title: Cutting edge: a TLR9 cytoplasmic tyrosine motif is selectively required for proinflammatory cytokine production.
abstract: Compartmentalization of nucleic acid sensing TLR9 has been implicated as a mechanism to prevent recognition of self nucleic acid structures. Furthermore, recognition of CpG DNA in different endosomal compartments leads to the production of the proinflammatory cytokine TNF-α, or type I IFN. We previously characterized a tyrosine-based motif at aa 888-891 in the cytoplasmic tail of TLR9 important for appropriate intracellular localization. In this article, we show that this motif is selectively required for the production of TNF, but not IFN. In response to CpG DNA stimulation, the proteolytically processed 80-kDa fragment is tyrosine phosphorylated. Although Y888 is not itself phosphorylated, the structure of this motif is necessary for both TLR9 phosphorylation and TNF-α production in response to CpG DNA. We conclude that bifurcation in TLR9 signaling is regulated by a critical tyrosine motif in the cytoplasmic tail.
authors.affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Annapoorani
authors.initials: A
authors.lastname: Chockalingam
authors.forename: William Alfred
authors.initials: WA
authors.lastname: Rose
authors.forename: Maroof
authors.initials: M
authors.lastname: Hasan
authors.forename: Chia-Hsin
authors.initials: CH
authors.lastname: Ju
authors.forename: Cynthia Anne
authors.initials: CA
authors.lastname: Leifer
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics / Q000276:immunology; D000818:Animals; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis* / Q000502:physiology; D003593:Cytoplasm / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D017354:Point Mutation; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014443:Tyrosine / Q000235:genetics / Q000502:physiology*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine