TLR3 • If substituted with histidine, no signaling occurs • All TLRs likely have a MyD88 pathway (TLR3 is an exception) • TLR4 has a MyD88 independent pathway as well

  8. MyD88 Adaptor • MyD88 knockout mice have no response to LPS • MyD88 is essential to all inflammatory signaling pathways • MyD88s, a splice variant of MyD88 down regulates the inflammatory response • MyD88 interacts with TIR domain of TLR and recruits IRAK-4, IRAK-1 and TRAF-6

  9. IRAK and TRAF6 • 4 IRAKs known, IRAK1, IRAK-2, IRAK-M and IRAK-4 • IRAK are serine/threonine kinases • IRAK-4 phosphorylates IRAK-1 • IRAK-M plays an inhibitory role in TLR signaling • IRAK-4 phosphorylates IRAK-1 • TRAF6 is a member of the TNF receptor associated factor (TRAF) family • TRAF6 interacts with IRAK-1 and gets activated • Release of TRAF6/IRAK-1 ensues

  10. IRAK and TRAF6 Release • TRAF6/IRAK-1 complex associates with 3 proteins • TAK1 (TGF-B activated kinase) • TAB1 (TAK1 binding proteins) • TAB2 (TAK1 binding proteins) • Large complex associates with membrane • Eventually IRAK-1 stays in membrane while TRAF6/TAK1/TAB1/TAB2 move to cytosol • E2 Ligases such as Ubc13 and Uev1A join further enlarging complex

  11. TAK-1 Activation • The enlarged complex that includes • TRAF6, TAK1, TAB1, TAB2, Ubc13, Uev1A activate TAK1 • Activated TAK1 phosphorylates IKK complex • Activated TAK1 can also phosphorylate MAP Kinases • IKK complex consists of IKK,  and /NEMO • IB phosphorylation results in NF- B translocation to nucleus

  12. MyD88 Independent Pathway • MyD88 Knock out mice do not produce inflammatory cytokines such as TNF- • However with TLR4 stimulation NF-B and JNK delayed activity occurs • This strongly suggests the existence of 2 pathways in TLR signaling • a MyD88 dependent pathway (early) • a MyD88 independent pathway (late) • TLR3 stimulation also exchibits a MyD88 independent pathway TLR4

  13. Acknowledgements • Figures obtained from: • Takeda and Akira, 2004 • Wikipedia • Kuby, 6th edition