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.
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 3A and Figure 7-figure supplement 2.
- Pietro Farinelli
- Lotte B Pedersen
- Lotte B Pedersen
- Jens S Andersen
- Carlo Rivolta
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Jens Lüders, Institute for Research in Biomedicine, Spain
- Received: October 5, 2020
- Accepted: July 13, 2021
- Accepted Manuscript published: July 14, 2021 (version 1)
© 2021, Goncalves et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.