title: EB virus-encoded RNAs are recognized by RIG-I and activate signaling to induce type I IFN.
abstract: Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) are nonpolyadenylated, untranslated RNAs, exist most abundantly in latently EBV-infected cells, and are expected to show secondary structures with many short stem-loops. Retinoic acid-inducible gene I (RIG-I) is a cytosolic protein that detects viral double-stranded RNA (dsRNA) inside the cell and initiates signaling pathways leading to the induction of protective cellular genes, including type I interferons (IFNs). We investigated whether EBERs were recognized by RIG-I as dsRNA. Transfection of RIG-I plasmid induced IFNs and IFN-stimulated genes (ISGs) in EBV-positive Burkitt's lymphoma (BL) cells, but not in their EBV-negative counterparts or EBER-knockout EBV-infected BL cells. Transfection of EBER plasmid or in vitro-synthesized EBERs induced expression of type I IFNs and ISGs in RIG-I-expressing, EBV-negative BL cells, but not in RIG-I-minus counterparts. EBERs activated RIG-I's substrates, NF-kappaB and IFN regulatory factor 3, which were necessary for type I IFN activation. It was also shown that EBERs co-precipitated with RIG-I. These results indicate that EBERs are recognized by RIG-I and activate signaling to induce type I IFN in EBV-infected cells.
authors.affiliation: Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Mrinal
authors.initials: M
authors.lastname: Samanta
authors.forename: Dai
authors.initials: D
authors.lastname: Iwakiri
authors.forename: Teru
authors.initials: T
authors.lastname: Kanda
authors.forename: Tadaatsu
authors.initials: T
authors.lastname: Imaizumi
authors.forename: Kenzo
authors.initials: K
authors.lastname: Takada
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D049452:Green Fluorescent Proteins / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis*; D016328:NF-kappa B / Q000378:metabolism; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012367:RNA, Viral / Q000235:genetics*; D011971:Receptors, Immunologic; D011994:Recombinant Proteins / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection
chemical_list: C099537:Epstein-Barr virus encoded RNA 1; C106732:Epstein-Barr virus encoded RNA 2; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D016328:NF-kappa B; D012367:RNA, Viral; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D020365:RNA Helicases