Pirh2 E3 Ubiquitin Ligase Modulates Keratinocyte Differentiation Through p63

p63, a homologue of the tumor suppressor p53, is essential for the development of epidermis and limb. p63 is highly expressed in epithelial cell layer and acts as a molecular switch that initiates epithelial stratification. However, the mechanisms controlling p63 protein level is still far from fully understood. Here, we demonstrate a regulatory protein for the p63 activity. We found that Pirh2 E3 ubiquitin ligase physically interacts with p63 and targets p63 for polyubiquitination and subsequently proteasomal degradation. We also found that ectopic expression of Pirh2 in HaCaT cells suppresses cell proliferation. Consistent with this, we found that along with altered expression of ΔNp63 protein, ectopic expression of Pirh2 promotes, whereas knockdown of Pirh2 inhibits, keratinocyte differentiation. Collectively, our data suggest that Pirh2 plays a physiologically relevant role in keratinocyte differentiation through posttranslational modification of p63 protein.