Antiapoptotic herpesvirus Bcl-2 homologs escape caspase-mediated conversion to proapoptotic proteins

The antiapoptotic Bcl-2 and Bcl-x(L), proteins of mammals are converted int o potent proapoptotic factors when they are cleaved by caspases, a family o f apoptosis-inducing proteases (E H.-Y. Cheng, D. G. Kirsch, R. J. Clem, R. Ravi, M. B. Kastan, A. Bedi, R. Ueno, and J. R I. Hardwick, Science 278:19 66-1968, 1997; R. J. Clem, E. H.-Y. Cheng, C. L. Karp, D. G. Kirsch, Ii. Ue no, A. Takahashi, M. B. Kastan, D. E. Griffin, W. C. Earnshaw, M. A. Veliuo na, and J. M. Hardwick, Proc. Natl. Acad. Sci. USA 95:554-559, 1998). Gamma herpesviruses also encode homologs of the Bcl-2 family. All tested herpesv irus Bcl-2 homologs possess antiapoptotic activity, including the more dist antly related homologs encoded by murine gammaherpesvirus 68 (gamma HV68) a nd bovine herpesvirus 4 (BHV4), as described here. To determine if viral Bc l-2 proteins can be converted into death factors, similar to their cellular counterparts, five herpesvirus Bcl-2 homologs from five different viruses, were tested for their susceptibility to caspases. Only the viral Bcl-2 prot ein encoded by gamma HV68 was susceptible to caspase digestion. However, un like the caspase cleavage products of cellular Bcl-2, Bcl-x(L),, and Bid, w hich are potent inducers of apoptosis, the cleavage product of gamma HV68 B cl-2 lacked proapoptotic activity. KSBcl 2, encoded by the Kaposi's sarcoma -associated herpesvirus. was the only viral Bcl-2 homolog that was capable of killing cells when expressed as an N-terminal truncation. However, becau se KSBcl-2 was not cleavable by caspases, the latent proapoptotic activity of KSBcl-2 apparently cannot be released. The Bcl-2 homologs encoded by her pesvirus saimiri, Epstein-Barr virus, and BHV4 were not cleaved by apoptoti c cell extracts and did not possess latent proapoptotic activities. Thus, h erpesvirus Bcl-2 homologs escape negative regulation by retaining their ant iapoptotic activities and/or failing to be converted into proapoptotic prot eins by caspases during programmed cell death.