E3 Ubiquitin Ligase WWP2 Facilitates RUNX2 Transactivation Through A Mono-ubiquitination Manner During Osteogenic Differentiation [Protein Synthesis and Degradation]

Poly-ubiquitination-mediated RUNX2 degradation is an important cause of age and inflammation-related bone loss. NEDD4 family E3 ubiquitin protein ligases are thought to be the major regulators of RUNX2 poly-ubiquitination. However, we observed a mono-ubiquitination of RUNX2 that was catalyzed by WWP2, the member of NEDD4 family E3 ubiquitin ligases. WWP2 has been reported to catalyze mono-ubiquitination of Gooseicoid in chondrocytes, thus facilitating craniofacial skeleton development. In the current studies, we found that osteogenic differentiation of mesenchymal stem cells promoted WWP2 expression and nuclear accumulation. Knockdown of Wwp2 in mesenchymal stem cells and osteoblasts led to significant deficiencies of osteogenesis, including decreased mineral deposition and down-regulation of osteogenic marker genes. Co-immunoprecipitation experiments showed the interaction of WWP2 with RUNX2 in vitro and in vivo. The mono-ubiquitination by WWP2 leads to RUNX2 transactivation, as evidenced by the wide-type of WWP2 but not its ubiquitin ligase-dead mutant augmenting RUNX2-reponsive reporter activity. Moreover, the deletion of WWP2-dependent mono-ubiquitination resulted in striking defects of RUNX2 osteoblastic activity. In addition, ectopic expression of constitutively active type 1A BMP receptor enhanced WWP2-dependent RUNX2 ubiquitination and transactivation, thus demonstrating a regulatory role of BMP signaling in WWP2-RUNX2 axis. Taken together, our results provide evidence that WWP2 serves as a positive regulator of osteogenesis by augmenting RUNX2 transactivation in a non-proteolytic mono-ubiquitination manner.

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