The cGAS-STING (cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)) axis integrates DNA damage and cellular stress with type I interferon (IFN) signalling to facilitate transcriptional changes underlying inflammatory stress responses. The cGAS-STING pathway responds to cytosolic DNA in the form of double-stranded DNA, micronuclei, and long interspersed nuclear element 1 (L1) retroelements. L1 retroelements are a class of self-propagating non-long terminal repeat transposons that have remained highly active in mammalian genomes. L1 retroelements are emerging as important inducers of cGAS-STING and IFN signalling, which are often dysregulated in several diseases, including cancer. A key repressor of cGAS-STING and L1 activity is the exonuclease three prime repair exonuclease 1 (TREX1), and loss of TREX1 promotes the accumulation of L1. In addition, L1 dysregulation is a common theme among diseases with chronic induction of type I IFN signalling through cGAS-STING, such as Aicardi-Goutières syndrome, Fanconi anemia, and dermatomyositis. Although TREX1 is highly conserved in tetrapod species, other suppressor proteins exist that inhibit L1 retrotransposition. These suppressor genes when mutated are often associated with diseases characterized by unchecked inflammation that is associated with high cGAS-STING activity and elevated levels of L1 expression. In this review, we discuss these interconnected pathways of L1 suppression and their role in the regulation of cGAS-STING and inflammation in disease.

中文翻译：

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LINE-1：一种新兴的 cGAS-STING 信号传导和炎症启动子，在疾病中失调。

cGAS-STING（环 GMP-AMP 合酶 (cGAS)-干扰素基因刺激剂 (STING)）轴将 DNA 损伤和细胞应激与 I 型干扰素 (IFN) 信号整合，以促进炎症应激反应中的转录变化。cGAS-STING 通路以双链 DNA、微核和长散布核元件 1 (L1) 逆转录元件的形式对胞质 DNA 做出反应。L1 逆转录元件是一类自我繁殖的非长末端重复转座子，在哺乳动物基因组中仍然保持高度活跃。L1 逆转录元件正在成为 cGAS-STING 和 IFN 信号传导的重要诱导剂，这些信号传导在包括癌症在内的多种疾病中经常失调。cGAS-STING 和 L1 活性的关键抑制因子是核酸外切酶三素修复核酸外切酶 1 (TREX1)，TREX1 的缺失会促进 L1 的积累。此外，L1 失调是通过 cGAS-STING 慢性诱导 I 型 IFN 信号传导的疾病的常见主题，例如 Aicardi-Goutières 综合征、范可尼贫血和皮肌炎。尽管 TREX1 在四足动物物种中高度保守，但存在其他抑制 L1 逆转录转座的抑制蛋白。这些抑制基因突变时通常与以不受控制的炎症为特征的疾病相关，而炎症与高 cGAS-STING 活性和 L1 表达水平升高有关。在这篇综述中，我们讨论了 L1 抑制的这些相互关联的途径及其在 cGAS-STING 和疾病炎症调节中的作用。