Cytomegalovirus inhibits p53 nuclear localization signal function

Area of Science:

• Virology
• Cell Biology
• Cardiovascular Research

Background:

• Endothelial cells (EC) infected with cytomegalovirus (CMV) exhibit resistance to apoptosis.
• This resistance may stem from the p53 protein being sequestered in the cytoplasm, preventing its nuclear function.
• p53 normally functions in the nucleus to regulate apoptosis and cellular responses.

Purpose of the Study:

• To investigate the hypothesis that CMV infection blocks p53 nuclear localization signal (NLS) function, leading to cytoplasmic sequestration.
• To understand the role of p53 inactivation in CMV-infected EC dysfunction and atherogenesis.

Main Methods:

• Transfection of CMV-infected EC with a construct linking p53 NLS inhibitor (NLSI) to chicken muscle pyruvate kinase (PK).
• Utilizing double-labeling immunofluorescence staining to track the localization of p53 NLSI-conjugated PK.
• Assessing the impact of CMV infection stage on NLSI function.

Main Results:

• CMV infection effectively sequesters both PK and p53 in the cytoplasm by inhibiting NLSI function.
• This inhibition of NLSI is observed during the early and late phases of CMV infection, but not the immediate early phase.
• The findings indicate a virus-mediated mechanism for p53 inactivation.

Conclusions:

• CMV infection inactivates p53 by blocking its nuclear import, contributing to endothelial dysfunction and potentially atherogenesis.
• This study reveals a novel viral strategy for p53 inactivation, with implications for viral pathogenesis, atherogenesis, and tumorigenesis.