title: Bifurcation of Toll-like receptor 9 signaling by adaptor protein 3.
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.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Miwa
authors.initials: M
authors.lastname: Sasai
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Linehan
authors.forename: Akiko
authors.initials: A
authors.lastname: Iwasaki
mesh_terms: D033963:Adaptor Protein Complex 3 / Q000235:genetics / Q000378:metabolism*; D033966:Adaptor Protein Complex beta Subunits; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000276:immunology; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation; D051040:Vesicle-Associated Membrane Protein 3 / Q000378:metabolism
chemical_list: D033963:Adaptor Protein Complex 3; D033966:Adaptor Protein Complex beta Subunits; C418506:Ap3b1 protein, mouse; D016207:Cytokines; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; C494235:Irf7 protein, mouse; D052119:Lysosomal-Associated Membrane Protein 2; D026901:Membrane Transport Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009838:Oligodeoxyribonucleotides; D011993:Recombinant Fusion Proteins; D048008:TNF Receptor-Associated Factor 3; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C512254:UNC93B1 protein, mouse; D051040:Vesicle-Associated Membrane Protein 3; C494953:vesicle-associated membrane protein 3, mouse