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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism
  • Adaptor Proteins, Vesicular Transport / physiology
  • Amino Acid Motifs / immunology
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Down-Regulation / genetics
  • Down-Regulation / immunology
  • Endocytosis / genetics
  • Endocytosis / physiology*
  • Humans
  • Interferon-beta / biosynthesis*
  • Intracellular Fluid / immunology
  • Intracellular Fluid / metabolism
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / metabolism
  • Membrane Glycoproteins / physiology*
  • Membrane Transport Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Myeloid Differentiation Factor 88 / metabolism
  • Myeloid Differentiation Factor 88 / physiology
  • Receptors, Interleukin-1 / metabolism
  • Receptors, Interleukin-1 / physiology
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Toll-Like Receptor 4 / antagonists & inhibitors
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*
  • Toll-Like Receptor 4 / physiology

Substances

  • Adaptor Proteins, Vesicular Transport
  • MYD88 protein, human
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Myeloid Differentiation Factor 88
  • Receptors, Interleukin-1
  • TICAM1 protein, human
  • TIRAP protein, human
  • TLR4 protein, human
  • TRAM1 protein, human
  • Toll-Like Receptor 4
  • Interferon-beta