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¹ Division of Infectious Genetics and ² Medical Proteomics Laboratory, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Tokyo 108-8639, Japan
³ Center for Transdisciplinary Research, Niigata University, Gakkocho-Dori, Niigata 951-8514, Japan
⁴ Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037

CORRESPONDENCE Kensuke Miyake: kmiyake{at}ims.u-tokyo.ac.jp

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.

Abbreviations used: BM-DC, BM-derived DC; HA, hemagglutinin; LC-MS/MS, liquid chromatography tandem mass spectrometry; SILAC, stable isotope labeling with aa; TLR, Toll-like receptor; XIC, extracted ion current.

© 2009 Fukui et al.
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