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Ribonuclease H2 mutations induce a cGASSTING-dependent innate immune response

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Original languageEnglish
JournalEMBO Journal
Early online date22 Feb 2016
Publication statusPublished - 15 Apr 2016


Aicardi-Goutières syndrome (AGS) provides a monogenic model of nucleic acidmediated inflammation relevant to the pathogenesis of systemic autoimmunity. Mutations that impair ribonuclease (RNase) 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 Rnaseh2bA174T/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.

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