We demonstrate that TPA-induced reactivation of lytic EBV infection in NOKs proceeds through a differentiation-dependent mechanism and show that IRF6 knock-down, as well as knock-down of the upstream IRF6 activators, PKCδ and RIPK4, prevents the TPA-mediated lytic EBV reactivation. The gene discussed is RIPK4; the disease is Epstein-Barr virus infection.