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

André Brás Gonçalves, Sarah Kirstine Hasselbalch, Beinta Biskopstø Joensen, Sebastian Patzke, Pernille Martens, Signe Krogh Ohlsen, Mathieu Quinodoz, Konstantinos Nikopoulos, Reem Suleiman, Magnus Per Damsø Jeppesen, Catja Weiss, Søren Tvorup Christensen, Carlo Rivolta, Jens S. Andersen, Pietro Farinelli*, Lotte Bang Pedersen*

*Corresponding author for this work

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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 lig- ase 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 cen- trosomal recruitment of EDD 1. 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 pro- mote ciliogenesis by negatively regulating CP110 levels via an EDD 1-dependent mechanism.

Original languageEnglish
Article numbere63731
Number of pages34
Publication statusPublished - Aug 2021

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