CEP78 functions downstream of CEP350 to control biogenesis of primary cilia by negatively regulating CP110 levels

eLife

Jens S Andersen¹  Signe Krogh Ohlsen¹  Catja Weiss²  Lotte Bang Pedersen²  Reem Suleiman²  Pietro Farinelli²  Magnus Per Damsø Jeppesen²  Søren Tvorup Christensen²  Sarah Kirstine Hasselbalch²  André Brás Gonçalves²  Beinta Biskopstø Joensen²  Pernille Martens²  Konstantinos Nikopoulos³  Sebastian Patzke⁴  Mathieu Quinodoz⁵  Carlo Rivolta⁵ 

[1] Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark;Department of Biology, Section for Cell Biology and Physiology, University of Copenhagen, Copenhagen, Denmark;Department of Computational Biology, University of Lausanne, Lausanne, Switzerland;Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway;Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland;Department of Ophthalmology, University of Basel, Basel, Switzerland;Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom;

关键词: cilia;    centrosome;    CEP78;    CEP350;    CP110;    ubiquitin;    Human;   

DOI  :  10.7554/eLife.63731

来源: eLife Sciences Publications, Ltd

【 摘 要 】

CEP78 is a centrosomal protein implicated in ciliogenesis and ciliary length control, and mutations in the CEP78 gene cause retinal cone-rod dystrophy associated with hearing loss. However, the mechanism by which CEP78 affects cilia formation is unknown. Based on a recently discovered disease-causing CEP78 p.L150S mutation, we identified the disease-relevant interactome of CEP78. We confirmed that CEP78 interacts with the EDD1-DYRK2-DDB1VPRBP E3 ubiquitin ligase complex, which is involved in CP110 ubiquitination and degradation, and identified a novel interaction between CEP78 and CEP350 that is weakened by the CEP78L150S mutation. We show that CEP350 promotes centrosomal recruitment and stability of CEP78, which in turn leads to centrosomal recruitment of EDD1. Consistently, cells lacking CEP78 display significantly increased cellular and centrosomal levels of CP110, and depletion of CP110 in CEP78-deficient cells restored ciliation frequency to normal. We propose that CEP78 functions downstream of CEP350 to promote ciliogenesis by negatively regulating CP110 levels via an EDD1-dependent mechanism.

【 授权许可】

CC BY