RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway.
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.
Chiu
Yu-Hsin
YH
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Macmillan
John B
JB
Chen
Zhijian J
ZJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015551:Autoimmunity; D002460:Cell Line; D002474:Cell-Free System; D003600:Cytosol / Q000276:immunology*; D004247:DNA / Q000276:immunology*; D004267:DNA Viruses / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D016952:Legionella pneumophila / Q000276:immunology; D051379:Mice; D011122:Polyphosphates / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D012320:RNA Polymerase III / Q000276:immunology* / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000378:metabolism; D015398:Signal Transduction; D014544:Uridine Triphosphate / Q000378:metabolism
D053583:Interleukin-1beta; D011122:Polyphosphates; D012330:RNA, Double-Stranded; D012313:RNA; D016899:Interferon-beta; D000255:Adenosine Triphosphate; D004247:DNA; D012320:RNA Polymerase III; C005692:triphosphoric acid; D014544:Uridine Triphosphate