The E3 ubiquitin ligase complex CDC20-activated anaphase-promoting complex/Cyclosome (APC/C^CDC20) plays a critical role in governing mitotic progression by targeting key cell cycle regulators for degradation. Cell division cycle protein 20 homolog (CDC20), the co-activator of APC/C, is required for full ubiquitin ligase activity. In addition to its well-known cell cycle-related functions, we demonstrate that CDC20 plays an essential role in osteogenic commitment of bone marrow mesenchymal stromal/stem cells (BMSCs). Cdc20 conditional knockout mice exhibit decreased bone formation and impaired bone regeneration after injury. Mechanistically, we discovered a functional interaction between the WD40 domain of CDC20 and the DNA-binding domain of p65. Moreover, CDC20 promotes the ubiquitination and degradation of p65 in an APC11-dependent manner. More importantly, knockdown of p65 rescues the bone loss in Cdc20 conditional knockout mice. Our current work reveals a cell cycle-independent function of CDC20, establishes APC11^CDC20 as a pivotal regulator for bone formation by governing the ubiquitination and degradation of p65, and may pave the way for treatment of bone-related diseases.

中文翻译：

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CDC20 通过 APC/C 依赖性泛素化和 p65 降解促进骨形成

E3泛素连接酶复合物CDC20激活的后期促进复合物/环体（APC/C ^CDC20) 通过靶向关键的细胞周期调节剂进行降解，在控制有丝分裂进程中发挥着关键作用。细胞分裂周期蛋白 20 同源物 (CDC20) 是 APC/C 的共激活剂，是完全泛素连接酶活性所必需的。除了众所周知的细胞周期相关功能外，我们还证明 CDC20 在骨髓间充质基质/干细胞 (BMSCs) 的成骨定型中起重要作用。Cdc20 条件性敲除小鼠在损伤后表现出骨形成减少和骨再生受损。从机制上讲，我们发现了 CDC20 的 WD40 结构域和 p65 的 DNA 结合结构域之间的功能相互作用。此外，CDC20 以 APC11 依赖性方式促进 p65 的泛素化和降解。更重要的是，p65 的敲低挽救了 Cdc20 条件性敲除小鼠的骨质流失。^CDC20通过调控p65的泛素化和降解作为骨形成的关键调节因子，可能为骨相关疾病的治疗铺平道路。