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    Nat Immunol. 2008 Apr;9(4):361-8. Epub 2008 Feb 24.

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

    Kagan JC, Su T, Horng T, Chow A, Akira S, Medzhitov R.

    Source

    Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. jonathan.kagan@childrens.harvard.edu

    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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    PMID:
    18297073
    [PubMed - indexed for MEDLINE]

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