Regulation by TREX1

Three prime repair exonuclease 1 (TREX1) is a DNase type III enzyme, which targets and digests unpaired nucleotides on ssDNA and dsDNA ends through a 3'to 5' exonuclease activity (Perrino FW et al. 1994; de Silva U et al. 2007; Lehtinen DA et al. 2008; Fye JM et al 2011). TREX1 is an endoplasmic reticulum (ER)-associated protein, which is anchored to ER membrane via the C-terminal transmembrane domain (Chowdhury D et al. 2006; Richards A et al. 2007; Stetson DB et al. 2009). TREX1 has been implicated in innate immune responses against self (damaged or retrotransposons-derived DNA) and retroviral-derived DNA (Stetson DB et al. 2009; Yan N et al. 2010; Hasan M et al. 2012). TREX1 deficiency in human and mouse cells led to accumulation of cytosolic DNA which resulted in a continual activation of cytosolic DNA-sensors. In addition, cells lacking TREX1 function were less susceptible to infection with different types of RNA viruses (Yan N et al. 2010; Hasan M et al. 2012).Thus, the physiological role of the exonuclease TREX1 is to digest cytosolic host DNA to avoid autoimmunity. Loss-of-function mutations in the gene encoding human TREX1 are associated with several autoimmune diseases (Aicardi-Goutieres syndrome (AGS), familial chilblain lupus (FCL), systemic lupus erythematosus (SLE)) that result in increased levels of interferon and circulating antibodies to DNA (Crow YJ et al. 2006; Rice G et al. 2007; Lee-Kirsch MA et al. 2007). During infection with human immunodeficiency virus (HIV) or other RNA viruses, TREX1 activity may inhibit the innate immune responses by processing viral DNA generated during reverse transcription (Yan N et al. 2010; Hasan M et al. 2012). It's not yet known whether TREX1 is also involved in regulation of host responses to DNA viruses.<p>Detection of nucleic acids is known to launch signaling cascades leading to induction of type I interferons, which in turn orchestrate an immune response that involves the expression of hundreds of interferon-stimulated genes (ISGs). It is interesting to note that interferon(IFN)-independent activation of a subset of ISGs was detected in mouse and human cells lacking functional TREX1 (Hasan M et al. 2012). Hasan et al. have also observed that TREX1-deficiency resulted in an increased lysosomal compartment. Trex1 was found to control mTORC1 activity in mouse embryonic fibroblasts (MEF), which in turn negatively regulates translocation of transcription factor EB (TFEB) to the nucleus thereby controlling lysosomal biogenesis (Hasan M et al. 2012; Roczniak-Ferguson A et al. 2012). The authors linked the altered lysosomal compartment to innate immune responses by suggesting that lysosomal biogenesis (regulated by TFEB and mTORC1) acted upstream of IFN-independent ISG expression (regulated by IRF3 and IRF7) (Hasan M et al. 2012).

三链修复外切核酸酶1（TREX1）是一种DNase III型核酸酶，它通过3'至5'外切酶活性靶向并降解单链DNA（ssDNA）和双链DNA（dsDNA）末端的非配对核苷酸（Perrino FW et al. 1994; de Silva U et al. 2007; Lehtinen DA et al. 2008; Fye JM et al 2011）。TREX1是一种内质网（ER）相关蛋白，通过其C端跨膜结构域锚定于ER膜（Chowdhury D et al. 2006; Richards A et al. 2007; Stetson DB et al. 2009）。TREX1与针对自身（受损或反转录转座子衍生的DNA）和逆转录病毒衍生的DNA的先天免疫反应相关（Stetson DB et al. 2009; Yan N et al. 2010; Hasan M et al. 2012）。人类和小鼠细胞中TREX1缺乏导致细胞质DNA积累，从而持续激活细胞质DNA传感器。此外，缺乏TREX1功能的细胞对不同类型的RNA病毒感染抵抗力较低（Yan N et al. 2010; Hasan M et al. 2012）。因此，外切核酸酶TREX1的生理作用是降解细胞质宿主DNA，以避免自身免疫。编码人类TREX1的基因功能缺失突变与多种自身免疫疾病（Aicardi-Goutieres综合征（AGS）、家族性冻疮性狼疮（FCL）、系统性红斑狼疮（SLE））相关，这些疾病导致干扰素和循环抗DNA抗体水平升高（Crow YJ et al. 2006; Rice G et al. 2007; Lee-Kirsch MA et al. 2007）。在人类免疫缺陷病毒（HIV）或其他RNA病毒感染期间，TREX1活性可能通过处理逆转录过程中产生的病毒DNA来抑制先天免疫反应（Yan N et al. 2010; Hasan M et al. 2012）。目前尚不清楚TREX1是否也参与调节宿主对DNA病毒的响应。<p>已知核酸的检测会启动信号级联反应，导致I型干扰素的诱导，而干扰素进而编排涉及数百个干扰素刺激基因（ISGs）表达的免疫反应。值得注意的是，在缺乏功能性TREX1的小鼠和人类细胞中检测到了ISGs子集的干扰素（IFN）非依赖性激活（Hasan M et al. 2012）。Hasan等人还观察到TREX1缺乏导致溶酶体区室增加。研究发现，Trex1在成纤维细胞（MEF）中调控mTORC1活性，进而负向调节转录因子EB（TFEB）向核的转位，从而控制溶酶体发生（Hasan M et al. 2012; Roczniak-Ferguson A et al. 2012）。作者通过提出溶酶体发生（由TFEB和mTORC1调节）在干扰素（IFN）非依赖性ISG表达（由IRF3和IRF7调节）的上游作用，将改变的溶酶体区室与先天免疫反应联系起来（Hasan M et al. 2012）.