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Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing

Toll-like receptors (TLRs) 3, 7, and 9 recognize microbial nucleic acids in endolysosomes and initiate innate and adaptive immune responses. TLR7/9 in dendritic cells (DCs) also respond to self-derived RNA/DNA, respectively, and drive autoantibody production. Remarkably, TLR7 and 9 appear to have mu...

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Autores principales: Fukui, Ryutaro, Saitoh, Shin-ichiroh, Matsumoto, Fumi, Kozuka-Hata, Hiroko, Oyama, Masaaki, Tabeta, Koichi, Beutler, Bruce, Miyake, Kensuke
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715051/
https://www.ncbi.nlm.nih.gov/pubmed/19451267
http://dx.doi.org/10.1084/jem.20082316
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author Fukui, Ryutaro
Saitoh, Shin-ichiroh
Matsumoto, Fumi
Kozuka-Hata, Hiroko
Oyama, Masaaki
Tabeta, Koichi
Beutler, Bruce
Miyake, Kensuke
author_facet Fukui, Ryutaro
Saitoh, Shin-ichiroh
Matsumoto, Fumi
Kozuka-Hata, Hiroko
Oyama, Masaaki
Tabeta, Koichi
Beutler, Bruce
Miyake, Kensuke
author_sort Fukui, Ryutaro
collection PubMed
description Toll-like receptors (TLRs) 3, 7, and 9 recognize microbial nucleic acids in endolysosomes and initiate innate and adaptive immune responses. TLR7/9 in dendritic cells (DCs) also respond to self-derived RNA/DNA, respectively, and drive autoantibody production. Remarkably, TLR7 and 9 appear to have mutually opposing, pathogenic or protective, impacts on lupus nephritis in MRL/lpr mice. Little is known, however, about the contrasting relationship between TLR7 and 9. We show that TLR7 and 9 are inversely linked by Unc93B1, a multiple membrane-spanning endoplasmic reticulum (ER) protein. Complementation cloning with a TLR7-unresponsive but TLR9-responsive cell line revealed that amino acid D34 in Unc93B1 repressed TLR7-mediated responses. D34A mutation rendered Unc93B1-deficient DCs hyperresponsive to TLR7 ligand but hyporesponsive to TLR9 ligand, with TLR3 responses unaltered. Unc93B1 associates with and delivers TLR7/9 from the ER to endolysosomes for ligand recognition. The D34A mutation up-regulates Unc93B1 association with endogenous TLR7 in DCs, whereas Unc93B1 association with TLR9 was down-regulated by the D34A mutation. Consistently, the D34A mutation up-regulated ligand-induced trafficking of TLR7 but down-regulated that of TLR9. Collectively, TLR response to nucleic acids in DCs is biased toward DNA-sensing by Unc93B1.
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spelling pubmed-27150512009-12-08 Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing Fukui, Ryutaro Saitoh, Shin-ichiroh Matsumoto, Fumi Kozuka-Hata, Hiroko Oyama, Masaaki Tabeta, Koichi Beutler, Bruce Miyake, Kensuke J Exp Med Article Toll-like receptors (TLRs) 3, 7, and 9 recognize microbial nucleic acids in endolysosomes and initiate innate and adaptive immune responses. TLR7/9 in dendritic cells (DCs) also respond to self-derived RNA/DNA, respectively, and drive autoantibody production. Remarkably, TLR7 and 9 appear to have mutually opposing, pathogenic or protective, impacts on lupus nephritis in MRL/lpr mice. Little is known, however, about the contrasting relationship between TLR7 and 9. We show that TLR7 and 9 are inversely linked by Unc93B1, a multiple membrane-spanning endoplasmic reticulum (ER) protein. Complementation cloning with a TLR7-unresponsive but TLR9-responsive cell line revealed that amino acid D34 in Unc93B1 repressed TLR7-mediated responses. D34A mutation rendered Unc93B1-deficient DCs hyperresponsive to TLR7 ligand but hyporesponsive to TLR9 ligand, with TLR3 responses unaltered. Unc93B1 associates with and delivers TLR7/9 from the ER to endolysosomes for ligand recognition. The D34A mutation up-regulates Unc93B1 association with endogenous TLR7 in DCs, whereas Unc93B1 association with TLR9 was down-regulated by the D34A mutation. Consistently, the D34A mutation up-regulated ligand-induced trafficking of TLR7 but down-regulated that of TLR9. Collectively, TLR response to nucleic acids in DCs is biased toward DNA-sensing by Unc93B1. The Rockefeller University Press 2009-06-08 /pmc/articles/PMC2715051/ /pubmed/19451267 http://dx.doi.org/10.1084/jem.20082316 Text en © 2009 Fukui et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Fukui, Ryutaro
Saitoh, Shin-ichiroh
Matsumoto, Fumi
Kozuka-Hata, Hiroko
Oyama, Masaaki
Tabeta, Koichi
Beutler, Bruce
Miyake, Kensuke
Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing
title Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing
title_full Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing
title_fullStr Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing
title_full_unstemmed Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing
title_short Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing
title_sort unc93b1 biases toll-like receptor responses to nucleic acid in dendritic cells toward dna- but against rna-sensing
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715051/
https://www.ncbi.nlm.nih.gov/pubmed/19451267
http://dx.doi.org/10.1084/jem.20082316
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