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TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-β

Nature Immunology volume 9, pages 361–368 (2008)Cite this article

Abstract

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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Figure 1: Inhibition of TLR4 endocytosis selectively disrupts TRAM-TRIF signaling.
Figure 2: Distinct subcellular distribution of TRAM and TIRAP.
Figure 3: A bipartite localization motif regulates the localization of TRAM.
Figure 4: TLR4 can induce the production of type I interferon from early endosomes.
Figure 5: The subcellular localization of TRAF3 dictates the ability of TLRs to produce type I interferon.

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Acknowledgements

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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  1. Jonathan C Kagan, Tiffany Horng & Amy Chow

    Present address: Present addresses: GI Cell Biology, Children's Hospital Boston and the Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA (J.C.K.), Department of Pathology, Harvard Medical School, Immune Disease Institute, Boston, Massachusetts 02115, USA (T.H.), and Department of Biological Sciences, Rochester Institute of Technology, Rochester, New York 14623, USA (A.C.).,

Authors and Affiliations

  1. Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Jonathan C Kagan, Tian Su, Tiffany Horng, Amy Chow & Ruslan Medzhitov

  2. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, ERATO, Japan Science and Technology Agency, Osaka, Japan

    Shizuo Akira

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Correspondence to Jonathan C Kagan or Ruslan Medzhitov.

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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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