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 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.
Fukui
Ryutaro
R
Division of Infectious Genetics, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Tokyo 108-8639, Japan.
Saitoh
Shin-ichiroh
S
Matsumoto
Fumi
F
Kozuka-Hata
Hiroko
H
Oyama
Masaaki
M
Tabeta
Koichi
K
Beutler
Bruce
B
Miyake
Kensuke
K
D000818:Animals; D002460:Cell Line; D004247:DNA / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D020125:Mutation, Missense; D012313:RNA / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology*
D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D011993:Recombinant Fusion Proteins; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; C512254:UNC93B1 protein, mouse; D012313:RNA; D004247:DNA