Viral versus cellular BCL-2 proteins

Abstract

All gamma herpesviruses and a few other viruses encode at least one homologue of the mammalian cell death inhibitor BCL-2. Gamma herpesviruses are associated with human and animal lymphoid and epithelial tumours. However, the role of these viral BCL-2 homologues in the virus replication cycle or in human disease is not known, though recent developments show progress in this area. The structure of viral BCL-2 family protein, KSBcl-2, is similar to that of cellular family members, but viral BCL-2 proteins differ functionally from the cellular proteins, apparently escaping the regulatory mechanisms to which their cellular counterparts are subjected. Thus, exploring the biochemical and biological functions of the viral BCL-2 family proteins will increase our understanding of their role in virus infections and will undoubtedly teach us something about their cellular kin. Cell Death and Differentiation (2003) 10, S68 ± S76. doi:10.1038/ sj.cdd.4401133Keywords: virus; BCL-2; BAX; BHRF1; Epstein ± Barr virus (EBV); Kaposi's sarcoma-associated herpesvirus (KSHV); KSBcl-2; herpesvirus Abbreviations: Abbreviations for viruses and their BCL-2 homologues are all found in the legend to Figure 1.

BH3 domains define selective inhibitory interactions with BHRF-1 and KSHV BCL-2

“…7 Epstein-Barr virus (EBV) was discovered first in association with Burkitt's lymphoma and more recently has been found to be associated with Hodgkin's disease, T-cell lymphoma, nasopharyngeal carcinoma, and post-transplant lymphoproliferative disease. 8,9 Patients receiving immuno-suppressive anti-cancer therapy and individuals with HIV have an increased susceptibility to develop EBV-associated lymphomas.…”

“…BCL-2 homologs encoded by a-and g-herpesvirus and the African swine fever virus share 20-30% homology with one another and cellular BCL-2. 7 All viral homologs contain a BH1 sequence motif. The BH2 motif is also conserved in the almost all viral BCL-2 homologs except for murine g-herpesvirus 68 (gHV68).…”

“…The BH2 motif is also conserved in the almost all viral BCL-2 homologs except for murine g-herpesvirus 68 (gHV68). 7 Both BH1 and BH2 sequence motifs are critical for BH3 domain binding and the death repressor effects of the anti-apoptotic proteins. 29 The BH3 domain, thought to be important for killing cells, is poorly conserved in the viral homologs.…”

“…There is very little homology shared among the viral BCL-2 homologs in the BH4 domain, which is also true of the cellular proteins. 7 Certain cellular anti-apoptotic proteins like BCL-2 are converted to pro-apoptotic proteins via caspase cleavage, likely as a positive feedback loop to accelerate apoptosis. 26,30 Most viral BCL-2 homologs cannot be converted into proapoptotic proteins because they are not cleavable by proteases or their C termini lack pro-apoptotic activity.…”

The function of temporally ordered viral gene expression in the intracellular replication of herpes simplex virus type 1 (HSV-1)

“…It is reported that the apoptosis is positively or negatively regulated when cell is infected by the various viruses (Everett & McFadden, 1999;Benedict et al, 2002). For example, gamma herpesviruses and herpes simplex viruses induce or inhibit apoptosis through the BCL-2 homologs which is key mediator of apoptotic signal transduction (Hardwick & Bellows, 2003;Sciortino et al, 2006). The waiting time for apoptosis plays critical role determining the optimal ratio of γ E /γ L .…”