TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta.
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.
Kagan
Jonathan C
JC
Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. jonathan.kagan@childrens.harvard.edu
Su
Tian
T
Horng
Tiffany
T
Chow
Amy
A
Akira
Shizuo
S
Medzhitov
Ruslan
R
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism / Q000502:physiology; D020816:Amino Acid Motifs / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004705:Endocytosis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis*; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D026901:Membrane Transport Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D033942:Adaptor Proteins, Vesicular Transport; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; C470409:TICAM1 protein, human; C434984:TIRAP protein, human; C495345:TLR4 protein, human; C486174:TRAM1 protein, human; D051197:Toll-Like Receptor 4; D016899:Interferon-beta