A BCL-2 HOMOLOG ENCODED BY KAPOSI SARCOMA-ASSOCIATED VIRUS, HUMAN HERPESVIRUS-8, INHIBITS APOPTOSIS BUT DOES NOT HETERODIMERIZE WITH BAX ORBAK

The Bcl-2 protein family is characterized by the ability to modulate c ell death, and members of this family share two highly conserved domai ns called Bcl-2 homology 1 (BH1) and 2 (BH2) which have been shown to be critical for the death-repressor activity of Bcl-2 and Bcl-x(L). Th rough sequence analysis we identified a novel viral Bcl-2 homolog, des ignated KSbcl-2, from human herpesvirus 8 (HHV8) or Kaposi sarcoma-ass ociated herpesvirus, The overall amino acid sequence identity between KSbcl-2 and other Bcl-2 homologs is low (15-20%) but concentrated with in the BH1 and BH2 regions, Overexpression of KSbcl-2 blocked apoptosi s as efficiently as Bcl-2, Bcl-x(L), or another viral Bcl-2 homolog en coded by Epstein-Barr virus, BHRF1. Interestingly, KSbcl-2 neither hom odimerizes nor heterodimerizes with other Bcl-2 family members, sugges ting that KSbcl-2 may have evolved to escape any negative regulatory e ffects of the cellular Bar and Bah proteins, Furthermore, the herpesvi rus Bcl-2 homologs including KSbcl-2, BHRF1, and ORF16 of herpesvirus saimiri contain poorly conserved Bcl-2 homology 3 (BH3) domains compar ed with other mammalian Bcl-2 homologs, implying that BH3 may not be e ssential for anti-apoptotic function, This is consistent with our obse rvation that amino acid substitutions within the BH3 domain of Bcl-x(L ) had no effect on its death suppressor activity.