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‐DDB1VprBP and CRL4VprBP, Cep78 binds specifically to EDD‐DYRK2‐DDB1VprBP and inhibits its activity. A pool of EDD‐DYRK2‐DDB1VprBP is active at the centrosome and mediates ubiquitination of CP110, a novel centrosomal substrate. Deregulation of Cep78 or EDD‐DYRK2‐DDB1VprBP 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‐DDB1VprBP.
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‐DDB1VprBP that ubiquitinates the centriolar marker CP110 and regulates organelle homeostasis.
Cep78 inhibits the HECT‐type E3 ligase EDD‐DYRK2‐DDB1VprBP at the centrosome in a cell cycle‐dependent manner.
EDD‐DYRK2‐DDB1VprBP ubiquitinates CP110, a protein that regulates centriole length and ciliogenesis.
Deregulation of Cep78 or EDD‐DYRK2‐DDB1VprBP disrupts centrosome homeostasis.
- Received March 14, 2016.
- Revision received January 13, 2017.
- Accepted February 3, 2017.
- © 2017 The Authors
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