nature-immunology201301-5_副本

Trex1是一种能够限制细胞感应胞内DNA的细胞质基质核酸内切酶。来自美国德州大学西南医学中心的Yan及其同事发现Trex1缺陷能够通过一条参与溶酶体生物合成的途径,自发地提高适配体蛋白STING依赖的促炎反应。相关的研究论文于2012年11月18日在线发表在《Nature Immunology》杂志上。

-2013年1月《自然-免疫》

中文翻译


【题目】Trex1调控溶酶体的生物合成和干扰素依赖的抗病毒基因激活

【译文】先天免疫系统感应病毒核酸,激活免疫细胞分泌I型干扰素,然后I型干扰素激活干扰素刺激基因(ISGs),并指导多层面的抗病毒反应。ISGs也能够通过与干扰素无关的途径被激活,尽管其中的精细机制还不可捉摸。本研究发现细胞质基质核酸外切酶Trex1调控一类ISGs的激活,且这一过程与干扰素无关。Trex1−/−小鼠细胞和Trex1突变的人细胞都具有高表达的、编码抗病毒分子的基因(抗病毒基因),且难以被病毒感染。Trex1−/−细胞中抗病毒基因的干扰素无关激活需要适配体蛋白STING、TBK1激酶和转录因子IRF3和IRF7。本研究也发现Trex1缺陷细胞内的溶酶体的区室膨大,结果改变转录因子TFEB的亚细胞定位及减小调节蛋白mTORC1的活性。总之,本研究鉴定到Trex1是溶酶体生物合成和抗病毒基因的干扰素无关激活的调节因子,同时表明溶酶体的代谢失调能够引发先天免疫响应。

英文原稿


[Title]: Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes

[Authors]:Maroof Hasan, James Koch, Dinesh Rakheja, Asit K Pattnaik, James Brugarolas, Igor Dozmorov, Beth Levine, Edward K Wakeland, Min Ae Lee-Kirsch & Nan Yan

[Abstract]: The sensing of viral nucleic acids by the innate immune system triggers the production of type I interferons, which activates interferon-stimulated genes (ISGs) and directs a multifaceted antiviral response. ISGs can also be activated through interferon-independent pathways, although the precise mechanisms remain elusive. Here we found that the cytosolic exonuclease Trex1 regulated the activation of a subset of ISGs independently of interferon. Both Trex1−/− mouse cells and Trex1-mutant human cells had high expression of genes encoding antiviral molecules (‘antiviral genes’) and were refractory to viral infection. The interferon-independent activation of antiviral genes in Trex1−/− cells required the adaptor STING, the kinase TBK1 and the transcription factors IRF3 and IRF7. We also found that Trex1-deficient cells had an expanded lysosomal compartment, altered subcellular localization of the transcription factor TFEB and diminished activity of the regulator mTORC1. Together our data identify Trex1 as a regulator of lysosomal biogenesis and interferon-independent activation of antiviral genes and show that dysregulation of lysosomes can elicit innate immune responses.

原文地址

http://www.nature.com/ni/journal/v14/n1/full/ni.2475.html

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