CRL4 antagonizes SCFFbxo7-mediated turnover of cereblon and BK channel to regulate learning and memory

doi:10.1371/journal.pgen.1007165

	CRL4 antagonizes SCFFbxo7-mediated turnover of cereblon and BK channel to regulate learning and memory
	Song, Tianyu 1,2; Liang, Shenghui 3; Liu, Jiye 1,2; Zhang, Tingyue 1,2; Yin, Yifei 1,2; Geng, Chenlu 1,2; Gao, Shaobing 1,2; Feng, Yan 1,2; Xu, Hao 4; Guo, Dongqing 4; Roberts, Amanda 5; Gu, Yuchun 3; Cang, Yong1,2,6
	2018-01
发表期刊	PLOS GENETICS (IF:4.0[JCR-2023],4.9[5-Year])
ISSN	1553-7404
卷号	14 期号:1
发表状态	已发表
DOI	10.1371/journal.pgen.1007165
摘要	Intellectual disability (ID), one of the most common human developmental disorders, can be caused by genetic mutations in Cullin 4B (Cul4B) and cereblon (CRBN). CRBN is a substrate receptor for the Cul4A/B-DDB1 ubiquitin ligase (CRL4) and can target voltage- and calcium-activated BK channel for ER retention. Here we report that ID-associated CRL4 CRBN mutations abolish the interaction of the BK channel with CRL4, and redirect the BK channel to the SCFFbxo7 ubiquitin ligase for proteasomal degradation. Glioma cell lines harbouring CRBN mutations record density-dependent decrease of BK currents, which can be restored by blocking Cullin ubiquitin ligase activity. Importantly, mice with neuron-specific deletion of DDB1 or CRBN express reduced BK protein levels in the brain, and exhibit similar impairment in learning and memory, a deficit that can be partially rescued by activating the BK channel. Our results reveal a competitive targeting of the BK channel by two ubiquitin ligases to achieve exquisite control of its stability, and support changes in neuronal excitability as a common pathogenic mechanism underlying CRL4(CRBN)-associated ID.
收录类别	SCI ; SCIE
语种	英语
资助项目	National Natural Science Foundation of China[31671334]
WOS研究方向	Genetics & Heredity
WOS类目	Genetics & Heredity
WOS记录号	WOS:000423718600023
出版者	PUBLIC LIBRARY SCIENCE
WOS关键词	UBIQUITIN LIGASE COMPLEX ; INTELLECTUAL DISABILITY ; MUTATION ; CUL4B ; SUBUNIT ; GENES ; CRBN ; SCF ; UBIQUITYLATION ; THALIDOMIDE
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/16234
专题	生命科学与技术学院_PI研究组_仓勇组
通讯作者	Gu, Yuchun; Cang, Yong
作者单位	1.Zhejiang Univ, Life Sci Inst, Hangzhou, Zhejiang, Peoples R China 2.Zhejiang Univ, Innovat Ctr Cell Signalling Network, Hangzhou, Zhejiang, Peoples R China 3.Aston Univ, Aston Med Sch, Translat & Regenerat Med Ctr, Birmingham, W Midlands, England 4.Peking Univ, Inst Mol Med, Lab Mol Pharmacol, Beijing, Peoples R China 5.Univ Calif San Diego, Scripps Res Inst, Mol & Cellular Neurosci Dept, La Jolla, CA 92093 USA 6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Song, Tianyu,Liang, Shenghui,Liu, Jiye,et al. CRL4 antagonizes SCFFbxo7-mediated turnover of cereblon and BK channel to regulate learning and memory[J]. PLOS GENETICS,2018,14(1).
APA	Song, Tianyu.,Liang, Shenghui.,Liu, Jiye.,Zhang, Tingyue.,Yin, Yifei.,...&Cang, Yong.(2018).CRL4 antagonizes SCFFbxo7-mediated turnover of cereblon and BK channel to regulate learning and memory.PLOS GENETICS,14(1).
MLA	Song, Tianyu,et al."CRL4 antagonizes SCFFbxo7-mediated turnover of cereblon and BK channel to regulate learning and memory".PLOS GENETICS 14.1(2018).