Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response
Open accessAbstract
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.
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- Authors
- Mackenzie, K. J., Carroll, P., Lettice, L., Tarnauskaitė, Ž., Reddy, K., Dix, F., Revuelta, A., Abbondati, E., Rigby, R. E., Rabe, B., Kilanowski, F., Grimes, G., Fluteau, A., Devenney, P. S., Hill, R. E., Reijns, M. A., & Jackson, A. P.
- Affiliations
- Institute of Genetics and Cancer (GB)
- Roslin Institute (GB)
- Corresponding author
- Jackson, Andrew P
- ORCID
- Venue
- The EMBO Journal
- Published
- 2016-02-22
- Volume
- 35
- Issue
- 8
- Pages
- 831-844
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC4855687
- OpenAlex
- W2274643654
- Cited by
- 248
- References
- 61
- Citations by year
- 2026: 14 · 2025: 15 · 2024: 20 · 2023: 25 · 2022: 31 · 2021: 27 · 2020: 20 · 2019: 35 · 2018: 25 · 2017: 26 · 2016: 10
- FWCI
- 19.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The EMBO Journal (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- MRC
- Newlife Foundation for Disabled Children and The Wellcome Trust‐University of Edinburgh (ISSF2)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- Aicardi-Goutières syndrome, cGAS-STING pathway, innate immune response, interferon-stimulated genes, interferonopathies, nucleic acid sensing, RNA-DNA hybrids, ribonucleotide excision repair, DNA damage, systemic lupus erythematosus, autoinflammatory disease, knock-in mice
- MeSH terms
- STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, DNA Damage, Gene Expression Regulation, Humans, Immunity, Innate, Interferons, Membrane Proteins, Mice, Inbred C57BL, Mice, Mutant Strains, Nervous System Malformations, Nucleotidyltransferases, Ribonucleases, Autoimmunity, Ribonuclease H, Mutation, Missense, Autoimmune Diseases of the Nervous System
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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