title: Cep78 controls centrosome homeostasis by inhibiting EDD-DYRK2-DDB1VprBP.
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 (VprBP). Although VprBP is a component of two distinct E3 ubiquitin ligases, EDD-DYRK2-DDB1VprBPand CRL4VprBP, Cep78 binds specifically to EDD-DYRK2-DDB1VprBPand inhibits its activity. A pool of EDD-DYRK2-DDB1VprBPis active at the centrosome and mediates ubiquitination of CP110, a novel centrosomal substrate. Deregulation of Cep78 or EDD-DYRK2-DDB1VprBPperturbs 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.
authors.affiliation: Institut de recherches cliniques de Montréal, Montréal, QC, Canada.|Division of Experimental Medicine, McGill University, Montréal, QC, Canada.
authors.forename: Delowar
authors.initials: D
authors.lastname: Hossain
authors.affiliation: Institut de recherches cliniques de Montréal, Montréal, QC, Canada.|Faculté de Médecine, Université de Montréal, Montréal, QC, Canada.
authors.forename: Yalda
authors.initials: Y
authors.lastname: Javadi Esfehani
authors.affiliation: Institut de recherches cliniques de Montréal, Montréal, QC, Canada.|Faculté de Médecine, Université de Montréal, Montréal, QC, Canada.
authors.forename: Arindam
authors.initials: A
authors.lastname: Das
authors.affiliation: Institut de recherches cliniques de Montréal, Montréal, QC, Canada william.tsang@ircm.qc.ca.|Division of Experimental Medicine, McGill University, Montréal, QC, Canada.|Faculté de Médecine, Université de Montréal, Montréal, QC, Canada.
authors.forename: William Y
authors.identifier: 0000-0002-1584-616X
authors.initials: WY
authors.lastname: Tsang
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002502:Centrioles / Q000378:metabolism; D018385:Centrosome / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D006706:Homeostasis; D006801:Humans; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D000097603:Dyrk Kinases
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D044767:Ubiquitin-Protein Ligases; D000097603:Dyrk Kinases; C000618001:CEP78 protein, human; C117617:UBR5 protein, human; C530533:DCAF1 protein, human
keywords: Cep78; E3 ligase; centrosome; inhibitor; ubiquitin