WWP2-WWP1 Ubiquitin Ligase Complex Coordinated by PPM1G Maintains the Balance between Cellular p73 and ΔNp73 Levels

The balance between transcription factor p73 and its functionally opposing N-terminally truncated Delta Np73 isoform is critical for cell survival, but the precise mechanism that regulates their levels is not clear. In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades Delta Np73. Further, we identified phosphatase PPM1G as a functional switch that controls the balance between monomeric WWP2 and a WWP2/WWP1 heterodimeric state in the cell. During cellular stress, WWP2 is inactivated, leading to upregulation of p73, whereas WWP2-WWP1 complex is intact to degrade Delta Np73, thus playing an important role in shifting the balance between p73 and Delta Np73. Collectively, our results reveal a new functional E3 ligase complex controlled by PPM1G that differentially regulates cellular p73 and Delta Np73.