Department of Medicine, Division of Infectious Diseases and Immunology
Animals; Base Sequence; Cell Membrane; Crystallography, X-Ray; DNA; Endocytosis; Endosomes; HEK293 Cells; HeLa Cells; Humans; Ligands; Lung; Mice; Mice, Inbred C57BL; Models, Molecular; NF-kappa B; Pneumonia; Protein Binding; Protein Multimerization; Protein Structure, Tertiary; Receptors, Immunologic; Static Electricity; Toll-Like Receptor 9
Biochemistry | Cellular and Molecular Physiology | Immunity | Immunopathology
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.
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Citation: J Exp Med. 2013 Oct 21;210(11):2447-63. doi: 10.1084/jem.20120201. Epub 2013 Sep 30. Link to article on publisher's site
The Journal of experimental medicine
Sirois, Cherilyn M.; Jin, Tengchuan; Miller, Allison L.; Bertheloot, Damien; Nakamura, Hirotaka; Horvath, Gabor; 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; and Latz, Eicke, "RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA" (2013). University of Massachusetts Medical School Faculty Publications. 782.
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