Characterization of Trex1 Induction by IFN-γ in Murine Macrophages

Abstract

3′ Repair exonuclease (Trex1) is the most abundant mammalian 3′→5′ DNA exonuclease with specificity for ssDNA. Trex1 deficiency has been linked to the development of autoimmune disease in mice and humans, causing Aicardi-Goutières syndrome in the latter. In addition, polymorphisms in Trex1 are associated with systemic lupus erythematosus. On the basis of all these observations, it has been hypothesized that Trex1 acts by digesting an endogenous DNA substrate. In this study, we report that Trex1 is regulated by IFN-γ during the activation of primary macrophages. IFN-γ upregulates Trex1 with the time course of an early gene, and this induction occurs at the transcription level. The half-life of mRNA is relatively short (half-life of 70 min). The coding sequence of Trex1 has only one exon and an intron of 260 bp in the promoter in the nontranslated mRNA. Three transcription start sites were detected, the one at −580 bp being the most important. In transient transfection experiments using the Trex1 promoter, we have found that two IFN-γ activation site boxes, as well as an adaptor protein complex 1 box, were required for the IFN-γ–dependent induction. By using EMSA assays and chromatin immune precipitation assays, we determined that STAT1 binds to the IFN-γ activation site boxes. The requirement of STAT1 for Trex1 induction was confirmed using macrophages from Stat1 knockout mice. We also establish that c-Jun protein, but not c-Fos, jun-B, or CREB, bound to the adaptor protein complex 1 box. Therefore, our results indicate that IFN-γ induces the expression of the Trex1 exonuclease through STAT1 and c-Jun.

The Innate Immune Factor Apolipoprotein L1 Restricts HIV-1 Infection

“…This lysosomal expansion was hypothesized to be intimately involved in the antiviral phenotype of Trex1-deficient cells. Moreover, induction of Trex1 by IFN-␥ in mouse macrophages (51) suggests that if Trex1 is similarly induced by IFN-␥ in human macrophages, it may reduce lysosomal biogenesis induced by APOL1 and possibly modulate anti-HIV-1 effects of APOL1. Thus, it would be worth evaluating how these two factors intersect in macrophages to control HIV-1 replication and regulate innate immune responses to HIV-1.…”

Roles of Pro- and Anti-Inflammatory Cytokines in the Pathogenesis of SLE

“…STAT-1 is a critical component in both IFN- α and IFN- γ signaling pathways. STAT-1 expression is increased in PBMCs from SLE patients and correlated significantly with disease activity and with the IFN-inducible expression of CD95 and HLA-DR. A lately described gene polymorphism in the 3′ Repair exonuclease (Trex1) induced by IFN- γ was reported to be associated with SLE [150]. …”

Aicardi–Goutieres syndrome: from patients to genes and beyond

“…In Trex1−/− mice, the autoinflammation mostly affects the heart and its vasculature, rather than the brain. Furthermore, results have indicated that TREX1 exonuclease expression is induced in an interferon-dependent manner (28,63), which suggest that the TREX1 response could be governed by a positive feedback loop which renders the clearing of nucleic acid debris more efficient following the initial trigger of the interferon response. IFNR1), interferon responsive factors (e.g.…”