title: Acidic amino acid residues in the juxtamembrane region of the nucleotide-sensing TLRs are important for UNC93B1 binding and signaling.
abstract: TLRs are divided into two groups based on their subcellular localization patterns. TLR1, 2, 4, 5, and 6 are expressed on the cell surface, whereas the nucleotide-sensing TLRs, such as TLR3, 7, 8, and 9 stay mainly inside cells. The polytopic membrane protein UNC93B1 physically interacts with the nucleotide-sensing TLRs and delivers them from the endoplasmic reticulum to endolysosomes, where the TLRs recognize their ligands and initiate signaling. In cells with nonfunctional UNC93B1, the nucleic acid-sensing TLRs fail to exit the endoplasmic reticulum and consequently do not signal. However, the detailed molecular mechanisms that underlie the UNC93B1-mediated TLR trafficking remain to be clarified. All nucleotide-sensing TLRs contain acidic amino acid residues in the juxtamembrane region between the leucine-rich repeat domain and the transmembrane segment. We show that the D812 and E813 residues of TLR9 and the D699 and E704 residues of TLR3 help to determine the interaction of these TLRs with UNC93B1. Mutation of the acidic residues in TLR3 and TLR9 prevents UNC93B1 binding, as well as impairs TLR trafficking and renders the mutant receptors incapable of transmitting signals. Therefore, the acidic residues in the juxtamembrane region of the nucleotide-sensing TLRs have important functional roles.
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
authors.forename: Jihee
authors.initials: J
authors.lastname: Kim
authors.forename: Jiwon
authors.initials: J
authors.lastname: Huh
authors.forename: Misun
authors.initials: M
authors.lastname: Hwang
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Kwon
authors.forename: Da-Jung
authors.initials: DJ
authors.lastname: Jung
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Brinkmann
authors.forename: Myoung Ho
authors.initials: MH
authors.lastname: Jang
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
authors.forename: You-Me
authors.initials: YM
authors.lastname: Kim
mesh_terms: D024342:Amino Acids, Acidic / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D003713:Dendritic Cells; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D024342:Amino Acids, Acidic; D026901:Membrane Transport Proteins; C519703:TLR3 protein, mouse; C495370:Tlr9 protein, mouse; D051196:Toll-Like Receptor 3; D051217:Toll-Like Receptor 9; C512254:UNC93B1 protein, mouse