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- W2610572826 abstract "Endosomal toll-like receptors, namely human TLR3, TLR7, TLR8, and TLR9 sense nucleic acids (NAs) derived from viruses and bacteria. Yet, these TLRs can also contribute to autoimmunity by recognizing host NAs. NA-sensing TLR activity is highly regulated by the correct subcellular localization. Experimental mislocalization of endosomal TLRs to the cell surface leads to insufficient microbial recognition and inflammatory disease due to the recognition of endogenous NAs. Under physiological conditions, efficient activation of murine TLR7 and TLR9 is restricted to acidic compartments due to the need for proteolytic processing. TLR trafficking within the endolysosomal system further determines the nature of signaling events, as type I IFN and proinflammatory responses are initiated from different compartments. UNC93B1 is a key-regulator of NA-sensing TLRs by controlling the translocation of TLRs from the endoplasmic reticulum (ER) into endolysosomes. Without functional UNC93B1, NA-sensing TLRs are retained in the ER, incapable of ligand recognition. Patients lacking UNC93B1 display defective signaling of endosomal TLRs, and are at increased risk of developing herpes simplex virus encephalitis. The precise mechanism of how UNC93B1 regulates TLR trafficking remains unknown. Recently, a highly conserved tyrosine-based motif of UNC93B1 was identified. This motif is essential for the correct localization and function of murine TLR9, but dispensable for murine TLR7, TLR11, TLR12, and TLR13. TLR11, TLR12, and TLR13 are not expressed in humans. In contrast, human TLR8 plays a crucial role in the initiation of immune responses to certain pathogens. To date, molecular insights into UNC93B1-mediated trafficking of human endosomal TLRs are missing. Our study reveals that the tyrosine-based motif of UNC93B1 differentially regulates human TLR7, TLR8, and TLR9 responses and thereby contributes to the understanding of human TLR trafficking." @default.
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- W2610572826 date "2013-09-01" @default.
- W2610572826 modified "2023-10-02" @default.
- W2610572826 title "197" @default.
- W2610572826 doi "https://doi.org/10.1016/j.cyto.2013.06.200" @default.
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