Edinburgh Research Explorer

Ribonuclease H2 mutations induce a cGASSTING-dependent innate immune response

Research output: Contribution to journalArticle

Related Edinburgh Organisations

Access status

Open

Documents

  • Download as Adobe PDF

    Accepted author manuscript, 767 KB, PDF-document

    License: Creative Commons: Attribution (CC-BY)

Original languageEnglish
JournalEMBO Journal
Early online date22 Feb 2016
DOIs
StatePublished - 15 Apr 2016

Abstract

Aicardi-Goutières syndrome (AGS) provides a monogenic model of nucleic acidmediated 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 Rnaseh2bA174T/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.

Download statistics

No data available

ID: 23423439