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: Nat Immunol
Publication Date: (2008)
Issue: 9(4): 361-8
Research Area:
Immunotherapy / Hematology
Cells used in publication:
Macrophage, mouse
Species: mouse
Tissue Origin: bone marrow
Macrophage, mouse - C57BL/6
Species: mouse
Tissue Origin: bone marrow
Macrophage, mouse - BALB/c
Species: mouse
Tissue Origin: bone marrow
Nucleofectorâ„¢ I/II/2b
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.