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

被引:148
作者
Fukui, Ryutaro [1 ]
Saitoh, Shin-ichiroh [1 ]
Matsumoto, Fumi [1 ]
Kozuka-Hata, Hiroko [2 ]
Oyama, Masaaki [2 ]
Tabeta, Koichi [3 ]
Beutler, Bruce [4 ]
Miyake, Kensuke [1 ]
机构
[1] Univ Tokyo, Inst Med Sci, Div Infect Genet, Tokyo 1088639, Japan
[2] Univ Tokyo, Inst Med Sci, Med Prote Lab, Tokyo 1088639, Japan
[3] Niigata Univ, Ctr Transdisciplinary Res, Niigata 9518514, Japan
[4] Scripps Res Inst, Dept Genet, La Jolla, CA 92037 USA
关键词
I INTERFERON; SYNERGISTIC ACTIVATION; AUTOIMMUNE-DISEASES; REGULATORY ROLES; INNATE IMMUNITY; SELF-DNA; CPG DNA; TLR9; ARTHRITIS; RECOGNITION;
D O I
10.1084/jem.20082316
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:1339 / 1350
页数:12
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