RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA

Recognition of DNA and RNA molecules derived from pathogens or self-antigen is one way the mammalian immune system senses infection and tissue damage. Activation of immune signaling receptors by nucleic acids is controlled by limiting the access of DNA and RNA to intracellular receptors, but the mec...

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Bibliographic Details
Published in:The Journal of experimental medicine 2013-10, Vol.210 (11), p.2447-2463
Main Authors: Sirois, Cherilyn M, Jin, Tengchuan, Miller, Allison L, Bertheloot, Damien, Nakamura, Hirotaka, Horvath, Gabor L, Mian, Abubakar, Jiang, Jiansheng, Schrum, Jacob, Bossaller, Lukas, Pelka, Karin, Garbi, Natalio, Brewah, Yambasu, Tian, Jane, Chang, ChewShun, Chowdhury, Partha S, Sims, Gary P, Kolbeck, Roland, Coyle, Anthony J, Humbles, Alison A, Xiao, T Sam, Latz, Eicke
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Cell Membrane - metabolism
Crystallography, X-Ray
DNA - chemistry
DNA - metabolism
Endocytosis
Endosomes - metabolism
HEK293 Cells
HeLa Cells
Humans
Ligands
Lung - metabolism
Lung - pathology
Mice
Mice, Inbred C57BL
Models, Molecular
NF-kappa B - metabolism
Pneumonia - metabolism
Pneumonia - pathology
Protein Binding
Protein Multimerization
Protein Structure, Tertiary
Receptor for Advanced Glycation End Products
Receptors, Immunologic - chemistry
Receptors, Immunologic - metabolism
Static Electricity
Toll-Like Receptor 9 - metabolism
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Summary:Recognition of DNA and RNA molecules derived from pathogens or self-antigen is one way the mammalian immune system senses infection and tissue damage. Activation of immune signaling receptors by nucleic acids is controlled by limiting the access of DNA and RNA to intracellular receptors, but the mechanisms by which endosome-resident receptors encounter nucleic acids from the extracellular space are largely undefined. In this study, we show that the receptor for advanced glycation end-products (RAGE) promoted DNA uptake into endosomes and lowered the immune recognition threshold for the activation of Toll-like receptor 9, the principal DNA-recognizing transmembrane signaling receptor. Structural analysis of RAGE-DNA complexes indicated that DNA interacted with dimers of the outermost RAGE extracellular domains, and could induce formation of higher-order receptor complexes. Furthermore, mice deficient in RAGE were unable to mount a typical inflammatory response to DNA in the lung, indicating that RAGE is important for the detection of nucleic acids in vivo.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20120201