A Role for the Adaptor Proteins TRAM and TRIF in Toll-Like Receptor 2 Signaling [Signal Transduction]

December 11th, 2014 by Nilsen, N. J., Vladimer, G. I., Stenvik, J., Orning, M. P. A., Zeid-Kilani, M. V., Bugge, M., Bergstroem, B., Conlon, J., Husebye, H., Hise, A. G., Fitzgerald, K. A., Espevik, T., Lien, E.

Toll-like receptors (TLRs) are receptors involved in sensing invading microbes by host innate immunity. TLR2 recognizes bacterial lipoproteins/lipopeptides, while lipopolysaccharide (LPS) activates TLR4. TLR2 and TLR4 signal via the Toll/Interleukin-1 receptor (TIR) adaptors MyD88 and MAL, leading to NF-κB activation. TLR4 also utilizes the adaptors TRAM and TRIF, resulting in activation of interferon regulatory factor (IRF)3. Here we report a new role for TRAM and TRIF in TLR2 regulation and signaling. Interestingly, we observed that TLR2-mediated induction of the chemokine CCL5 was impaired in TRAM-/- or TRIF-/- macrophages. Inhibition of endocytosis reduced CCL5 release, and the data also suggested that TRAM and TLR2 co-localize in early endosomes, supporting the hypothesis that signaling may occur from an intracellular compartment. CCL5 release following lipoprotein challenge additionally involved the kinase TBK-1 and IRF3, as well as MyD88 and IRF1. Induction of interferon-β and CCL4 by lipoproteins were also partially impaired in TRIF-/- cells. Our results show a novel function of TRAM and TRIF in TLR2-mediated signal transduction, and the findings broaden our understanding of how TIR adaptor proteins may participate in signaling downstream from TLR2.