Cited by 248interferon and immune responsesSystemic Lupus Erythematosus ResearchInflammasome and immune disorders

Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response

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Mackenzie, Karen J, Carroll, Paula, Lettice, Laura, Tarnauskaitė, Žygimantė, Reddy, Kaalak, Dix, Flora, Revuelta, Ailsa, Abbondati, Erika +9 more·2016·The EMBO Journal

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.

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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
Venue
The EMBO Journal
Published
2016-02-22
Volume
35
Issue
8
Pages
831-844
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
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
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

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