Acidic Amino Acid Residues in the Juxtamembrane Region of the Nucleotide-Sensing TLRs Are Important for UNC93B1 Binding and Signaling

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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.
Publisher
AMER ASSOC IMMUNOLOGISTS
Issue Date
2013-05
Language
English
Article Type
Article
Keywords

TOLL-LIKE RECEPTOR-3; NUCLEIC-ACID; INTRACELLULAR COMPARTMENTS; DENDRITIC CELLS; PROTEIN UNC93B; I INTERFERON; SELF-DNA; CPG DNA; RECOGNITION; LOCALIZATION

Citation

JOURNAL OF IMMUNOLOGY, v.190, no.10, pp.5287 - 5295

ISSN
0022-1767
DOI
10.4049/jimmunol.1202767
URI
http://hdl.handle.net/10203/240810
Appears in Collection
MSE-Journal Papers(저널논문)
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