Abstract
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 γ-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.
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Acknowledgements
We thank Xueliang Zhu for discussion, Shiyi Guo, Di An, Ruming Liu, Long Miao, and Chuanmao Zhang for technical assistance, and Tso-Pang Yao and Steven Y Cheng for reagents. This work was supported by grants from the National Basic Research Program of China (2012CB945002) and the National Natural Science Foundation of China (31130015, 31271437, and 31371382).
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
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Supplementary information, Figure S1
Polydactyly in CYLD knockout mice. (PDF 37 kb)
Supplementary information, Figure S2
Transmission electron microscopy images of the cross sections of axonemes in the tracheal epithelial cilia of CYLD knockout mice. (PDF 126 kb)
Supplementary information, Figure S3
Examination of the interaction between CYLD and Cep70 in different phases of the cell cycle and in vitro. (PDF 59 kb)
Supplementary information, Figure S4
CYLD interacts with HDAC6 and inhibits its activity toward tubulin deacetylation. (PDF 87 kb)
Supplementary information, Figure S5
CYLD regulates the Shh signaling. (PDF 110 kb)
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Yang, Y., Ran, J., Liu, M. et al. CYLD mediates ciliogenesis in multiple organs by deubiquitinating Cep70 and inactivating HDAC6. Cell Res 24, 1342–1353 (2014). https://doi.org/10.1038/cr.2014.136
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DOI: https://doi.org/10.1038/cr.2014.136
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