Aicardi-Goutières syndrome protein TREX1 suppresses L1 and maintains genome integrity through exonuclease-independent ORF1p depletion.
Aicardi-Goutières syndrome protein TREX1 suppresses L1 and maintains genome integrity through exonuclease-independent ORF1p depletion.
复制标题
Aicardi-Goutieres 综合征蛋白 TREX1 通过不依赖外切核酸酶的 ORF1p 耗竭抑制 L1 并维持基因组完整性
DOI：
10.1093/nar/gkx178
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发表时间：
2017-05-05
影响因子：
14.9
通讯作者：
Yu XF
中科院分区：
文献类型：
--
作者：
Li P;Du J;Goodier JL;Hou J;Kang J;Kazazian HH Jr;Zhao K;Yu XF
维持基因组的完整性对于细胞很重要，而DNA触发的自身免疫性疾病已经报告说，三局修复外核酸酶1（TREX1）是内源性DNA外核酸酶，可防止通过损害的DNA耗尽免疫反应，从而防止某些自身免疫性疾病的发育。一致地，TREX1中的突变与自身免疫性疾病（例如全身性狼疮，aicardi –goutières）但是，综合征（AG）和家族狼疮。并改变了其细胞内定位。与AG相关的TREX1突变体在诱导的ORF1P耗竭中是确定的，无法预防L1介导的DNA损伤，因此，我们的发现不仅显示了TREX1介导的L1抑制的新机制，并发现了TREX1在蛋白质上的新功能还提出了一种通过维持基因组完整性来抑制先天免疫激活的新型机制。
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.