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.

journal_name

Immunity

journal_title

Immunity

authors

Gehrke N,Mertens C,Zillinger T,Wenzel J,Bald T,Zahn S,Tüting T,Hartmann G,Barchet W

doi

10.1016/j.immuni.2013.08.004

subject

Has Abstract

pub_date

2013-09-19 00:00:00

pages

482-95

issue

3

eissn

1074-7613

issn

1097-4180

pii

S1074-7613(13)00332-4

journal_volume

39

pub_type

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