Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes.
Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes.
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TREX1调节溶酶体生物发生和抗病毒基因的干扰素非依赖性激活。
作者：
病毒核酸的先天免疫感应触发I型干扰素（IFN）的产生，其激活干扰素刺激基因（ISG）并指导多方面的抗病毒反应。ISG也可以通过IFN-非依赖性途径激活，尽管精确的机制仍然难以捉摸。在这里，我们发现，胞质核酸外切酶Trex 1调节激活的一个子集的ISGs独立的IFN。Trex 1 −/−小鼠和TREX 1突变体人类细胞都表达高水平的抗病毒基因，并且对病毒感染具有抗性。Trex 1 −/−细胞中抗病毒基因的IFN-依赖性激活需要STING，TBK 1和IRF 3和IRF 7。我们还发现，Trex 1缺陷细胞显示扩大的溶酶体室，改变亚细胞定位的转录因子EB（TFEB），并降低mTORC 1活性。总之，我们的数据确定Trex 1作为溶酶体生物发生和IFN-独立的抗病毒基因激活的调节剂，并显示溶酶体的失调可以引起先天免疫反应。
Innate immune sensing of viral nucleic acids triggers type I interferon (IFN) production, which activates interferon-stimulated genes (ISGs) and directs a multifaceted antiviral response. ISGs can also be activated through IFN-independent pathways, although the precise mechanisms remain elusive. Here we found that the cytosolic exonuclease Trex1 regulates the activation of a subset of ISGs independently of IFN. Both Trex1−/− mouse and TREX1-mutant human cells express high levels of antiviral genes and are refractory to viral infections. The IFN-independent activation of antiviral genes in Trex1−/− cells requires STING, TBK1 and IRF3 and IRF7. We also found that Trex1-deficient cells display expanded lysosomal compartment, altered subcellular localization of the transcription factor EB (TFEB), and reduced mTORC1 activity. Together, our data identify Trex1 as a regulator of lysosomal biogenesis and IFN-independent activation of antiviral genes, and shows dysregulation of lysosomes can elicit innate immune responses.
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