SCF Skp2 Complex Targeted by Epstein-Barr Virus Essential Nuclear Antigen

Abstract

ABSTRACT The stability of cell cycle checkpoint and regulatory proteins is controlled by the ubiquitin-proteasome degradation machinery. A critical regulator of cell cycle molecules is the E3 ubiquitin ligase SCF Skp2 , known to facilitate the polyubiquitination and degradation of p27, E2F, and c- myc . SCF Skp2 is frequently deregulated in human cancers. In this study, we have revealed a novel link between the essential Epstein-Barr virus (EBV) nuclear antigen EBNA3C and the SCF Skp2 complex, providing a mechanism for cell cycle regulation by EBV. EBNA3C associates with cyclin A/cdk2 complexes, disrupting the kinase inhibitor p27 and enhancing kinase activity. The recruitment of SCF Skp2 activity to cyclin A complexes by EBNA3C results in ubiquitination and SCF Skp2 -dependent degradation of p27. This is the first report of a viral protein usurping the function of the SCF Skp2 cell cycle regulatory machinery to regulate p27 stability, establishing the foundation for a mechanism by which EBV regulates cyclin/cdk activity in human cancers.