Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang, Cheongju 28116, Korea.
Department of Biological Sciences, Konkuk University, Seoul 05029, Korea.
Int J Mol Sci. 2021 Jul 15;22(14):7572. doi: 10.3390/ijms22147572.
Primary cilia are nonmotile cellular signal-sensing antenna-like structures composed of microtubule-based structures that distinguish them from motile cilia in structure and function. Primary ciliogenesis is regulated by various cellular signals, such as Wnt, hedgehog (Hh), and platelet-derived growth factor (PDGF). The abnormal regulation of ciliogenesis is closely related to developing various human diseases, including ciliopathies and cancer. This study identified a novel primary ciliogenesis factor Cullin 1 (CUL1), a core component of Skp1-Cullin-F-box (SCF) E3 ubiquitin ligase complex, which regulates the proteolysis of dishevelled 2 (Dvl2) through the ubiquitin-proteasome system. Through immunoprecipitation-tandem mass spectrometry analysis, 176 Dvl2 interacting candidates were identified, of which CUL1 is a novel Dvl2 modulator that induces Dvl2 ubiquitination-dependent degradation. Neddylation-dependent CUL1 activity at the centrosomes was essential for centrosomal Dvl2 degradation and primary ciliogenesis. Therefore, this study provides a new mechanism of Dvl2 degradation by CUL1, which ultimately leads to primary ciliogenesis, and suggest a novel target for primary cilia-related human diseases.
原发性纤毛是由微管为基础的结构组成的非运动细胞信号感应天线样结构，与结构和功能上的运动纤毛不同。原发性纤毛发生受多种细胞信号的调节，如 Wnt、Hedgehog（Hh）和血小板衍生生长因子（PDGF）。纤毛发生的异常调节与各种人类疾病的发展密切相关，包括纤毛病和癌症。本研究鉴定了一种新的原发性纤毛发生因子 Cullin 1（CUL1），它是 Skp1-Cullin-F-box（SCF）E3 泛素连接酶复合物的核心组成部分，通过泛素-蛋白酶体系统调节 Dishevelled 2（Dvl2）的蛋白水解。通过免疫沉淀-串联质谱分析，鉴定出 176 个 Dvl2 相互作用的候选物，其中 CUL1 是一种新的 Dvl2 调节剂，可诱导 Dvl2 泛素化依赖性降解。中心体上依赖 Neddylation 的 CUL1 活性对于中心体 Dvl2 降解和原发性纤毛发生是必不可少的。因此，本研究提供了 CUL1 降解 Dvl2 的新机制，最终导致原发性纤毛发生，并为与原发性纤毛相关的人类疾病提供了新的靶点。
