Conserved features in the extracellular domain of human toll-like receptor 8 are essential for pH-dependent signaling

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Abstract

Toll-like receptor (TLR) 8 has an important role in initiating immune responses to viral single-stranded RNA and the antiviral compound resiquimod. Together with TLR3, -7, and -9, it forms a subgroup of the TLRs that are localized intracellularly and signal in response to pathogen-derived nucleic acids. In this work, we have used site-directed mutagenesis to identify regions of the TLR8 extracellular domain that are required for stimulus-induced signal transduction. We have shown that a cysteine-rich sequence predicted to form a loop projecting from the solenoidal ectodomain structure at leucine-rich repeat 8 is essential for signaling in response to both single-stranded RNA and resiquimod. A second region, centered on an aspartic acid residue in leucine-rich repeat 17, is also required for TLR8 function. The corresponding residue in TLR9 is known to be important for pH-dependent binding and signaling in response to unmethylated CpG DNA, suggesting that the TLR7/8/9 subgroups share a common signaling mechanism. We have also shown that TLR8 is localized predominantly in the endoplasmic reticulum but that signaling is completely abolished by an inhibitor of vesicle-type H+ ATPases. This indicates that TLR8 is present at low levels in an acidified compartment and that a lowered pH is required for receptor function. We propose that pH-dependent changes in the ligand facilitate activation of the receptor. The protonated form of resiquimod, a cell-permeable weak base, is likely to concentrate significantly (∼100x) in acidified compartments, and this may potentiate low affinity interactions with either the receptor or a specific binding protein. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

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Gibbard, R. J., Morley, P. J., & Gay, N. J. (2006). Conserved features in the extracellular domain of human toll-like receptor 8 are essential for pH-dependent signaling. Journal of Biological Chemistry, 281(37), 27503–27511. https://doi.org/10.1074/jbc.M605003200

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