Negative regulation of p53 by the poliovirus receptor PVR is a target of a human cytomegalovirus immune evasion molecule

Initially characterised for its role in maintaining genome integrity, p53 has emerged as a critical hub for coordinating cellular responses to diverse types of stress. Here we identify cell surface receptor loss as a signal for p53 induction. The poliovirus receptor (PVR) regulates angiogenesis, leucocyte adhesion and immune surveillance. We demonstrate that loss of PVR from endothelial cells also promotes cell cycle arrest through the induction of a p53 transcriptional programme. The p53 induction is post-translational and, despite remaining associated with MDM2, p53 exhibits reduced ubiquitination, aiding its stabilisation. Increased expression of PVR marks malignant or infected cells, and retention of PVR in the endoplasmic reticulum by human cytomegalovirus (HCMV) UL141 protein allows HCMV infected cells to evade immunity. We show that intracellular retention of PVR by UL141 prevents p53 induction, allowing HCMV to escape both the immune- and p53-mediated surveillance functions of PVR. These data reveal that p53 coordinates responses to changes in cell surface composition and that the cell intrinsic PVR-p53 pathway coupled with PVR-mediated immune surveillance functions provide a sensor mechanism to maintain expression of this multi-functional cell surface molecule.