Truncated form of the Epstein-Barr virus protein EBNA-LP protects against caspase-dependent apoptosis by inhibiting protein phosphatase 2A.

in Journal of virology by Julie Garibal, Emilie Hollville, Andrew I Bell, Gemma L Kelly, Benjamin Renouf, Yasushi Kawaguchi, Alan B Rickinson, Joëlle Wiels

TLDR

  • The study investigates why some cells infected with a virus called Epstein-Barr virus (EBV) are resistant to a type of cell death called apoptosis. The study found that this resistance is due to a protein called EBNA-LP, which is produced in cells infected with EBV. The study also found that a shorter version of EBNA-LP is produced in cells infected with EBV strains that lack a protein called EBNA2. The study found that this shorter version of EBNA-LP interacts with a protein called protein phosphatase 2A (PP2A) and inactivates it, which leads to resistance to apoptosis. The study suggests that targeting this interaction could be a potential treatment for EBV-associated cancers like Burkitt's lymphoma.

Abstract

The Epstein-Barr virus (EBV)-encoded leader protein, EBNA-LP, strongly activates the EBNA2-mediated transcriptional activation of cellular and viral genes and is therefore important for EBV-induced B-cell transformation. However, a truncated form of EBNA-LP is produced in cells infected with variant EBV strains lacking EBNA2 due to a genetic deletion. The function of this truncated form is unknown. We show here that some Burkitt's lymphoma cells harboring defective EBV strains are specifically resistant to the caspase-dependent apoptosis induced by verotoxin 1 (VT-1) or staurosporine. These cells produced low-molecular-weight Y1Y2-truncated isoforms of EBNA-LP, which were partly localized in the cytoplasm. The transfection of sensitive cells with constructs encoding truncated EBNA-LP isoforms, but not full-length EBNA-LP, induced resistance to caspase-mediated apoptosis. Furthermore, VT-1 induced protein phosphatase 2A (PP2A) activation in sensitive cells but not in resistant cells, in which the truncated EBNA-LP interacted with this protein. Thus, the resistance to apoptosis observed in cells harboring defective EBV strains most probably results from the inactivation of PP2A via interactions with low-molecular-weight Y1Y2-truncated EBNA-LP isoforms.

Overview

  • The study investigates the role of the Epstein-Barr virus (EBV)-encoded leader protein, EBNA-LP, in B-cell transformation and apoptosis. The study compares the function of full-length EBNA-LP and truncated forms produced in cells infected with variant EBV strains lacking EBNA2. The study aims to understand the mechanism of resistance to caspase-dependent apoptosis in Burkitt's lymphoma cells harboring defective EBV strains and identify potential therapeutic targets for the treatment of these cancers.

Comparative Analysis & Findings

  • The study found that some Burkitt's lymphoma cells harboring defective EBV strains are specifically resistant to caspase-dependent apoptosis induced by verotoxin 1 (VT-1) or staurosporine. The cells produced low-molecular-weight Y1Y2-truncated isoforms of EBNA-LP, which were partly localized in the cytoplasm. The transfection of sensitive cells with constructs encoding truncated EBNA-LP isoforms, but not full-length EBNA-LP, induced resistance to caspase-mediated apoptosis. Furthermore, VT-1 induced protein phosphatase 2A (PP2A) activation in sensitive cells but not in resistant cells, in which the truncated EBNA-LP interacted with this protein. These findings suggest that the resistance to apoptosis observed in cells harboring defective EBV strains most probably results from the inactivation of PP2A via interactions with low-molecular-weight Y1Y2-truncated EBNA-LP isoforms.

Implications and Future Directions

  • The study's findings have significant implications for the treatment of Burkitt's lymphoma and other EBV-associated cancers. The study identifies a potential therapeutic target for the treatment of these cancers by targeting the inactivation of PP2A via interactions with low-molecular-weight Y1Y2-truncated EBNA-LP isoforms. The study also highlights the importance of understanding the mechanism of resistance to apoptosis in EBV-associated cancers for the development of effective treatments. Future research should focus on identifying other potential therapeutic targets and developing novel approaches to target the inactivation of PP2A in EBV-associated cancers.
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