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PLoS Genet. 2018 Jan 25;14(1):e1007165. doi: 10.1371/journal.pgen.1007165. eCollection 2018 Jan.

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

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Life Sciences Institute and Innovation Center for Cell Signalling Network, Zhejiang University, Hangzhou, Zhejiang, China.
Translational and Regenerative Medicine Center, Aston Medical School, Aston University, Birmingham, United Kingdom.
Laboratory of Molecular Pharmacology, Institute of Molecular Medicine, Peking University, Peking, China.
Molecular and Cellular Neurosciences Department, The Scripps Research Institute, University of California, San Diego, La Jolla, California, United States of America.
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.


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 CRL4CRBN 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 CRL4CRBN-associated ID.

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