Bifurcation of Toll-like receptor 9 signaling by adaptor protein 3

Science. 2010 Sep 17;329(5998):1530-4. doi: 10.1126/science.1187029.

Abstract

Endosomal Toll-like receptors (TLRs) 7 and 9 recognize viral pathogens and induce signals leading to the activation of nuclear factor κB (NF-κB)-dependent proinflammatory cytokines and interferon regulatory factor 7 (IRF7)-dependent type I interferons (IFNs). Recognition of viral nucleic acids by TLR9 requires its cleavage in the endolysosomal compartment. Here, we show that TLR9 signals leading to the activation of type I IFN, but not proinflammatory cytokine genes, require TLR9 trafficking from endosomes to a specialized lysosome-related organelle. Furthermore, we identify adapter protein-3 as the protein complex responsible for the trafficking of TLR9 to this subcellular compartment. Our results reveal an intracellular mechanism for bifurcation of TLR9 signals by selective receptor trafficking within the endosomal system.

Publication types

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

MeSH terms

  • Adaptor Protein Complex 3 / genetics
  • Adaptor Protein Complex 3 / metabolism*
  • Adaptor Protein Complex beta Subunits
  • Animals
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / immunology
  • Cytokines / metabolism
  • Cytoplasmic Vesicles / metabolism
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Endosomes / metabolism
  • Interferon Regulatory Factor-7 / metabolism
  • Interferon Type I / genetics
  • Interferon Type I / immunology
  • Interferon Type I / metabolism
  • Lysosomal-Associated Membrane Protein 2 / metabolism
  • Macrophages / immunology
  • Membrane Transport Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Differentiation Factor 88 / metabolism
  • Oligodeoxyribonucleotides / immunology
  • Protein Transport
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • TNF Receptor-Associated Factor 3 / metabolism
  • Toll-Like Receptor 9 / immunology
  • Toll-Like Receptor 9 / metabolism*
  • Transcriptional Activation
  • Vesicle-Associated Membrane Protein 3 / metabolism

Substances

  • Adaptor Protein Complex 3
  • Adaptor Protein Complex beta Subunits
  • Ap3b1 protein, mouse
  • Cytokines
  • Interferon Regulatory Factor-7
  • Interferon Type I
  • Irf7 protein, mouse
  • Lysosomal-Associated Membrane Protein 2
  • Membrane Transport Proteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Oligodeoxyribonucleotides
  • Recombinant Fusion Proteins
  • TNF Receptor-Associated Factor 3
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • UNC93B1 protein, mouse
  • Vesicle-Associated Membrane Protein 3
  • vesicle-associated membrane protein 3, mouse