Epstein-Barr virus EBNA2 blocks Nur77-mediated apoptosis

Epstein-Barr virus infection in vitro immortalizes primary 8 cells. EBNA2 is an Epstein-Barr virus-encoded transcriptional transactivator that mimics the effects of activated Notch signaling and is essential for this proliferative response. An assay using Sindbis virus (SV) as a cell death inducer revealed that, like Notch, EBNA2 also has antiapoptotic activity. We show that Nur77 is a mediator of SV-induced cell death and that EBNA2 antiapoptotic activity results from interaction with Nur77. EBNA2 colocalized with Nur77 in transfected cells and coprecipitated with Nur77 in IB4 B cells. EBNA2 binds to Nur77 through sequences in the EBNA2 amino acid 123-147 conserved domain and an EBNA2 mutant unable to bind Nur77 also lost the ability to protect cells from SV-induced apoptosis. EBNA2 exerted its antideath function by retaining Nur77 in the nucleus and preventing Nur77 from targeting mitochondria in response to apoptotic stimuli. Thus, targeting of Nur77 can be added to the list of strategies used by viruses to counter apoptosis.