Li Peng, Du Juan, Goodier John L, Hou Jingwei, Kang Jian, Kazazian Haig H, Zhao Ke, Yu Xiao-Fang
Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin 130061, China.
Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Nucleic Acids Res. 2017 May 5;45(8):4619-4631. doi: 10.1093/nar/gkx178.
Maintaining genome integrity is important for cells and damaged DNA triggers autoimmunity. Previous studies have reported that Three-prime repair exonuclease 1(TREX1), an endogenous DNA exonuclease, prevents immune activation by depleting damaged DNA, thus preventing the development of certain autoimmune diseases. Consistently, mutations in TREX1 are linked with autoimmune diseases such as systemic lupus erythematosus, Aicardi-Goutières syndrome (AGS) and familial chilblain lupus. However, TREX1 mutants competent for DNA exonuclease activity are also linked to AGS. Here, we report a nuclease-independent involvement of TREX1 in preventing the L1 retrotransposon-induced DNA damage response. TREX1 interacted with ORF1p and altered its intracellular localization. Furthermore, TREX1 triggered ORF1p depletion and reduced the L1-mediated nicking of genomic DNA. TREX1 mutants related to AGS were deficient in inducing ORF1p depletion and could not prevent L1-mediated DNA damage. Therefore, our findings not only reveal a new mechanism for TREX1-mediated L1 suppression and uncover a new function for TREX1 in protein destabilization, but they also suggest a novel mechanism for TREX1-mediated suppression of innate immune activation through maintaining genome integrity.
维持基因组完整性对细胞很重要，而受损DNA会引发自身免疫。先前的研究报道，内源性DNA外切核酸酶3′-修复外切核酸酶1（TREX1）通过清除受损DNA来防止免疫激活，从而预防某些自身免疫性疾病的发生。一致的是，TREX1突变与自身免疫性疾病如系统性红斑狼疮、Aicardi-Goutières综合征（AGS）和家族性冻疮狼疮有关。然而，具有DNA外切核酸酶活性的TREX1突变体也与AGS有关。在这里，我们报道了TREX1在预防L1逆转录转座子诱导的DNA损伤反应中存在不依赖核酸酶的作用。TREX1与ORF1p相互作用并改变其细胞内定位。此外，TREX1引发ORF1p的消耗并减少L1介导的基因组DNA切口。与AGS相关的TREX1突变体在诱导ORF1p消耗方面存在缺陷，无法预防L1介导的DNA损伤。因此，我们的发现不仅揭示了TREX1介导的L1抑制的新机制，还揭示了TREX1在蛋白质不稳定方面的新功能，而且还提出了TREX1通过维持基因组完整性介导先天免疫激活抑制的新机制。
