Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response. (22nd February 2016)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: EMBO journal. Volume 35:Number 8(2016)
• Page Start: 831
• Page End: 844
• Publication Date: 2016-02-22
• Subjects: Aicardi–Goutières syndrome -- autoinflammation -- cGAS‐STING -- ribonuclease H2; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201593339
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Aicardi–Goutières syndrome (AGS) provides a monogenic model of nucleic acid‐mediated 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 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. Synopsis: Mutations in the RNase H2 enzyme complex are the most frequent cause of the autoinflammatory condition Aicardi–Goutières syndrome (AGS). It is thought that nucleic acid sensing is responsible for initiating inflammation; however, the nature of the nucleic acid‐sensing pathway has not been determined. Here, we establish that: Rnaseh2b A174T/A174T mice upregulate interferon‐stimulated genes (ISG) in tissues. ISG response is dependent on the nucleic acid sensor cyclic GMP‐AMP synthase (cGAS) and its adaptor STING. ISG induction is associated with reduced ribonucleotide excision repair (RER) activity and increased DNA damage. Abstract : A new mouse model reveals the key nucleic acid‐sensing and signalling pathway in autoinflammatory Aicardi–Goutières syndrome caused by RNase H2 mutations.