EBV BCL-2 homologue BHRF1 drives chemoresistance and lymphomagenesis by inhibiting multiple cellular pro-apoptotic proteins
Details
Publication Year 2020-10-23,Volume 27,Issue #5,Page 1554-1568
Journal Title
Cell Death and Differentiation
Abstract
Epstein-Barr virus (EBV), which is ubiquitous in the adult population, is causally associated with human malignancies. Like many infectious agents, EBV has evolved strategies to block host cell death, including through expression of viral homologues of cellular BCL-2 pro-survival proteins (vBCL-2s), such as BHRF1. Small molecule inhibitors of the cellular pro-survival BCL-2 family proteins, termed 'BH3-mimetics', have entered clinical trials for blood cancers with the BCL-2 inhibitor venetoclax already approved for treatment of therapy refractory chronic lymphocytic leukaemia and acute myeloid leukaemia in the elderly. The generation of BH3-mimetics that could specifically target vBCL-2 proteins may be an attractive therapeutic option for virus-associated cancers, since these drugs would be expected to only kill virally infected cells with only minimal side effects on normal healthy tissues. To achieve this, a better understanding of the contribution of vBCL-2 proteins to tumorigenesis and insights into their biochemical functions is needed. In the context of Burkitt lymphoma (BL), BHRF1 expression conferred strong resistance to diverse apoptotic stimuli. Furthermore, BHRF1 expression in mouse haematopoietic stem and progenitor cells accelerated MYC-induced lymphoma development in a model of BL. BHRF1 interacts with the cellular pro-apoptotic BCL-2 proteins, BIM, BID, PUMA and BAK, but its capability to inhibit apoptosis could not be mapped solely to one of these interactions, suggesting plasticity is a key feature of BHRF1. Site-directed mutagenesis revealed a site in BHRF1 that was critical for its interaction with PUMA and blocking DNA-damage-induced apoptosis, identifying a potentially therapeutically targetable vulnerability in BHRF1.
Publisher
Springer Nature
Keywords
Animals; Apoptosis/genetics; Bcl-2-Like Protein 11/metabolism; Burkitt Lymphoma/*pathology/virology; Carcinogenesis/*pathology; Cell Death; Cell Line, Tumor; Cytoprotection; Drug Resistance, Neoplasm/genetics; Humans; Loss of Function Mutation; Mice; Mice, Inbred C57BL; Protein Binding; Proto-Oncogene Proteins c-bcl-2/*chemistry; Proto-Oncogene Proteins c-myc/metabolism; *Sequence Homology, Amino Acid; Viral Proteins/chemistry/genetics/*metabolism; Virus Latency
Research Division(s)
Structural Biology; Ubiquitin Signalling; Blood Cells And Blood Cancer
PubMed ID
31645677
ARC Grants
ARC/FT130101349,
Terms of Use/Rights Notice
Refer to copyright notice on published article.


Creation Date: 2023-06-14 10:36:56
Last Modified: 2023-06-15 01:51:16
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