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.
Highlights
The innate immune system discriminates self from non-self by expressing germ-line encoded receptors that recognize pathogen- or damage-associated molecular patterns [1,2,3]
TLR7 and TLR9 are selectively expressed in B cells and plasmacytoid dendritic cell (DC), while TLR3 and TLR8 are expressed in myeloid DCs [5,6,7,8]
TLR3 and TLR8 are expressed in myeloid DCs, while TLR7 and TLR9 are expressed in plasmacytoid DCs [6]
Summary
The innate immune system discriminates self from non-self by expressing germ-line encoded receptors that recognize pathogen- or damage-associated molecular patterns [1,2,3]. The Toll-like receptor (TLR) family of type I transmembrane proteins were the first group of pattern recognition receptors to be identified [4]. Within this family, TLRs 3, 7, 8, and 9 recognize microbial nucleic acids and induce cytokine production, including type I interferon (IFN), and dendritic cell (DC) maturation [2]. Human/mouse TLR7 strongly induces type I IFN production in response to ssRNA and an imidazoquinoline compound. The differential expression and cytokine profiles of human TLR8 compared with those of human/mouse TLR7 suggest that human TLR8 plays a distinct role in the anti-viral immune response
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