USP7 manipulation by viral proteins.

Ubiquitin Specific Protease 7 (USP7) is a deubiquitinating enzyme (DUB) that plays critical roles in the regulation of many cellular processes including epigenetics, tumour suppression, oncogenesis, DNA damage response, immunity and viral infection. USP7 was the first DUB associated with viral infection. Since then other DUB:viral protein interactions have been discovered, however, USP7 continues to be the most targeted DUB interacting with many proteins from various viruses. The selective pressures of evolution have allowed viruses to develop mechanisms that subvert host cellular machinery, promoting survival of the viral niche. Numerous viral proteins have been identified to target and usurp the function of USP7 to their advantage. This review explores novel developments in research focusing on the mechanisms underlying the manipulation of USP7 by viruses.

Structural Basis of the Interaction Between Ubiquitin Specific Protease 7 and Enhancer of Zeste Homolog 2.

USP7 is a deubiquitinase that regulates many diverse cellular processes, including tumor suppression, epigenetics, and genome stability. Several substrates, including GMPS, UHRF1, and ICP0, were shown to bear a specific KxxxK motif that interacts within the C-terminal region of USP7. We identified a similar motif in Enhancer of Zeste 2 (EZH2), the histone methyltransferase found within Polycomb Repressive Complex 2 (PRC2). PRC2 is responsible for the methylation of Histone 3 Lys27 (H3K27) leading to gene silencing. GST pull-down and coimmunoprecipitation experiments showed that USP7 interacts with EZH2. We determined the structural basis of interaction between USP7 and EZH2 and identified residues mediating the interaction. Mutations in these critical residues disrupted the interaction between USP7 and EZH2. Furthermore, USP7 silencing and knockout experiments showed decreased EZH2 levels in HCT116 carcinoma cells. Finally, we demonstrated decreased H3K27Me3 levels in HCT116 USP7 knockout cells. These results indicate that USP7 interacts with EZH2 and regulates both its stability and function.