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Journal of Virology, March 2002, p. 2469-2479, Vol. 76, No. 5
0022-538X/02/$04.00+0     DOI: 10.1128/jvi.76.5.2469-2479.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus BALF1 Is a BCL-2-Like Antagonist of the Herpesvirus Antiapoptotic BCL-2 Proteins

*** David S. Bellows,1 Melanie Howell,2 Colin Pearson,2 Sheila A. Hazlewood,2 and J. Marie Hardwick1,3*

Departments of Pharmacology and Molecular Sciences,1 Molecular Microbiology and Immunology, The Johns Hopkins University Schools of Medicine and Public Health, Baltimore, Maryland 21205,3 School of Life Sciences, Keele University, Keele, Staffordshire, United Kingdom2

Received 11 September 2001/ Accepted 5 December 2001

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-xL. 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.

* Corresponding author. Mailing address: Department of Molecular Microbiology and Immunology, Johns Hopkins University, E5132 Bloomberg SPH, 615 N. Wolfe St., Baltimore, MD 21205. Phone: (410) 955-2716. Fax: (410) 955-0105. E-mail: hardwick{at}jhu.edu.

Journal of Virology, March 2002, p. 2469-2479, Vol. 76, No. 5
0022-538X/02/$04.00+0     DOI: 10.1128/jvi.76.5.2469-2479.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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