PMID:18084238

Citation	Flanagan, AM and Letai, A (2008) BH3 domains define selective inhibitory interactions with BHRF-1 and KSHV BCL-2. Cell Death Differ. 15:580-8
Abstract	The Epstein-Barr and Kaposi's sarcoma gamma-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.
Links	PubMed PMC3280951 Online version:10.1038/sj.cdd.4402292
Keywords	Amino Acid Sequence; Apoptosis; Apoptosis Regulatory Proteins/metabolism; Cell Line; DNA Damage; Humans; Intercellular Signaling Peptides and Proteins/physiology; Membrane Proteins/metabolism; Molecular Sequence Data; Oncogene Proteins/antagonists & inhibitors; Oncogene Proteins/chemistry; Oncogene Proteins/metabolism; Peptides/chemistry; Peptides/metabolism; Protein Interaction Domains and Motifs; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-bcl-2/chemistry; Viral Proteins/antagonists & inhibitors; Viral Proteins/chemistry; Viral Proteins/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
EBVB9:EAR		GO:0033668: negative regulation by symbiont of host apoptotic process	ECO:0000314:		P		Figure 4 shows significantly lower %apoptosis in cells with the BHRF-1 regulator.	complete CACAO 5034
EBVB9:EAR		GO:0090201: negative regulation of release of cytochrome c from mitochondria	ECO:0000314:		P		Figure 6C shows the measurements of release of cytochrome C. When BHRF-1 and KSHV BCL-2 were introduced, cytochrome c release was reduced.	complete CACAO 5154
EBVB9:EAR	involved_in	GO:0090201: negative regulation of release of cytochrome c from mitochondria	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
EBVB9:EAR	involved_in	GO:0033668: negative regulation by symbiont of host apoptotic process	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:BID		GO:0001836: release of cytochrome c from mitochondria	ECO:0000314:		P		Figures 6a and 6b shows by comparison of % cytochrome release in multiple proteins, that tBID is capable of release of cytochrome c from mitochondria in a mouse liver.	complete CACAO 5090
MOUSE:BID	involved_in	GO:0001836: release of cytochrome c from mitochondria	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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