TLR Lecture
TLR Lecture
TLR Lecture
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
LipoPolySaccharides (LPS)
Large molecules found in outer membrane of Gramnegative 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
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 IRAK4, IRAK-1 and TRAF-6
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
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 IB phosphorylation results in NF- B translocation to nucleus
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)
Acknowledgements
Figures obtained from: Takeda and Akira, 2004 Wikipedia Kuby, 6th edition