ERK/c-Jun Recruits Tet1 to Induce Zta Expression and Epstein-Barr Virus Reactivation through DNA Demethylation

DNA demethylation plays an essential role in the reactivation of Epstein-Barr virus (EBV) from latency infection. However, it is unclear how epigenetic modification is initiated in responding to stimuli. Here, we demonstrate that ERK/c-Jun signaling is involved in DNA demethylation of EBV immediate early (IE) gene Zta in response to 12-O-Tetradecanoylphorbol-13-acetate (TPA) stimulation. Remarkably, Ser73 phosphorylation of c-Jun facilitates Zta promoter demethylation and EBV reactivation, whereas knockdown of c-Jun attenuates Zta demethylation and viral reactivation. More importantly, we reveal for the first time that c-Jun interacts with DNA dioxygenase Tet1 and facilitates Tet1 to bind to Zta promoter. The binding of c-Jun and Tet1 to Zta enhances promoter demethylation, resulting in the activation of Zta, the stimulation of BHRF1 (a lytic early gene) and gp350/220 (a lytic late gene), and ultimately the reactivation of EBV. Knockdown of Tet1 attenuates TPA-induced Zta demethylation and EBV reactivation. Thus, TPA activates ERK/c-Jun signaling, which subsequently facilitates Tet1 to bind to Zta promoter, leading to DNA demethylation, gene expression, and EBV reactivation. This study reveals important roles of ERK/c-Jun signaling and Tet1 dioxygenase in epigenetic modification, and provides new insights into the mechanism underlying the regulation of virus latent and lytic infection.