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Nat Immunol. 2008 Apr;9(4):361-8. doi: 10.1038/ni1569. Epub 2008 Feb 24.

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

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1
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.

PMID:
18297073
PMCID:
PMC4112825
DOI:
10.1038/ni1569
[Indexed for MEDLINE]
Free PMC Article

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