Cancer therapies activate RIG-I-like receptor pathway through endogenous non-coding RNAs
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Diana Rose E. Ranoa1, Akash D. Parekh1, Sean P. Pitroda1, Xiaona Huang1, Thomas Darga1,†, Anthony C. Wong1, Lei Huang2, Jorge Andrade2, Jonathan P. Staley3, Takashi Satoh4, Shizuo Akira4, Ralph R. Weichselbaum1,*, Nikolai N. Khodarev1,*
1Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA
2Center for Research Informatics, Biological Sciences Division, The University of Chicago, Chicago, IL 60637, USA
3Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA
4Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan
*These authors have contributed equally to this work
Ralph R. Weichselbaum, email: email@example.com
Nikolai N. Khodarev, email: firstname.lastname@example.org
Keywords: ionizing radiation, DNA damage, small non-coding RNAs, Type I interferon, RIG-I-like receptor (RLR)
Received: February 27, 2016 Accepted: March 05, 2016 Published: March 28, 2016
Emerging evidence indicates that ionizing radiation (IR) and chemotherapy activate Type I interferon (IFN) signaling in tumor and host cells. However, the mechanism of induction is poorly understood. We identified a novel radioprotective role for the DEXH box RNA helicase LGP2 (DHX58) through its suppression of IR-induced cytotoxic IFN-beta . LGP2 inhibits activation of the RIG-I-like receptor (RLR) pathway upon binding of viral RNA to the cytoplasmic sensors RIG-I (DDX58) and MDA5 (IFIH1) and subsequent IFN signaling via the mitochondrial adaptor protein MAVS (IPS1). Here we show that MAVS is necessary for IFN-beta induction and interferon-stimulated gene expression in the response to IR. Suppression of MAVS conferred radioresistance in normal and cancer cells. Germline deletion of RIG-I, but not MDA5, protected mice from death following total body irradiation, while deletion of LGP2 accelerated the death of irradiated animals. In human tumors depletion of RIG-I conferred resistance to IR and different classes of chemotherapy drugs. Mechanistically, IR stimulated the binding of cytoplasmic RIG-I with small endogenous non-coding RNAs (sncRNAs), which triggered IFN-beta activity. We demonstrate that the small nuclear RNAs U1 and U2 translocate to the cytoplasm after IR treatment, thus stimulating the formation of RIG-I: RNA complexes and initiating downstream signaling events. Taken together, these findings suggest that the physiologic responses to radio-/chemo-therapy converge on an antiviral program in recruitment of the RLR pathway by a sncRNA-dependent activation of RIG-I which commences cytotoxic IFN signaling. Importantly, activation of interferon genes by radiation or chemotherapy is associated with a favorable outcome in patients undergoing treatment for cancer. To our knowledge, this is the first demonstration of a cell-intrinsic response to clinically relevant genotoxic treatments mediated by an RNA-dependent mechanism.
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