title: Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing.
abstract: Immune sensing of DNA is critical for antiviral immunity but can also trigger autoimmune diseases such as lupus erythematosus (LE). Here we have provided evidence for the involvement of a damage-associated DNA modification in the detection of cytosolic DNA. The oxidized base 8-hydroxyguanosine (8-OHG), a marker of oxidative damage in DNA, potentiated cytosolic immune recognition by decreasing its susceptibility to 3' repair exonuclease 1 (TREX1)-mediated degradation. Oxidizative modifications arose physiologically in pathogen DNA during lysosomal reactive oxygen species (ROS) exposure, as well as in neutrophil extracellular trap (NET) DNA during the oxidative burst. 8-OHG was also abundant in UV-exposed skin lesions of LE patients and colocalized with type I interferon (IFN). Injection of oxidized DNA in the skin of lupus-prone mice induced lesions that closely matched respective lesions in patients. Thus, oxidized DNA represents a prototypic damage-associated molecular pattern (DAMP) with important implications for infection, sterile inflammation, and autoimmunity.
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud Straße 25, 53127 Bonn, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Gehrke
authors.forename: Christina
authors.initials: C
authors.lastname: Mertens
authors.forename: Thomas
authors.initials: T
authors.lastname: Zillinger
authors.forename: Jörg
authors.initials: J
authors.lastname: Wenzel
authors.forename: Tobias
authors.initials: T
authors.lastname: Bald
authors.forename: Sabine
authors.initials: S
authors.lastname: Zahn
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
authors.forename: Gunther
authors.initials: G
authors.lastname: Hartmann
authors.forename: Winfried
authors.initials: W
authors.lastname: Barchet
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D005090:Exodeoxyribonucleases / Q000378:metabolism*; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000099197:STING Protein
chemical_list: D004247:DNA; D005090:Exodeoxyribonucleases; D006151:Guanosine; D007370:Interferon Type I; D008565:Membrane Proteins; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; C530855:Sting1 protein, mouse; D000099197:STING Protein; C046215:8-hydroxyguanosine; C429526:three prime repair exonuclease 1