A new molecule named Toll-interleukin 1 receptor domain (TIR)-containing adaptor molecule (TICAM-1) has been identified as the elusive adaptor molecule that induces INF- production through TLR3 signaling in a MyD88-independent pathway.
The family of ten mammalian Toll-like receptors (TLRs) initiate various signaling pathways involved in innate immune response by recognizing a variety of microbial components. Adaptor proteins act as molecular scaffolds to recruit effector molecules to TLRs. The adaptor molecule MyD88 mediates signaling via MAPK or NF-B by a handful of TLR receptors to induce the production of TNF- and interleukin-6. Another recently identified adaptor protein, TIRAP, is specific for TLR2 and TLR4, as discussed in a previous featured article, Toll-like receptors: TIRAP it up. But some TLRs participate in MyD88 and TIRAP-independent pathways, and the adaptor molecule involved in these pathways has remained unknown.
TLR3 works by recognizing microbial double-stranded RNA, inducing the production of NF-B and interferon- (IFN-), which then go on to activate macrophages and natural killer cells. By using the yeast two-hybrid system with the cytoplasmic tail of TLR3 as bait, Oshiumi et al. have now identified a new MyD88-independent adaptor protein, the Toll-interleukin 1 receptor domain (TIR)-containing adaptor molecule (TICAM-1). TICAM-1 consists of a N-terminal proline-rich domain, a C-terminal proline-rich domain and a TIR motif that bears little similarity to those of TIRAP and MyD88. Through immunoprecipitation studies the researchers found that dimerized TICAM-1 predominantly binds with TLR3, and that TICAM-1 works independently of TIRAP and MyD88. In addition the team discovered that the TIR domain of TICAM-1 is sufficient to mediate downstream TLR3 signaling and activate the IFN- promoter, with TICAM-1 also contributing to TLR3-mediated NF-B activation.
In separate studies by Yamamoto et al., published in The Journal of Immunology (J. Immunol. 169, 6668–6672), the same molecule (alternatively named TRIF) has been identified as a MyD88-independent adaptor protein. Yamamoto's group achieved these results through the use of database searches for TIR domain-containing adaptors, thus further reinforcing Seya's findings. Although in vivo relevance remains to be demonstrated, these results have helped to shed more light on the complex set of interactions that dictate TLR signaling.
The Signaling Gateway Team
References
Oshiumi, Hiroyuki Matsumoto, Misako Funami, Kenji Akazawa, Takashi Seya, Tsukasa TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon- induction.
Nature Immunology, 4, 161–167
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Imler, Jean-Luc Hoffmann, Jules A. Toll signaling: the TIReless quest for specificty.
Nature Immunology, 4, 105–106 (February 2003); 10.1038/ni0203-105 | PubMed |
production through TLR3 signaling in a MyD88-independent pathway.
B by a handful of TLR receptors to induce the production of TNF-
and interleukin-6. Another recently identified adaptor protein, TIRAP, is specific for TLR2 and TLR4, as discussed in a previous featured article, Toll-like receptors: TIRAP it up. But some TLRs participate in MyD88 and TIRAP-independent pathways, and the adaptor molecule involved in these pathways has remained unknown.
