RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III–transcribed RNA intermediate

Ablasser et al. Nat. Immunol. 10, 1065 - 1072 (2009)

Speaker: Hsueh-Chi Lu(呂學奇)                                   Time: 14:10~15:00, Oct. 28, 2009

Commentator: Dr. Hsiao-Sheng Liu(劉校生博士)       Place: Room 601

Abstract:

Innate immunity is the first line to protect host cells from microbial invasion. Host cells use their pattern recognition receptors(PRRs) to sense microbial pathogen-associated molecular patterns(PAMPS). However, the sensors of microbial DNA are still less known. In plasmacytoid dendritic cells (DCs), TLR9 is responsible for recognizing CpG DNA to activate the production of type I interferon. Two other DNA sensors were recently found. One is DAI which detects dsDNA and results in the induction of type I interferon, and the other is AIM2 which also detects dsDNA, then leading to the inflammasome activation and IL-1 production. But AIM2 does not stimulate the transcription of genes encoding type I interferon(1). In this study, the authors discovered another DNA sensor that could sense poly(dA:dT). First, they used different kinds of siRNAs to silence PRRs and found that RIG-I siRNA could decrease the production of type I interferon by poly(dA:dT), suggesting the involvement of the RIG-I pathway in DNA sensing. Previous study also revealed that the induction of IFN-b by transfected double-stranded DNA depends on RIG-I and MAVS in certain human cell lines (2). Because RIG-I is an RNA sensor, they hypothesized that poly(dA:dT) activates RIG-I through an RNA intermediate. They showed that RNA extracted from poly(dA:dT)-transfected 293T cells could trigger the production of type I interferon in peripheral blood mononuclear cells(PBMCs), whereas RNA derived from untransfected cells non-transfected cells failed to do so. Moreover, they further confirmed that the RNA intermediate is a polyphosphated-dsRNA transcribed by RNA polymerase Ⅲ. Induction of type I interferon by poly(dA:dT) was decreased in the presence of a RNA polymerase Ⅲ inhibitor, ML-60218. Finally, siRNA knockdown of RIG-I also reduced interferon production in response to the stimulation of EBER, which is the transcripts of EBV by RNA polymeraseⅢ. In summary, RNA polymeraseⅢ is a cytosolic DNAsensor for the production of type I interferon via the RIG-I pathway.

References:

1.Vilaysane A et al. The innate immune response to DNA. Semin Immunol. 21,208-214 (2009).

2. Ishii, K.J., Coban, C., Kato, H., Takahashi, K., Torii, Y., Takeshita, F., Ludwig, H., Sutter, G., Suzuki, K., Hemmi, H., et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat. Immunol. 7, 40–48(2006).