A role for the adaptor proteins TRAM and TRIF in toll-like receptor 2 signaling
Department of Medicine, Division of Infectious Diseases and Immunology, Program in Innate Immunity
Toll-like receptors (TLRs) are involved in sensing invading microbes by host innate immunity. TLR2 recognizes bacterial lipoproteins/lipopeptides, and lipopolysaccharide activates TLR4. TLR2 and TLR4 signal via the Toll/interleukin-1 receptor adaptors MyD88 and MAL, leading to NF-kappaB 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 deficient 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-beta and Ccl4 by lipoproteins was also partially impaired in cells lacking 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 Toll/interleukin-1 receptor adaptor proteins may participate in signaling downstream from TLR2.
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Citation: J Biol Chem. 2015 Feb 6;290(6):3209-22. doi: 10.1074/jbc.M114.593426. Link to article on publisher's site
Nilsen, Nadra J.; Vladimer, Gregory I.; Stenvik, Jorgen; Orning, M. Pontus A.; Zeid-Kilani, Maria V.; Bugge, Marit; Bergstroem, Bjarte; Conlon, Joseph E.; Husebye, Harald; Hise, Amy G.; Fitzgerald, Katherine A.; Espevik, Terje; and Lien, Egil, "A role for the adaptor proteins TRAM and TRIF in toll-like receptor 2 signaling" (2015). Infectious Diseases and Immunology Publications and Presentations. 194.