title: Cancer therapies activate RIG-I-like receptor pathway through endogenous non-coding RNAs.
abstract: 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 [1]. 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.
authors.affiliation: Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Diana Rose E
authors.initials: DR
authors.lastname: Ranoa
authors.affiliation: Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Akash D
authors.initials: AD
authors.lastname: Parekh
authors.affiliation: Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Pitroda
authors.affiliation: Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Xiaona
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Darga
authors.affiliation: Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Wong
authors.affiliation: Center for Research Informatics, Biological Sciences Division, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.affiliation: Center for Research Informatics, Biological Sciences Division, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Andrade
authors.affiliation: Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Staley
authors.affiliation: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Satoh
authors.affiliation: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.affiliation: Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Nikolai N
authors.initials: NN
authors.lastname: Khodarev
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000071457:DEAD Box Protein 58 / Q000187:drug effects* / Q000378:metabolism* / Q000528:radiation effects*; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000378:metabolism* / Q000628:therapy; D058727:RNA, Small Untranslated / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects
chemical_list: D058727:RNA, Small Untranslated; D016899:Interferon-beta; D000071457:DEAD Box Protein 58
keywords: DNA damage; RIG-I-like receptor (RLR); Type I interferon; ionizing radiation; small non-coding RNAs