The Epstein-Barr virus BCL-2 homologues: interactions with cellular BCL-2 proteins and their role in apoptosis

摘要

Epstein-Barr virus (EBV) encodes two viral BCL-2 homologues, BHRF1 and BALF1. BHRF1 is expressed in a subset of EBV-positive Burkitt’s lymphoma (BL) tumours; as BHRF1 is highly anti-apoptotic, expression could result in treatment-resistant BL. Little is known about BALF1, including whether BALF1 is pro- or anti-apoptotic.ududInteractions between BHRF1 and cellular BCL-2 homologues have not been fully characterised, but previous studies have focused on BIM as a key binding partner. We stably expressed wild-type or mutant vBCL-2s in EBV-negative BL lines to investigate interactions between BHRF1 and cellular BCL-2 homologues. The ability to bind BIM, whilst well documented, had no impact on BHRF1-mediated protection. Our data suggests that BHRF1’s protective ability may be mediated through binding to BID and BAK. This work also identified two amino acids, located in the binding groove of BHRF1, which are highly important for protein function. We detected BALF1 expression, at potentially functionally relevant levels, in a wide variety of EBV-associated tumour lines. BALF1 mRNA was detectable in lines with highly varied patterns of viral gene expression, indicating that expression is not restricted to one part of the viral life-cycle. In BL, BALF1 was found to be anti-apoptotic, and co-operated with, rather than antagonized, BHRF1.