Toll-like receptor 4 (TLR4) induces two distinct signaling pathways controlled by the TIRAP-MyD88 and TRAM-TRIF pairs of adaptor proteins, which elicit the production of proinflammatory cytokines and type I interferons, respectively. How TLR4 coordinates the activation of these two pathways is unknown. Here we show that TLR4 activated these two signaling pathways sequentially in a process organized around endocytosis of the TLR4 complex. We propose that TLR4 first induces TIRAP-MyD88 signaling at the plasma membrane and is then endocytosed and activates TRAM-TRIF signaling from early endosomes. Our data emphasize a unifying theme in innate immune recognition whereby all type I interferon–inducing receptors signal from an intracellular location.
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We thank K. Miyake (Institute for Medical Sciences, University of Toyko) for Sa15-21; S. Akira (Osaka University) for TRAM-KO mice; C. Roy (Yale University) for Rab5 plasmids; T. Kirchhausen (Immune Disease Institute and Harvard Medical School) for dynasore; L. Marek, D. Hargreaves and C. Sokol for discussions; and T. Medjitov for help with bioinformatics analysis. Supported by the National Institutes of Health (1K99AI072955-01 to J.C.K., and R37 AI046688, P01 AI44220 and AI 061360 to R.M.) and the Howard Hughes Medical Institute (R.M.).
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Kagan, J., Su, T., Horng, T. et al. TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-β. Nat Immunol 9, 361–368 (2008). https://doi.org/10.1038/ni1569
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