title: UNC93B1 physically associates with human TLR8 and regulates TLR8-mediated signaling.
abstract: Toll-like receptors (TLRs) 3, 7, 8, and 9 are localized to intracellular compartments where they encounter foreign or self nucleic acids and activate innate and adaptive immune responses. The endoplasmic reticulum (ER)-resident membrane protein, UNC93B1, is essential for intracellular trafficking and endolysosomal targeting of TLR7 and TLR9. TLR8 is phylogenetically and structurally related to TLR7 and TLR9, but little is known about its localization or function. In this study, we demonstrate that TLR8 localized to the early endosome and the ER but not to the late endosome or lysosome in human monocytes and HeLa transfectants. UNC93B1 physically associated with human TLR8, similar to TLRs 3, 7, and 9, and played a critical role in TLR8-mediated signaling. Localization analyses of TLR8 tail-truncated mutants revealed that the transmembrane domain and the Toll/interleukin-1 receptor domain were required for proper targeting of TLR8 to the early endosome. Hence, although UNC93B1 participates in intracellular trafficking and signaling for all nucleotide-sensing TLRs, the mode of regulation of TLR localization differs for each TLR.
authors.affiliation: Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Itoh
authors.forename: Megumi
authors.initials: M
authors.lastname: Tatematsu
authors.forename: Ayako
authors.initials: A
authors.lastname: Watanabe
authors.forename: Katsunori
authors.initials: K
authors.lastname: Iwano
authors.forename: Kenji
authors.initials: K
authors.lastname: Funami
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
authors.forename: Misako
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D004721:Endoplasmic Reticulum / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D008247:Lysosomes / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D018613:Microscopy, Confocal / Q000379:methods; D009000:Monocytes / Q000166:cytology; D009154:Mutation; D010802:Phylogeny; D010957:Plasmids / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D051200:Toll-Like Receptor 8 / Q000378:metabolism*
chemical_list: D026901:Membrane Transport Proteins; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; C454130:UNC93B1 protein, human