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Immunol."],"abstract":"<jats:p>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-Gouti\u00e8res syndrome (AGS) that can be caused by defects of the cytosolic DNase 3\u2019repair exonuclease 1 (TREX1). <jats:italic>TREX1<\/jats:italic> 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 <jats:italic>Trex1<jats:sup>-\/-<\/jats:sup><\/jats:italic> mice was partially rescued by additional knock out of exonuclease 1, a multifunctional enzyme providing 5\u2019 flap endonuclease activity for Okazaki fragment processing and postreplicative ribonucleotide excision repair. 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