Ribonuclease H2 mutations induce a cGAS/STING-dependent innate immune response.
EMBO J
; 35(8): 831-44, 2016 Apr 15.
Article
en En
| MEDLINE
| ID: mdl-26903602
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 eitherRNADNAhybrid 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Ribonucleasas
/
Ribonucleasa H
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Mutación Missense
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Enfermedades Autoinmunes del Sistema Nervioso
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Inmunidad Innata
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Proteínas de la Membrana
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Malformaciones del Sistema Nervioso
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Nucleotidiltransferasas
Límite:
Animals
/
Humans
Idioma:
En
Revista:
EMBO J
Año:
2016
Tipo del documento:
Article
País de afiliación:
Reino Unido