Genome Replication Is Associated With Release of Immunogenic DNA Waste.
Front Immunol
; 13: 880413, 2022.
Article
em En
| MEDLINE
| ID: mdl-35634291
ABSTRACT
Innate DNA sensors detect foreign and endogenous DNA to induce responses to infection and cellular stress or damage. Inappropriate activation by self-DNA triggers severe autoinflammatory conditions, including Aicardi-Goutières syndrome (AGS) that can be caused by defects of the cytosolic DNase 3'repair exonuclease 1 (TREX1). TREX1 loss-of-function alleles are also associated with systemic lupus erythematosus (SLE). Chronic activation of innate antiviral immunity in TREX1-deficient cells depends on the DNA sensor cGAS, implying that accumulating TREX1 DNA substrates cause the inflammatory pathology. Retrotransposon-derived cDNAs were shown to activate cGAS in TREX1-deficient neuronal cells. We addressed other endogenous sources of cGAS ligands in cells lacking TREX1. We find that induced loss of TREX1 in primary cells induces a rapid IFN response that requires ongoing proliferation. The inflammatory phenotype of Trex1-/- mice was partially rescued by additional knock out of exonuclease 1, a multifunctional enzyme providing 5' flap endonuclease activity for Okazaki fragment processing and postreplicative ribonucleotide excision repair. Our data imply genome replication as a source of DNA waste with pathogenic potential that is efficiently degraded by TREX1.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doenças Autoimunes do Sistema Nervoso
/
Malformações do Sistema Nervoso
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
Front Immunol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Alemanha