Mitochondrial protein, TBRG4, modulates KSHV and EBV reactivation from latency

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr (EBV) are gammaherpesviruses associated with multiple human malignancies. KSHV is the etiological agent of Kaposi’s Sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD). EBV is associated with Burkitt’s lymphoma (BL), Hodgkin’s lymphoma (HL), nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). KSHV and EBV establish life-long latency in the human host with intermittent periods of lytic reactivation. Here, we identified a cellular factor named transforming growth factor-beta regulator 4 (TBRG4) that plays a role in the gammaherpesvirus lifecycle. We find that TBRG4, a protein that is localized to the mitochondria, can regulate lytic reactivation from latency of both KSHV and EBV. Knockdown of TBRG4 in cells latently infected with KSHV or EBV induced viral lytic gene transcription and replication. TBRG4 deficiency causes mitochondrial stress and increases reactive oxygen species (ROS) production. Treatment with a ROS scavenger decreased viral reactivation from latency in TBRG4-depleted cells. These data suggest that TBRG4 serves as a cellular repressor of KSHV and EBV reactivation through the regulation of ROS production. Author summary Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein-Barr (EBV) are double-stranded DNA tumor viruses that are associated with multiple cancers in the human population. These include both B and T cell lymphomas, as well as epithelial- and endothelial-derived cancers. Both EBV and KSHV exhibit two phases of their lifecycle, latency and lytic replication. During lytic reactivation, the virus switches from latency and replicates its viral genome to produce new infectious progeny. Here we report that the mitochondrial protein, TBRG4, serves as a cellular repressor of KSHV and EBV lytic reactivation through the regulation of ROS production.