Comparative and phylogenetic analyses of three TIR domain-containing adaptors in metazoans: implications for evolution of TLR signaling pathways.

Toll-like receptor adaptor molecule 1/2 (TICAM-1/2) and Toll-interleukin 1 receptor (TIR) domain-containing adaptor protein (TIRAP) play key roles in the Toll-like receptor (TLR) signaling pathways, which respond to viral and bacterial infections. These genes have been identified and studied in several vertebrates. However, our understanding of their evolutionary history and their roles in immune responses is far from complete. In this study, comparative and evolutionary analyses were performed for TICAM-1, TICAM-2 and TIRAP within the range of 25 representative species. Our data show that the origin of the TICAM-like and TIRAP-like genes may coincide with the origin of chordates (amphioxus). Several putative TICAMs and TIRAPs were identified for different chordate species. Shark is the only non-mammalian species whose genome contains a TICAM-2 gene. Structural modeling and comparison of TIR domains of these adaptors support their potential functional motifs and residues. Together with analyses of other genes involved in the TLR signaling pathways, we speculate that TICAM-1, TICAM-2 and TIRAP might have co-evolved with the TLR3/22 antivirus signaling, the LPS-specific TLR4 signaling and the Gram-positive bacteria-induced TLR2 signaling pathways, respectively. Our results are valuable contributions to the understanding of TICAM/TIRAP evolutional functions and may provide targets for therapeutic intervention in TLR-mediated vertebrate diseases.