title: Cytoplasmic targeting motifs control localization of toll-like receptor 9.
abstract: Toll-like receptors (TLRs) are essential for host defense. Although several TLRs reside on the cell surface, nucleic acid recognition of TLRs occurs intracellularly. For example, the receptor for CpG containing bacterial and viral DNA, TLR9, is retained in the endoplasmic reticulum. Recent evidence suggests that the localization of TLR9 is critical for appropriate ligand recognition. Here we have defined which structural features of the TLR9 molecule control its intracellular localization. Both the cytoplasmic and ectodomains of TLR9 contain sufficient information, whereas the transmembrane domain plays no role in intracellular localization. We identify a 14-amino acid stretch that directs TLR9 intracellularly and confers intracellular localization to the normally cell surface-expressed TLR4. Truncation or mutation of the cytoplasmic tail of TLR9 reveals a vesicle localization motif that targets early endosomes. We propose a model whereby modification of the cytoplasmic tail of TLR9 results in trafficking to early endosomes where it encounters CpG DNA.
authors.affiliation: Cornell University College of Veterinary Medicine, Ithaca, New York 14853, USA. cal59@cornell.edu
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Leifer
authors.forename: James C
authors.initials: JC
authors.lastname: Brooks
authors.forename: Karin
authors.initials: K
authors.lastname: Hoelzer
authors.forename: Jody
authors.initials: J
authors.lastname: Lopez
authors.forename: Margaret N
authors.initials: MN
authors.lastname: Kennedy
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mazzoni
authors.forename: David M
authors.initials: DM
authors.lastname: Segal
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D002460:Cell Line; D018899:CpG Islands; D003593:Cytoplasm / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D004247:DNA