Article abstract
Nature Immunology 9, 361 - 368 (2008)
Published online: 24 February 2008 | doi:10.1038/ni1569
TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-
Jonathan C Kagan1,3, Tian Su1, Tiffany Horng1,3, Amy Chow1,3, Shizuo Akira2 & Ruslan Medzhitov1
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.
- Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
- Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, ERATO, Japan Science and Technology Agency, Osaka, Japan.
- 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.).
Correspondence to: Jonathan C Kagan1,3 e-mail: ruslan.medzhitov@yale.edu
Correspondence to: Ruslan Medzhitov1 e-mail: jonathan.kagan@childrens.harvard.edu
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