| First Author | Schubert N | Year | 2022 |
| Journal | Front Immunol | Volume | 13 |
| Pages | 880413 | PubMed ID | 35634291 |
| Mgi Jnum | J:326465 | Mgi Id | MGI:7282796 |
| Doi | 10.3389/fimmu.2022.880413 | Citation | Schubert N, et al. (2022) Genome Replication Is Associated With Release of Immunogenic DNA Waste. Front Immunol 13:880413 |
| abstractText | 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-Goutieres 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. |
