The Troll in Toll: Mal and Tram as bridges for TLR2 and TLR4 signaling

two adaptor proteins, MyD88 adaptor-like (Mal) and Toll/IL-1 receptor (TIR) domain-containing adaptor-inducing IFN- (Trif)-related adaptor molecule (TRAM). Recently, new insights into the functioning of these two adapters have emerged. Mal is required by both TLRs to act as a bridge to recruit the adaptor MyD88, leading ultimately to NF-B activation. Similarly, TRAM acts as a bridge to recruit TRIF to the TLR4 complex, leading to activation of the transcription factor IFN regula-tory factor 3. Consistent with Mal and TRAM being key points of control, recent evidence suggests that they are subject to regulation by phosphorylation. Further, a variant in Mal in humans has been found to protect against multiple infectious diseases. Fi-nally, another TIR domain-containing adaptor, sterile and HEAT/armadillo motif protein (SARM), has been shown to act as an inhibitor of TRIF-dependent signaling. These recent discoveries add to the complexity of TLR signaling and highlight specific control mechanisms for TLR2 and TLR4 signaling. J. Leukoc. Biol. 82: 196–203; 2007. Key Words: Toll-like receptor signal transduction TLR adapters SARM innate immunity inflammatio