Proteomic screening identifies HNRNPA2B1 as a novel factor that controls Epstein-Barr virus reactivation through chromatin regulation

Functional analyses across multiple EBV+ cell models demonstrated that HNRNPA2B1 acts as a restriction factor for EBV lytic reactivation. Depletion of HNRNPA2B1 led to increased expression of IE and downstream lytic genes, enhanced RNA polymerase II recruitment to the ZTA and RTA promoters, and elevated the proportion of cells entering the lytic cycle. Conversely, enforced expression of HNRNPA2B1 suppressed EBV lytic reactivation.

Mechanistically, HNRNPA2B1 enhances repressive viral chromatin states by facilitating recruitment of the histone demethylase KDM1A to EBV IE gene promoters, thereby limiting the activating histone H3K4 trimethylation. Together, these findings identify HNRNPA2B1 as a key epigenetic regulator of EBV latency and link RNA-binding proteins to chromatin control of viral reactivation.