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EMBO J. 2016 Apr 15;35(8):831-44. doi: 10.15252/embj.201593339. Epub 2016 Feb 22.

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

Author information

1
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK.
2
Roslin Institute, The University of Edinburgh, Edinburgh, UK.
3
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK andrew.jackson@igmm.ed.ac.uk.

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.

KEYWORDS:

Aicardi–Goutières syndrome; autoinflammation; cGAS‐STING; ribonuclease H2

PMID:
26903602
PMCID:
PMC4855687
DOI:
10.15252/embj.201593339
[Indexed for MEDLINE]
Free PMC Article

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