TollLike Receptors TLR TollLike Receptor Signaling Toll receptor

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Toll-Like Receptors (TLR)

Toll-Like Receptors (TLR)

Toll-Like Receptor Signaling • Toll receptor initially discovered in Drosophila as important receptor in

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

Toll-Like Receptors

Toll-Like Receptors

Toll-Like Receptors

Toll-Like Receptors

Lipo. Poly. Saccharides (LPS) • Large molecules found in outer membrane of Gramnegative bacteria

Lipo. Poly. Saccharides (LPS) • Large molecules found in outer membrane of Gramnegative bacteria • Comprised of a lipid and saccharide component • Highly immunogenic • Recognized by TLR 4 • 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

Viral Nucleic Acids • TLR 3, TLR 7 and TLR 8 detect viral nucleic

Viral Nucleic Acids • TLR 3, TLR 7 and TLR 8 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 TLR 3 that mimics binding of ds. RNA to TLR 3

TLRs and TIR Domain Ø Cytoplasmic tails of TLRs show similarities to IL-1 receptor

TLRs and TIR Domain Ø Cytoplasmic tails of TLRs show similarities to IL-1 receptor (TIR) Ø Common adaptor to TLRs is My. D 88 Ø Crucial proline residue in all TLR TIR domains, except TLR 3 Ø If substituted with histidine, no signaling occurs Ø All TLRs likely have a My. D 88 pathway (TLR 3 is an exception) Ø TLR 4 has a My. D 88 independent pathway as well Cytoplasmic TIR domain

My. D 88 Adaptor Ø My. D 88 knockout mice have no response to

My. D 88 Adaptor Ø My. D 88 knockout mice have no response to LPS Ø My. D 88 is essential to all inflammatory signaling pathways Ø My. D 88 s, a splice variant of My. D 88 down regulates the inflammatory response Ø My. D 88 interacts with TIR domain of TLR and recruits IRAK-4, IRAK 1 and TRAF-6

IRAK and TRAF 6 • 4 IRAKs known, IRAK 1, IRAK-2, IRAK-M and IRAK-4

IRAK and TRAF 6 • 4 IRAKs known, IRAK 1, 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 • TRAF 6 is a member of the TNF receptor associated factor (TRAF) family • TRAF 6 interacts with IRAK-1 and gets activated • Release of TRAF 6/IRAK-1 ensues

IRAK and TRAF 6 Release • TRAF 6/IRAK-1 complex associates with 3 proteins –

IRAK and TRAF 6 Release • TRAF 6/IRAK-1 complex associates with 3 proteins – TAK 1 (TGF-B activated kinase) – TAB 1 (TAK 1 binding proteins) – TAB 2 (TAK 1 binding proteins) • Large complex associates with membrane • Eventually IRAK-1 stays in membrane while TRAF 6/TAK 1/TAB 2 move to cytosol • E 2 Ligases such as Ubc 13 and Uev 1 A join further enlarging complex

TAK-1 Activation • The enlarged complex that includes – TRAF 6, TAK 1, TAB

TAK-1 Activation • The enlarged complex that includes – TRAF 6, TAK 1, TAB 2, Ubc 13, Uev 1 A activate TAK 1 • Activated TAK 1 phosphorylates IKK complex • Activated TAK 1 can also phosphorylate MAP Kinases • IKK complex consists of IKK , and /NEMO • I B phosphorylation results in NF- B translocation to nucleus

My. D 88 Independent Pathway Ø My. D 88 Knock out mice do not

My. D 88 Independent Pathway Ø My. D 88 Knock out mice do not produce inflammatory cytokines such as TNF- Ø However with TLR 4 stimulation NF- B and JNK delayed activity occurs Ø This strongly suggests the existence of 2 pathways in TLR signaling § a My. D 88 dependent pathway (early) § a My. D 88 independent pathway (late) Ø TLR 3 stimulation also exchibits a My. D 88 independent pathway TLR 4

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

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