Abstract
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.
Highlights
Primary cilia are antenna-like sensory organelles that play pivotal roles in coordinating various signaling pathways important for human development and tissue homeostasis [1]
We confirmed that CEP78 interacts with the EDD1-DYRK2-DDB1VPRBP E3 ubiquitin lig40 ase complex, which is involved in coil protein 110 (CP110) ubiquitination and degradation, and identified a novel 41 interaction between CEP78 and CEP350 that is weakened by the CEP78L150S mutation
(ARL13B) and centrosomal (CEP350) markers showed that the frequency of ciliated cells is significantly reduced in all four CEP78 KO clones compared to wild type (WT) cells (Figure 1A, B; Figure 1-Figure supplement 1B)
Summary
Primary cilia are antenna-like sensory organelles that play pivotal roles in coordinating various signaling pathways important for human development and tissue homeostasis [1]. Mutations in genes that affect assembly, structure or function of cilia are causative for a growing number of pleiotropic diseases and syndromes called ciliopathies, which include cone-rod dystrophy in the retina and hearing loss (CRDHL; MIM# 617236) amongst others [3]. Ciliopathy genes include those coding for components of the centrosome, which contains the daughter and mother centriole and gives rise to the ciliary basal body. The centrosome contains pericentriolar material and is associated with centriolar satellites that affect cilia biogenesis and function in various ways [4]
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