CEP78 functions downstream of CEP350 to control biogenesis of primary cilia by negatively regulating CP110 levels.
CEP78 functions downstream of CEP350 to control biogenesis of primary cilia by negatively regulating CP110 levels.
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DOI：
10.7554/elife.63731
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发表时间：
2021-07-14
期刊：
影响因子：
7.7
通讯作者：
Pedersen LB
中科院分区：
文献类型：
--
作者：
Gonçalves AB;Hasselbalch SK;Joensen BB;Patzke S;Martens P;Ohlsen SK;Quinodoz M;Nikopoulos K;Suleiman R;Damsø Jeppesen MP;Weiss C;Christensen ST;Rivolta C;Andersen JS;Farinelli P;Pedersen LB
CEP78是一种中心体蛋白，与纤毛发生和纤毛长度控制有关，CEP78基因的突变会导致与听力损失相关的视网膜视锥-杆营养不良。然而，CEP78影响纤毛形成的机制尚不清楚。根据最近发现的一个致病基因CEP78 p.L150S突变，我们确定了CEP78与疾病相关的相互作用组。我们证实了CEP78与参与CP110泛素化和降解的EDD1-DYRK2-DDB1VPRBP E3泛素连接酶复合体相互作用，并确定了CEP78与CEP350之间的一种新的相互作用，该作用被CEP78L150S突变所削弱。我们发现CEP350促进了CEP78的中心体招募和稳定性，进而导致EDD1的中心体招募。一直以来，缺乏CEP78的细胞显示CP110的细胞和中心体水平显著增加，而在CEP78缺失的细胞中，CP110的缺失使中介频率恢复到正常。我们认为，CEP78在CEP350下游发挥作用，通过EDD1依赖的机制负调控CP110水平，从而促进纤毛发生。
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.