The E3 ubiquitin ligase WWP2 facilitates RUNX2 protein transactivation in a mono-ubiquitination manner during osteogenic differentiation
The E3 ubiquitin ligase WWP2 facilitates RUNX2 protein transactivation in a mono-ubiquitination manner during osteogenic differentiation
复制标题
E3泛素连接酶WWP2在成骨分化过程中以单泛素化方式促进RUNX2蛋白反式激活
DOI：
10.1074/jbc.m116.772277
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发表时间：
2017-05
影响因子：
4.8
通讯作者：
Gan Xiaoqing
中科院分区：
文献类型：
--
作者：
Zhu Wei;He Xinyu;Hua Yue;Li Qian;Wang Jiyong;Gan Xiaoqing
多聚泛素化介导的RUNX 2降解是年龄和炎症相关骨丢失的重要原因。NEDD 4家族E3泛素蛋白连接酶被认为是RUNX 2多聚泛素化的主要调节因子。然而，我们观察到RUNX 2的单泛素化由WWP 2催化，WWP 2是E3泛素连接酶的NEDD 4家族的成员。据报道，WWP 2催化软骨细胞中Goosecoid的单泛素化，促进颅面骨骼发育。在这项研究中，我们发现间充质干细胞的成骨分化促进了WWP 2的表达和核积累。间充质干细胞和成骨细胞中Wwp 2的敲低导致成骨的显著缺陷，包括减少的矿物质沉积和成骨标记基因的下调。免疫共沉淀实验显示了WWP 2与RUNX 2在体外和体内的相互作用。WWP 2的单泛素化导致RUNX 2反式激活，如野生型WWP 2所证明的，但不是其泛素连接酶死亡突变体，增加了RUNX 2反应性报告活性。此外，WWP 2依赖的单泛素化的缺失导致RUNX 2成骨细胞活性的显著缺陷。此外，异位表达的组成型活性1A型骨形态发生蛋白受体增强WWP 2依赖的RUNX 2泛素化和反式激活，表明骨形态发生蛋白信号在WWP 2-RUNX 2轴的调节作用。综上所述，我们的研究结果提供了证据，WWP 2作为一个积极的调节骨生成的增加RUNX 2的反式激活的非蛋白水解单泛素化的方式。
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, a member of the NEDD4 family of E3 ubiquitin ligases. WWP2 has been reported to catalyze the mono-ubiquitination of Goosecoid in chondrocytes, facilitating craniofacial skeleton development. In this study, 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. Mono-ubiquitination by WWP2 leads to RUNX2 transactivation, as evidenced by the wild type of WWP2, but not its ubiquitin ligase-dead mutant, augmenting RUNX2-reponsive reporter activity. Moreover, deletion of WWP2-dependent mono-ubiquitination resulted in striking defects of RUNX2 osteoblastic activity. In addition, ectopic expression of the constitutively active type 1A bone morphogenetic protein receptor enhanced WWP2-dependent RUNX2 ubiquitination and transactivation, demonstrating a regulatory role of bone morphogenetic protein signaling in the 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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影响因子：
7.5
作者：
Gibon E;Lu L;Goodman SB
通讯作者：
Goodman SB
CHIP 促进 Runx2 降解并负向调节成骨细胞分化
影响因子：
7.8
作者：
Li, Xueni;Huang, Mei;Zheng, Huiling;Wang, Yinyin;Ren, Fangli;Shang, Yu;Zhai, Yonggong;Irwin, David M.;Shi, Yuguang;Chen, Di;Chang, Zhijie
通讯作者：
Chang, Zhijie
影响因子：
4
作者：
Sinha, Krishna M.;Zhou, Xin
通讯作者：
Zhou, Xin
影响因子：
4.1
作者：
Krings, A.;Rahman, S.;Huang, S.;Lu, Y.;Czernik, P. J.;Lecka-Czernik, B.
通讯作者：
Lecka-Czernik, B.
影响因子：
30.8
作者：
C. Yoshida;T. Furuichi;T. Fujita;R. Fukuyama;Naoko Kanatani;Shinji Kobayashi;M. Satake;K. Takada
通讯作者：
C. Yoshida;T. Furuichi;T. Fujita;R. Fukuyama;Naoko Kanatani;Shinji Kobayashi;M. Satake;K. Takada