Toll/interleukin-1 Receptor Domain-containing Proteins Research Articles

The expanding family of MyD88-like adaptors in Toll-like receptor signal transduction

Toll-like receptors (TLRs) play an essential role in the detection and elimination of invading microbes. They are type-1 transmembrane receptors, containing extracellular leucine rich repeats and an intracellular Toll/interleukin-1 receptor (TIR) domain. Upon stimulation, these receptors interact with specific TIR domain-containing adaptor proteins. Five such adaptors have been discovered to date, MyD88, Mal (MyD88 adaptor-like)/TIRAP (TIR domain-containing adaptor protein), Trif (TIR-domain-containing adaptor inducing interferon-β), TRAM (Trif-related adaptor molecule) and SARM (SAM and ARM-containing protein). Different TLRs use different combinations of these adaptors, leading to the activation of common and unique pathways involved in the elimination of the invading microbe.

TIRP, a Novel Toll/Interleukin-1 receptor (TIR) Domain-containing Adapter Protein Involved in TIR Signaling

The Toll/interleukin-1 receptor (TIR) family members play important roles in host defense. These receptors signal through TIR domain-containing adapter proteins. In this report, we identified a novel TIR domain-containing adapter protein designated as TIRP. Co-immunoprecipitation experiments suggest that TIRP is associated with IL-1 receptors. TIRP also interacts with kinase-inactive mutants of IRAK and IRAK-4, IRAK-2, IRAK-M, and TRAF6. Overexpression of TIRP activates NF-kappaB and potentiates IL-1 receptor-mediated NF-kappaB activation. A dominant negative mutant of TIRP inhibits IL-1- but not tumor necrosis factor-triggered NF-kappaB activation. Moreover, TIRP-mediated NF-kappaB activation is inhibited by dominant negative mutants of IRAK, IRAK-2, TRAF6, and IKKbeta. Our findings suggest that TIRP is involved in IL-1-triggered NF-kappaB activation and functions upstream of IRAK, IRAK-2, TRAF6, and IKKbeta