Merkel Cell Polyomavirus Small T Antigen Controls Viral Replication and Oncoprotein Expression by Targeting the Cellular Ubiquitin Ligase SCFFbw7

Merkel cell polyomavirus (MCV) causes an aggressive human skin cancer, Merkel cell carcinoma, through expression of small T (sT) and large T (LT) viral oncoproteins. MCV sT is also required for efficient MCV DNA replication by the multifunctional MCV LT helicase protein. We find that LT is targeted for proteasomal degradation by the cellular SCFFbw7 E3 ligase, which can be inhibited by sT through its LT-stabilization domain (LSD). Consequently, sT also stabilizes cellular SCFFbw7 targets, including the cell-cycle regulators c-Myc and cyclin E. Mutating the sT LSD decreases LT protein levels and eliminates synergism in MCV DNA replication as well as sT-induced cell transformation. SCFFbw7 knockdown mimics sT-mediated stabilization of LT, but this knockdown is insufficient to fully reconstitute the transforming activity of a mutant LSD sT protein. Thus, MCV has evolved a regulatory system involving SCFFbw7 that controls viral replication but also contributes to host cell transformation. •MCV sT prevents turnover of the MCV helicase LT to enhance viral DNA replication•The MCV sT domain, LSD, inhibits MCV LT turnover by targeting the cellular ligase SCFFbw7•MCV sT inhibition of SCFFbw7 also attenuates the degradation of cellular oncoproteins•MCV sT LSD mediates rodent cell transformation