title: Epstein-Barr virus BALF1 is a BCL-2-like antagonist of the herpesvirus antiapoptotic BCL-2 proteins.
abstract: Cellular BCL-2 family proteins can inhibit or induce programmed cell death in part by counteracting the activity of other BCL-2 family members. All sequenced gammaherpesviruses encode a BCL-2 homologue that potently inhibits apoptosis and apparently escapes some of the regulatory mechanisms that govern the functions of their cellular counterparts. Examples of these protective proteins include BHRF1 of Epstein-Barr virus (EBV) and KSBcl-2 of Kaposi's sarcoma-associated herpesvirus, also known as human herpesvirus 8. The gamma-1 subgroup of these viruses, such as EBV, encodes a second BCL-2 homologue. We have now found that this second BCL-2 homologue encoded by EBV, BALF1, inhibits the antiapoptotic activity of EBV BHRF1 and of KSBcl-2 in several transfected cell lines. However, BALF1 failed to inhibit the cellular BCL-2 family member, BCL-x(L). Thus, BALF1 acts as a negative regulator of the survival function of BHRF1, similar to the counterbalance observed between cellular BCL-2 family members. Unlike the cellular BCL-2 family antagonists, BALF1 lacked proapoptotic activity and could not be converted into a proapoptotic factor in a manner similar to cellular BCL-2 proteins by caspase cleavage or truncation of the N terminus. Coimmunoprecipitation experiments and immunofluorescence assays suggest that a minimal amount, if any, of the BHRF1 and BALF1 proteins colocalizes inside cells, suggesting that mechanisms other than direct interaction explain the suppressive function of BALF1.
authors.affiliation: Department of Pharmacology and Molecular Science, The Johns Hopkins University Schools of Medicine and Public Health, 615 N. Wolfe St., Baltimore, MD 21205, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Bellows
authors.forename: Melanie
authors.initials: M
authors.lastname: Howell
authors.forename: Colin
authors.initials: C
authors.lastname: Pearson
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Hazlewood
authors.forename: J Marie
authors.initials: JM
authors.lastname: Hardwick
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004854:Herpesvirus 4, Human / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D008969:Molecular Sequence Data; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012845:Sindbis Virus / Q000472:pathogenicity; D014162:Transfection; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C449194:BALF1 protein, Human herpesvirus 4; C083278:BHRF1 protein, Human herpesvirus 4; D019253:Proto-Oncogene Proteins c-bcl-2; D014764:Viral Proteins