Cep78 controls centrosome homeostasis by inhibiting EDD ‐ DYRK 2‐ DDB 1 Vpr BP

Abstract

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 (Vpr BP ). Although Vpr BP is a component of two distinct E3 ubiquitin ligases, EDD ‐ DYRK 2‐ DDB 1 Vpr BP and CRL 4 Vpr BP , Cep78 binds specifically to EDD ‐ DYRK 2‐ DDB 1 Vpr BP and inhibits its activity. A pool of EDD ‐ DYRK 2‐ DDB 1 Vpr BP is active at the centrosome and mediates ubiquitination of CP 110, a novel centrosomal substrate. Deregulation of Cep78 or EDD ‐ DYRK 2‐ DDB 1 Vpr BP perturbs CP 110 ubiquitination and protein stability, thereby affecting centriole length and cilia assembly. Mechanistically, ubiquitination of CP 110 entails its phosphorylation by DYRK 2 and binding to Vpr BP . Cep78 specifically impedes the transfer of ubiquitin from EDD to CP 110 without affecting CP 110 phosphorylation and binding to Vpr BP . Thus, we identify Cep78 as a new player that regulates centrosome homeostasis by inhibiting the final step of the enzymatic reaction catalyzed by EDD ‐ DYRK 2‐ DDB 1 Vpr BP . image Deregulation of centrosome homeostasis is a feature of many human diseases. This study identifies Cep78 as an inhibitor of the HECT‐type E3 ubiquitin ligase EDD‐DYRK2‐DDB1 VprBP that ubiquitinates the centriolar marker CP110 and regulates organelle homeostasis. Cep78 inhibits the HECT‐type E3 ligase EDD‐DYRK2‐DDB1 VprBP at the centrosome in a cell cycle‐dependent manner. EDD‐DYRK2‐DDB1 VprBP ubiquitinates CP110, a protein that regulates centriole length and ciliogenesis. Deregulation of Cep78 or EDD‐DYRK2‐DDB1 VprBP disrupts centrosome homeostasis.