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 stemloops. 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 EBVinfected 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-jB 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.

Cutting Edge: Overlapping Functions of TLR7 and TLR9 for Innate Defense against a Herpesvirus Infection

“…Interestingly, the cytoplasmic receptor for uncapped 5Ј-phosphorylated RNA, RIG-I (retinoic acid-inducible gene I), has been recently demonstrated to trigger IFN-␣/␤ responses in cells infected by EBV in vitro (22), further supporting a possible role for RNA sensing in the detection of and the response to DNA virus infection. In infected cells, viral mRNAs locate into the cytosol and are therefore accessible to RIG-I.…”

RNA Polymerase III Detects Cytosolic DNA and Induces Type I Interferons through the RIG-I Pathway

“…Some DNA viruses, including adenovirus, herpes simplex virus 1 (HSV-1) and Epstein-Barr virus (EBV), induce IFN-β production in a RIG-I dependent matter (Cheng et al, 2007;Rasmussen et al, 2007;Samanta et al, 2006). To determine whether Pol-III plays a role in IFN induction by DNA viruses, we treated Raw264.7 cells with ML-60218 and then infected the cells with adenovirus, HSV-1 or Sendai virus (RNA virus as a control).…”

Epstein–Barr virus renders the infected natural killer cell line, NKL resistant to doxorubicin-induced apoptosis

“…EBVassociated gene products like EBNA1 and LMP1 were reported to modify the ubiquitin -proteasome activity and affect proteolysis of various cellular proteins including NF-kB (Masucci, 2004). In addition, EBERs appear to be involved in modulation of cellular response and were reported to activate NF-kB-signalling pathway (Nambo and Takada, 2002;Samanta et al, 2006). These observations strongly argue that the presence of EBV must render NKL more resistant to lethal stress like DNA damage at least partially through the NF-kB pathway.…”