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

Song, Tianyu, Liang, Shenghui, Liu, Jiye, Zhang, Tingyue, Yin, Yifei, Geng, Chenlu, Gao, Shaobing, Feng, Yan, Xu, Hao, Guo, Dongqing, Roberts, Amanda, Gu, Yuchun and Cang, Yong (2018). CRL4 antagonizes SCFFbxo7-mediated turnover of cereblon and BK channel to regulate learning and memory. PLoS Genetics, 14 (1),

Abstract

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 CRL4CRBNmutations abolish the interaction of the BK channel with CRL4, and redirect the BK channel to the SCFFbxo7ubiquitin 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 CRL4CRBN–associated ID.

Publication DOI: https://doi.org/10.1371/journal.pgen.1007165
Divisions: Aston Medical School
Additional Information: Copyright: © 2018 Song et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Uncontrolled Keywords: Ecology, Evolution, Behavior and Systematics,Molecular Biology,Genetics,Genetics(clinical),Cancer Research
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2018-01-25
Authors: Song, Tianyu
Liang, Shenghui
Liu, Jiye
Zhang, Tingyue
Yin, Yifei
Geng, Chenlu
Gao, Shaobing
Feng, Yan
Xu, Hao
Guo, Dongqing
Roberts, Amanda
Gu, Yuchun
Cang, Yong

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License: Creative Commons Attribution

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