Structural Basis for Apoptosis Inhibition by Epstein-Barr Virus BHRF1

Abstract

Epstein-Barr virus (EBV) is associated with human malignancies, especially those affecting the B cell compartment such as Burkitt lymphoma. The virally encoded homolog of the mammalian pro-survival protein Bcl-2, BHRF1 contributes to viral infectivity and lymphomagenesis. In addition to the pro-apoptotic BH3-only protein Bim, its key target in lymphoid cells, BHRF1 also binds a selective sub-set of pro-apoptotic proteins (Bid, Puma, Bak) expressed by host cells. A consequence of BHRF1 expression is marked resistance to a range of cytotoxic agents and in particular, we show that its expression renders a mouse model of Burkitt lymphoma untreatable. As current small organic antagonists of Bcl-2 do not target BHRF1, the structures of it in complex with Bim or Bak shown here will be useful to guide efforts to target BHRF1 in EBV-associated malignancies, which are usually associated with poor clinical outcomes.

Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells

“…Further study has shown that BHRF1 blocks apoptosis by binding to a crucial, lethal fraction of the BIM, but not the general BIM pool (Desbien et al, 2009). Moreover, the structure of BHRF1 in complex with BIM confirms that BHRF1 can counteract BIM directly (Kvansakul et al, 2010). These findings may facilitate the exploitation of small-molecule inhibitors of BHRF1 to improve the poor prognosis in EBV-associated diseases, since BHRF1 confers strong chemoresistance and current small organic inhibitors of Bcl-2 do not target BHRF1.…”

“…Other studies showed that BHRF1 binds to full-length BAK (Theodorakis et al, 1996;Cross et al, 2008). In fact, BHRF1 changes its structure to accommodate the BAK domain and therefore keeps the BAK inactive (Kvansakul et al, 2010). However, in cytokine-deprived cells BHRF1 appears to inhibit apoptosis by binding BIM, but not BAK (see below).…”

“…However, in cytokine-deprived cells BHRF1 appears to inhibit apoptosis by binding BIM, but not BAK (see below). In addition, although BHRF1 does not bind with Bax directly and Bax can replace BAK in cell death, it has been shown to repress the activation of Bax and BAK to preserve mitochondrial function (Kvansakul et al, 2010). So why BHRF1 binds an apparently irrelevant protein is a conundrum.…”

“…Accumulating evidence shows that BHRF1 is associated with PUMA and Bid, since it binds to them and interacts strongly with Bid protein (Flanagan and Letai, 2008;Kvansakul et al, 2010). EBV BHRF1 promotes cell survival by directly repressing pro-apoptotic Bcl-2 family proteins including PUMA and Bid (Kvansakul et al, 2010).…”

The N Terminus of the Vaccinia Virus Protein F1L Is an Intrinsically Unstructured Region That Is Not Involved in Apoptosis Regulation

“…These include EpsteinBarr virus BHRF1 (19), adenovirus E1B19K (20), Kaposi sarcoma herpesvirus KsBcl-2 (21), fowlpox virus FPV039 (22,23), and herpesvirus saimiri vBcl-2 (24), and structural studies of some of these confirmed that they adopt a Bcl-2 fold (25)(26)(27). However, a number of viral proteins have been identified that shared no discernible sequence identity to known inhibitors of apoptosis.…”