FIG 8.

Proposed model of a regulatory loop between ZIC2-mediated repression and K-Rta-dependent activation of KSHV lytic replication. In latent KSHV-infected cells, ZIC2 interacts with the PRC2 complex and maintains the localization of PRC2 on the immediate early (IE) gene region, setting a poised state of IE genes. Depletion of ZIC2 and/or K-Rta-mediated ZIC2 degradation leads to the derepression of IE genes by decreasing the amount of H3K27me3 marks at the genomic sites, which results in KSHV lytic reactivation. K-Rta expression further promotes ZIC2 for degradation and recruitment of transcriptional cofactors to maximize lytic gene expression.