Chiu Yu-Hsin, Macmillan John B, Chen Zhijian J
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Cell. 2009 Aug 7;138(3):576-91. doi: 10.1016/j.cell.2009.06.015. Epub 2009 Jul 23.
Type I interferons (IFNs) are important for antiviral and autoimmune responses. Retinoic acid-induced gene I (RIG-I) and mitochondrial antiviral signaling (MAVS) proteins mediate IFN production in response to cytosolic double-stranded RNA or single-stranded RNA containing 5'-triphosphate (5'-ppp). Cytosolic B form double-stranded DNA, such as poly(dA-dT)*poly(dA-dT) [poly(dA-dT)], can also induce IFN-beta, but the underlying mechanism is unknown. Here, we show that the cytosolic poly(dA-dT) DNA is converted into 5'-ppp RNA to induce IFN-beta through the RIG-I pathway. Biochemical purification led to the identification of DNA-dependent RNA polymerase III (Pol-III) as the enzyme responsible for synthesizing 5'-ppp RNA from the poly(dA-dT) template. Inhibition of RNA Pol-III prevents IFN-beta induction by transfection of DNA or infection with DNA viruses. Furthermore, Pol-III inhibition abrogates IFN-beta induction by the intracellular bacterium Legionella pneumophila and promotes the bacterial growth. These results suggest that RNA Pol-III is a cytosolic DNA sensor involved in innate immune responses.
I型干扰素（IFN）对于抗病毒和自身免疫反应至关重要。维甲酸诱导基因I（RIG-I）和线粒体抗病毒信号（MAVS）蛋白介导细胞对胞质双链RNA或含5'-三磷酸（5'-ppp）的单链RNA产生反应时的IFN生成。胞质B型双链DNA，如聚（dA-dT）*聚（dA-dT）[聚（dA-dT）]，也能诱导IFN-β，但其潜在机制尚不清楚。在此，我们表明胞质聚（dA-dT）DNA被转化为5'-ppp RNA，通过RIG-I途径诱导IFN-β。生化纯化鉴定出DNA依赖性RNA聚合酶III（Pol-III）是负责从聚（dA-dT）模板合成5'-ppp RNA的酶。抑制RNA Pol-III可通过转染DNA或感染DNA病毒来阻止IFN-β的诱导。此外，Pol-III抑制消除了细胞内细菌嗜肺军团菌诱导的IFN-β，并促进细菌生长。这些结果表明RNA Pol-III是参与先天免疫反应的胞质DNA传感器。
