CYLD mediates ciliogenesis in multiple organs by deubiquitinating Cep70 and inactivating HDAC6
CYLD mediates ciliogenesis in multiple organs by deubiquitinating Cep70 and inactivating HDAC6
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CYLD 通过去泛素化 Cep70 和灭活 HDAC6 介导多个器官中的纤毛发生。
DOI：
10.1038/cr.2014.136
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发表时间：
2014-11-01
期刊：
影响因子：
44.1
通讯作者：
Zhou, Jun
中科院分区：
文献类型：
--
作者：
Yang, Yunfan;Ran, Jie;Zhou, Jun
纤毛是从细胞表面延伸出来的毛状细胞器，具有重要的感觉和运动功能。纤毛缺陷会导致一系列被称为纤毛疾病的人类疾病。然而，控制纤毛发生的分子机制仍然不清楚。圆柱瘤病(CyLD)是一种具有去泛素酶活性的肿瘤抑制蛋白，在初级纤毛和运动纤毛在多个器官中的组装中起着关键作用。CyLD基因敲除小鼠表现出多指和各种纤毛缺陷，如基底体锚定失败和基底体和轴体的解体。CyLD的纤毛功能部分归因于它从70 kDa的中心体蛋白(Cep70)上解聚了多泛素链，这是Cep70与γ-微管蛋白相互作用并定位于中心体的必要条件。此外，CyLD介导的抑制组蛋白脱乙酰酶6(HDAC6)，促进微管蛋白乙酰化，是CyLD纤毛功能的另一种机制。HDAC6小分子抑制剂可部分修复CyLD基因敲除小鼠的睫状体缺损区。这些发现强调了蛋白质泛素化在纤毛发生调控中的重要性，发现CyLD是这一过程的关键调节因子，并提示CyLD缺陷参与了纤毛疾病的发生。
Cilia are hair-like organelles extending from the cell surface with important sensory and motility functions. Ciliary defects can result in a wide range of human diseases known as ciliopathies. However, the molecular mechanisms controlling ciliogenesis remain poorly defined. Here we show that cylindromatosis (CYLD), a tumor suppressor protein harboring deubiquitinase activity, plays a critical role in the assembly of both primary and motile cilia in multiple organs. CYLD knockout mice exhibit polydactyly and various ciliary defects, such as failure in basal body anchorage and disorganization of basal bodies and axenomes. The ciliary function of CYLD is partially attributed to its deconjugation of the polyubiquitin chain from centrosomal protein of 70 kDa (Cep70), a requirement for Cep70 to interact with gamma-tubulin and localize at the centrosome. In addition, CYLD-mediated inhibition of histone deacetylase 6 (HDAC6), which promotes tubulin acetylation, constitutes another mechanism for the ciliary function of CYLD. Small-molecule inhibitors of HDAC6 could partially rescue the ciliary defects in CYLD knockout mice. These findings highlight the importance of protein ubiquitination in the modulation of ciliogenesis, identify CYLD as a crucial regulator of this process, and suggest the involvement of CYLD deficiency in ciliopathies.