DDB1- and CUL4-associated factor 1
centrosome
Cep78 controls centrosome homeostasis by inhibiting EDD-DYRK2-DDB1<sup>Vpr</sup><sup>BP</sup>.
The centrosome plays a critical role in various cellular processes including cell division and cilia formation, and deregulation of centrosome homeostasis is a hallmark feature of many human diseases. Here, we show that centrosomal protein of 78 kDa (Cep78) localizes to mature centrioles and directly interacts with viral protein R binding protein (VprBP). Although VprBP is a component of two distinct E3 ubiquitin ligases, EDD-DYRK2-DDB1<sup>Vpr</sup><sup>BP</sup> and CRL4<sup>Vpr</sup><sup>BP</sup>, Cep78 binds specifically to EDD-DYRK2-DDB1<sup>Vpr</sup><sup>BP</sup> and inhibits its activity. A pool of EDD-DYRK2-DDB1<sup>Vpr</sup><sup>BP</sup> is active at the centrosome and mediates ubiquitination of CP110, a novel centrosomal substrate. Deregulation of Cep78 or EDD-DYRK2-DDB1<sup>Vpr</sup><sup>BP</sup> perturbs CP110 ubiquitination and protein stability, thereby affecting centriole length and cilia assembly. Mechanistically, ubiquitination of CP110 entails its phosphorylation by DYRK2 and binding to VprBP Cep78 specifically impedes the transfer of ubiquitin from EDD to CP110 without affecting CP110 phosphorylation and binding to VprBP Thus, we identify Cep78 as a new player that regulates centrosome homeostasis by inhibiting the final step of the enzymatic reaction catalyzed by EDD-DYRK2-DDB1<sup>Vpr</sup><sup>BP</sup>.