title: Ribonuclease H2 mutations induce a cGAS/STING-dependent innate immune response.
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 eitherRNA:DNAhybrid or genome-embedded ribonucleotide substrates is thought to lead to activation of a yet undefined nucleic acid-sensing pathway. Here, we establishRnaseh2b(A174T/A174T)knock-in mice as a subclinical model of disease, identifying significant interferon-stimulated gene (ISG) transcript upregulation that recapitulates theISGsignature seen inAGSpatients. The inflammatory response is dependent on the nucleic acid sensor cyclicGMP-AMPsynthase (cGAS) and its adaptorSTINGand is associated with reduced cellular ribonucleotide excision repair activity and increasedDNAdamage. This suggests thatcGAS/STINGis a key nucleic acid-sensing pathway relevant toAGS, providing additional insight into disease pathogenesis relevant to the development of therapeutics for this childhood-onset interferonopathy and adult systemic autoimmune disorders.
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Mackenzie
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
authors.forename: Paula
authors.initials: P
authors.lastname: Carroll
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Lettice
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
authors.forename: Žygimantė
authors.initials: Ž
authors.lastname: Tarnauskaitė
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
authors.forename: Kaalak
authors.initials: K
authors.lastname: Reddy
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
authors.forename: Flora
authors.initials: F
authors.lastname: Dix
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
authors.forename: Ailsa
authors.initials: A
authors.lastname: Revuelta
authors.affiliation: Roslin Institute, The University of Edinburgh, Edinburgh, UK.
authors.forename: Erika
authors.initials: E
authors.lastname: Abbondati
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Rigby
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
authors.forename: Björn
authors.initials: B
authors.lastname: Rabe
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Kilanowski
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
authors.forename: Graeme
authors.initials: G
authors.lastname: Grimes
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
authors.forename: Adeline
authors.initials: A
authors.lastname: Fluteau
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Devenney
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hill
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
authors.forename: Martin Am
authors.initials: MA
authors.lastname: Reijns
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK andrew.jackson@igmm.ed.ac.uk.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
mesh_terms: D000818:Animals; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity / Q000235:genetics; D004249:DNA Damage; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007372:Interferons / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D009421:Nervous System Malformations / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016914:Ribonuclease H / Q000235:genetics* / Q000378:metabolism; D012260:Ribonucleases / Q000235:genetics*; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D007372:Interferons; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; D016914:Ribonuclease H; D012260:Ribonucleases; C530855:Sting1 protein, mouse; D000099197:STING Protein; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase; C091139:ribonuclease HII; C000610382:ribonuclease H2, mouse
keywords: Aicardi–Goutières syndrome; autoinflammation; cGAS‐STING; ribonuclease H2