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

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-causin...

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Bibliographic Details
Published in:eLife 2021-07, Vol.10
Main Authors: Gonçalves, André Brás, Hasselbalch, Sarah Kirstine, Joensen, Beinta Biskopstø, Patzke, Sebastian, Martens, Pernille, Ohlsen, Signe Krogh, Quinodoz, Mathieu, Nikopoulos, Konstantinos, Suleiman, Reem, Damsø Jeppesen, Magnus Per, Weiss, Catja, Christensen, Søren Tvorup, Rivolta, Carlo, Andersen, Jens S, Farinelli, Pietro, Pedersen, Lotte Bang
Format: Article
Language:English
Subjects:
Biosynthesis
Cell Biology
Cell cycle
centrosome
CEP350
CEP78
Cilia
CP110
Dystrophy
Evolution
Fibroblasts
Genetic aspects
Hearing loss
Homeostasis
Kinases
Ligases
Mutation
Patients
Proteins
Scientific equipment and supplies industry
Ubiquitin
Ubiquitin-protein ligase
Ubiquitination
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Summary: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-DDB1 VPRBP 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 CEP78 L150S 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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.63731