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

  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},
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… 

Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway

It is shown that TRIF is essential for TLR3- and TLR4-mediated signaling pathways facilitating mammalian antiviral host defense and complete loss of nuclear factor kappa B activation in response toTLR4 stimulation is demonstrated.

Interferon response induced by Toll-like receptor signaling.

Observations demonstrate that IKK-i/TBK1 signaling is essential for both TLR3-dependent and TLR 3-independent viral and dsRNA-induced IFN responses.

Interferon response induced by Toll-like receptor signaling

Observations demonstrate that IKK-i/TBK1 signaling is essential for both TLR3-dependent and TLR 3-independent viral and dsRNA-induced IFN responses.

Mal Mediates TLR-Induced Activation of CREB and Expression of IL-10

A new role is described for Mal as a key upstream regulator of CREB and as a contributor to the expression of both pro- and anti-inflammatory genes.

Toll-Like Receptors: Ligands and Signaling

In vitro studies suggested that TIRAP specifically associates with TLR4 and acts as an adaptor in the MyD88-independent signaling pathway, and studies further indicate that the TIR domain-containing molecules provide the specificity for individual TLR-mediated signaling pathways.

TLR4/MyD88/PI3K interactions regulate TLR4 signaling

A hypothetical model in which sustained PI3K activity at the membrane limits the availability of thePI3K substrate, thereby negatively regulating signaling is proposed, which would negatively regulate signaling.

MyD88 Adaptor-Like Is Not Essential for TLR2 Signaling and Inhibits Signaling by TLR31

It is revealed that Mal is dispensable inTLR2 signaling at high ligand concentrations in macrophages and dendritic cells, with MyD88 probably coupling to the TLR2 receptor complex at sufficient levels to allow activation.

Identification of Lps2 as a key transducer of MyD88-independent TIR signalling

Using N-ethyl-N-nitrosourea, a germline mutation is induced called Lps2, which abolishes cytokine responses to double-stranded RNA and severely impairs responses to the endotoxin lipopolysaccharide (LPS), indicating that TLR3 and TLR4 might share a specific, proximal transducer.

TRAM is specifically involved in the Toll-like receptor 4–mediated MyD88-independent signaling pathway

TRAM provides specificity for the MyD88-independent component of TLR4 signaling, and is identified as a fourth TIR domain–containing adaptor, TRIF-related adaptor molecule (TRAM), and analyzed its physiological function by gene targeting.



TIRAP: an adapter molecule in the Toll signaling pathway

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

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

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

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.

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

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

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?