Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4

@article{Yamamoto2002EssentialRF,
  title={Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4},
  author={Masahiro Yamamoto and Shintaro Sato and Hiroaki Hemmi and Hideki Sanjo and Satoshi Uematsu and Tsuneyasu Kaisho and Katsuaki Hoshino and Osamu Takeuchi and Masaya Kobayashi and Takashi Fujita and Kiyoshi Takeda and Shizuo Akira},
  journal={Nature},
  year={2002},
  volume={420},
  pages={324-329}
}
Signal transduction through Toll-like receptors (TLRs) originates from their intracellular Toll/interleukin-1 receptor (TIR) domain, which binds to MyD88, a common adaptor protein containing a TIR domain. Although cytokine production is completely abolished in MyD88-deficient mice, some responses to lipopolysaccharide (LPS), including the induction of interferon-inducible genes and the maturation of dendritic cells, are still observed. Another adaptor, TIRAP (also known as Mal), has been cloned… 

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References

SHOWING 1-10 OF 49 REFERENCES

TIRAP: an adapter molecule in the Toll signaling pathway

TLDR
A Toll–interleukin 1 receptor–containing adapter protein (TIRAP) is identified and characterized and it is shown that it controls activation of MyD88-independent signaling pathways downstream of TLR4.

Lipopolysaccharide Stimulates the MyD88-Independent Pathway and Results in Activation of IFN-Regulatory Factor 3 and the Expression of a Subset of Lipopolysaccharide-Inducible Genes1

TLDR
The characterization of the MyD88-independent pathway via TLR4 is reported, a MyD 88-dependent pathway that is critical to the induction of inflammatory cytokines and a Myd88/TNFR-associated factor 6- independent pathway that regulates induction of IP-10.

Endotoxin-Induced Maturation of MyD88-Deficient Dendritic Cells1

TLDR
The present study provides the first evidence that the MyD88-independent pathway downstrem of TLR4 can lead to functional DC maturation, which is critical for a link between innate and adaptive immunity.

Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction

TLDR
A protein is described, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-containing protein in the human genome, which is therefore an adapter in TLR-4 signal transduction.

A variety of microbial components induce tolerance to lipopolysaccharide by differentially affecting MyD88-dependent and -independent pathways.

TLDR
Each microbial component induced LPS tolerance in macrophages through down-regulation of IRAK1 expression, and Imidazoquinoline compounds, which are recognized by TLR7, had no effect on the MyD 88-independent pathway, but inhibited LPS-induced activation of MyD88-dependent signaling through down the regulation of IRAk1 expression.

Unresponsiveness of MyD88-deficient mice to endotoxin.

Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3

TLDR
It is shown that mammalian TLR3 recognizes dsRNA, and that activation of the receptor induces the activation of NF-κB and the production of type I interferons (IFNs).

TLR4, but not TLR2, mediates IFN-β–induced STAT1α/β-dependent gene expression in macrophages

TLDR
These findings provide the first mechanistic basis for differential patterns of gene expression activated by TLR4 and TLR2 agonists.

Toll-like receptor signal transduction and the tailoring of innate immunity: a role for Mal?