Akira et al. and Medzhitov et al. have used knockout mice to study the adaptor protein TIRAP's role in the TLR signaling cascade, and show that TIRAP is specific to TLR2 and TLR4.
Toll-like receptors (TLR) play a critical role in early innate immunity by recognizing invading pathogens. In mammals, the TLR family consists of 10 different type-1 transmembrane receptors that are characterized by an intracellular Toll/interleukin-1 receptor (TIR) domain and an extracellular leucine-rich repeat domain. Each TLR works through a different ligand indicative of the type of pathogen invading the organism. The TLR4 receptor functions through the TIR-domain-containing adaptor proteins MyD88 and TIRAP, in response to bacterial lipopolysaccharide (LPS).
TIRAP functions downstream of TLR4 and, since its discovery in 2001, has been thought to be involved in a MyD88-independent signaling pathway. But two independent papers published in Nature now show that this may not be the case. Both Yamamoto et al. and Horng et al. show that TIRAP-deficient mice have defects in cytokine production and delayed kinetics in the LPS activation of NF-B and MAP-kinase, similar to MyD88-deficient mice, confirming that TIRAP is implicated in TLR4 signaling. TIRAP-deficient mice also show impaired response to the TLR2 ligands BLP, MALP2 and PGN, demonstrating that TIRAP has a role in TLR2 signaling.
Both papers conclude that TIRAP is not involved in TLR3, TLR5, TLR7, TLR9, IL-1 and IL-18 signaling pathways by showing that TIRAP (-/-) mice exhibit a normal response to activation of these receptors. These data indicate that MyD88 is sufficient to mediate signaling downstream of some TLRs (such as TLR7 and TLR9), but that other TLRs (such as TLR2 and TLR4) also require the TIRAP adaptor. The data also suggest that other—as yet unidentified—adaptors may be involved in MyD88-independent signaling.
Together these results define a specific role of TIRAP in signaling through a subset of TLR receptors.
The Signaling Gateway Team
References
Yamamoto, Masahiro et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4.
Nature, 420, 324–329
(21 November 2002); 10.1038/nature01182 | PubMed |
Horng, Tiffany Barton, Gregory M. Flavell, Richard A. Medzhitov, Ruslan The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors.
Nature, 420, 329–333 (21 November 2002); 10.1038/nature01180 | PubMed |
B and MAP-kinase, similar to MyD88-deficient mice, confirming that TIRAP is implicated in TLR4 signaling. TIRAP-deficient mice also show impaired response to the TLR2 ligands BLP, MALP2 and PGN, demonstrating that TIRAP has a role in TLR2 signaling.