Antiapoptotic Herpesvirus Bcl-2 Homologs Escape Caspase-Mediated Conversion to Proapoptotic Proteins

Bellows, David S.; Chau, B. Nelson; Lee, P; Lazebnik, Yuri; Burns, William H.; Hardwick, J. Marie

doi:10.1128/jvi.74.11.5024-5031.2000

Cited by 127 publications

(96 citation statements)

References 67 publications

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“…CED-9 is the Caenorhabhditis elegans homologue of mammalian Bcl-2 proteins, and vBcl-2 represents several homologues encoded by viruses . Unlike cellular Bcl-2 family proteins, viral homologues cannot be converted into pro-death factors (Bellows et al, 2000).…”

Section: 'Day Jobs' For Pro-death Mitochondrial Proteinsmentioning

confidence: 99%

Mitochondrial factors with dual roles in death and survival

Berman

Ivanovska

et al. 2006

Oncogene

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At least in mammals, we have some understanding of how caspases facilitate mitochondria-mediated cell death, but the biochemical mechanisms by which other factors promote or inhibit programmed cell death are not understood. Moreover, most of these factors are only studied after treating cells with a death stimulus. A growing body of new evidence suggests that cell death regulators also have 'day jobs' in healthy cells. Even caspases, mitochondrial fission proteins and pro-death Bcl-2 family proteins appear to have normal cellular functions that promote cell survival. Here, we review some of the supporting evidence and stretch beyond the evidence to seek an understanding of the remaining questions.

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Section: 'Day Jobs' For Pro-death Mitochondrial Proteinsmentioning

confidence: 99%

Mitochondrial factors with dual roles in death and survival

Berman

Ivanovska

et al. 2006

Oncogene

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“…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. 31 Thus, viral BCL-2 proteins escape cellular control mechanisms.…”

mentioning

confidence: 99%

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

Flanagan

Letai

2007

Cell Death Differ

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The Epstein-Barr and Kaposi's sarcoma c-herpesviruses (KSHVs) are associated with certain cancers, and encode B-cell leukemia/lymphoma 2 (BCL-2) homologs, BHRF-1 and KSHV BCL-2, respectively. Little is known, however, about the molecular interactions allowing viral BCL-2 homologs to mediate their anti-apoptotic function. Cellular anti-apoptotic proteins, such as BCL-2 and MCL-1, prevent death via selective interactions with pro-death BH3-only proteins. To investigate whether BHRF-1 and KSHV BCL-2 function similarly, we made recombinant BHRF-1 and KSHV BCL-2 proteins. We identified the individual binding patterns for BHRF-1 and KSHV BCL-2 to BH3 domains. These studies surprisingly showed that KSHV BCL-2 is more closely related to MCL-1 than to BCL-2, a result confirmed by sequence analysis. GST-BHRF-1 and GST-KSHV BCL-2 bound BH3-only family proteins from human cells. BHRF-1 protected mammalian cells from growth factor withdrawal, etoposide and adriamycin. We found that both BCL-2 and BHRF-1 sequestered pro-death BH3-only proteins under growth factor-deficient conditions. Finally, we tested the ability of a panel of BH3 peptides to inhibit BHRF-1 and KSHV BCL-2 function in a mitochondrial model of apoptosis. We found that each could be inhibited by the select group of BH3 peptides identified in our binding assay. Our studies define the biochemical interactions underlying BHRF-1 and KSHV BCL-2 anti-apoptotic function, and identify peptides that are prototypic inhibitors of this function.

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“…95 ± 97 Furthermore, the conservation of herpesvirus BCL-2 homologues among primary virus isolates and in the genomes of all gamma 1 and gamma 2 viruses sequenced to date indicates that viral BCL-2 is important in the biology of these viruses. 28,40,42,98 However, the biology of herpesvirus BCL-2 proteins or the BCL-2 homologue encoded by African swine fever virus 99 is poorly understood in part due to the difficulty in manipulating these viruses genetically and the lack of convenient cell culture systems and/or animal models, though recent advances have proven fruitful.…”

Section: What Does Viral Bcl-2 Do For the Virus?mentioning

confidence: 99%

“…The only viral BCL-2 protein tested that could be cleaved was that encoded by gHV68. 42 However, even if the viral proteins could be cleaved, their C-terminal fragments are unable to kill cells, with the exception of the C-terminal fragment of KSBcl-2 encoded by KSHV. But KSBcl-2 is apparently not susceptible to caspases or other proteases that are activated during cell death.…”

Section: Homology Between Cellular and Viral Bcl-2 Familymentioning

confidence: 99%

“…42 Viral BCL-2 homologues from several gamma herpesviruses, including EBV, KSHV/HHV8 (Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8), herpesvirus saimiri (HVS) and bovine herpesvirus 4 (BHV4) fail to be cleaved by caspases in vitro or by other proteases present in apoptotic cell extracts. The only viral BCL-2 protein tested that could be cleaved was that encoded by gHV68.…”

Section: Homology Between Cellular and Viral Bcl-2 Familymentioning

confidence: 99%

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Viral versus cellular BCL-2 proteins

Hardwick

Bellows

2003

Cell Death Differ

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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.

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Antiapoptotic Herpesvirus Bcl-2 Homologs Escape Caspase-Mediated Conversion to Proapoptotic Proteins

Cited by 127 publications

References 67 publications

Mitochondrial factors with dual roles in death and survival

Mitochondrial factors with dual roles in death and survival

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

Viral versus cellular BCL-2 proteins

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