University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Department of Medicine, Division of Infectious Diseases and Immunology

Publication Date

10-21-2013

Document Type

Article

Subjects

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

Disciplines

Biochemistry | Cellular and Molecular Physiology | Immunity | Immunopathology

Abstract

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.

Rights and Permissions

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

Comments

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

The Journal of experimental medicine

PubMed ID

24081950

Creative Commons License

Creative Commons Attribution-Noncommercial-Share Alike 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

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