vBcl-2 modulates ER stress-related proteins to maintain cellular homeostasis for human herpesvirus 8 replication

Human herpesvirus 8 (HHV-8) orf16 encodes a viral Bcl-2 (vBcl-2) protein. Independent of its anti-apoptotic and anti-autophagic activity, vBcl-2 plays an essential role in HHV-8 replication. Endoplasmic reticulum (ER) stress has been recognized as a key regulator of viral replication, exerting either proviral or antiviral effects. Cells experiencing ER stress activate the unfolded protein response (UPR) to restore ER homeostasis and promote cell survival. In this study, we demonstrate that overexpression of HHV-8 vBcl-2 enhances viral progeny production and is associated with increased UPR activation, as evidenced by elevated expression of key UPR markers. While the ER stress induction promoted viral gene expression and progeny production, it also increased cytotoxicity in primary effusion lymphoma (PEL) cells. Conversely, the disruption of ER-associated degradation (ERAD) impaired viral progeny production, suggesting that ER homeostasis is critical to HHV-8 life cycle. Notably, vBcl-2 overexpression attenuated ER stress-induced cytotoxicity and dampened excessive UPR activation, indicating a protective function within stressed host cells. These results indicate that induction of ER stress can activate HHV8 gene expression and cause PEL cell death. Increased expression of vBcl-2 may help HHV8-infected cells cope with altered cellular stress, thereby promoting virus survival in host cells.