The ability of BHRF1 to inhibit apoptosis is dependent on stimulus and cell type

The development of resistance to host defense mechanisms such as tumor necrosis factor (TNF)- and Fas-mediated apoptosis of transformed or virus-infected cells may be a critical component in the development of disease, To find genes that protect cells from apoptosis, we used an expression cloning strategy and identified BHRF1, an Epstein-Barr virus (EBV) early-lytic-cycle protein with distant homology to Bcl-2, as an anti-apoptosis protein. Expression of BHRF1 in MCF-Fas cells conferred nearly complete resistance against both anti-Fas antibody and TNF-mediated apoptosis, In addition, BHRF1 protected these cells from monocyte-mediated killing but failed to protect them from killing mediated by lymphokine-activated killer cells, The ability of BHRF1 to protect MCF-Fas cells from apoptosis induced by various stimuli was identical to that of Bcl-2 and Bcl-x(L), Moreover, the mechanism of action of BHRF1 resembled that of Bcl-2 and Bcl-x, as it inhibited TNF- and anti-Fas-induced activation of two enzymes participating in the apoptosis pathway, cytosolic phospholipase A(2) and caspase-3/CPP32, but did not interfere with the activation of NF-KB-like transcription factors, A putative function of BHRF1 in EBV-infected epithelial cells may be to protect virus-infected cells from TNF- and/or anti-Fas-induced cell death in order to maximize virus production. Surprisingly, expression of neither BHRF1 nor Bcl-2 in a B-cell line, BJAB, protected the cells from anti-Fas-mediated apoptosis even though they increased the survival of serum-starved cells, Thus, the protective role of BHRF1 against apoptosis resembles that of Bcl-2 in being cell type specific and dependent on the apoptotic stimulus.