Premium
Ribonuclease H2 mutations induce a cGAS / STING ‐dependent innate immune response
Author(s) -
Mackenzie Karen J,
Carroll Paula,
Lettice Laura,
Tarnauskaitė Žygimantė,
Reddy Kaalak,
Dix Flora,
Revuelta Ailsa,
Abbondati Erika,
Rigby Rachel E,
Rabe Björn,
Kilanowski Fiona,
Grimes Graeme,
Fluteau Adeline,
Devenney Paul S,
Hill Robert E,
Reijns Martin AM,
Jackson Andrew P
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201593339
Subject(s) - biology , innate immune system , rnase p , pathogenesis , immune system , nucleic acid , immunology , autoimmunity , inflammation , gene , rna , genetics
Aicardi–Goutières syndrome ( AGS ) provides a monogenic model of nucleic acid‐mediated inflammation relevant to the pathogenesis of systemic autoimmunity. Mutations that impair ribonuclease ( RN ase) H2 enzyme function are the most frequent cause of this autoinflammatory disorder of childhood and are also associated with systemic lupus erythematosus. Reduced processing of either RNA : DNA hybrid or genome‐embedded ribonucleotide substrates is thought to lead to activation of a yet undefined nucleic acid‐sensing pathway. Here, we establish Rnaseh2b A174T/A174T knock‐in mice as a subclinical model of disease, identifying significant interferon‐stimulated gene ( ISG ) transcript upregulation that recapitulates the ISG signature seen in AGS patients. The inflammatory response is dependent on the nucleic acid sensor cyclic GMP ‐ AMP synthase ( cGAS ) and its adaptor STING and is associated with reduced cellular ribonucleotide excision repair activity and increased DNA damage. This suggests that cGAS / STING is a key nucleic acid‐sensing pathway relevant to AGS , providing additional insight into disease pathogenesis relevant to the development of therapeutics for this childhood‐onset interferonopathy and adult systemic autoimmune disorders.