IRF4 promotes Epstein-Barr virus activation in Burkitt's lymphoma cells

Epstein-Barr virus (EBV) establishes a life-long latency in memory B cells, whereas plasma cell differentiation is linked to EBV lytic reactivation from latently infected B cells. EBV lytic replication is mediated by the two immediate-early switch proteins Zta and RTA. Both plasma cell transcription factors XBP-1 and Blimp-1 have been shown to enable the triggering of EBV lytic reactivation by activating the transcription of Zta or RTA. Here we show that interferon regulatory factor 4 (IRF4), another plasma cell transcription factor that is either not expressed or expressed at a low level in EBV-positive Burkitt's lymphoma (BL) cells, can activate the promoters of EBV Zta and RTA, but is not sufficient to elicit EBV lytic reactivation in latently infected BL cells. However, ectopic IRF4 expression can augment EBV lytic gene expression induced by anti-immunoglobulin (anti-Ig) or sodium butyrate treatment in all tested lymphoma cells, whereas IRF4 knockout in Raji cells, the only BL cell line with detectable endogenous IRF4 expression, abolishes EBV lytic gene expression induced by anti-Ig, and this is accompanied by the reduction of Blimp-1 expression, whose overexpression, in turn, can rescue EBV lytic gene expression in IRF4 knockout Raji cells. Furthermore, IRF4 knockout impairs B cell receptor (BCR) signalling activation, which is required for BCR-mediated EBV reactivation. Altogether, these results demonstrate that IRF4 facilitates EBV lytic reactivation in BL cells, which involves the regulation of Blimp-1 expression and BCR signalling pathways.