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

Tianyu Song; Shenghui Liang; Jiye Liu; Tingyue Zhang; Yifei Yin; Chenlu Geng; Shaobing Gao; Yan Feng; Hao Xu; Dongqing Guo; Amanda Roberts; Yuchun Gu; Yong Cang

doi:10.1371/journal.pgen.1007165

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

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

Authors

Tianyu Song¹, Shenghui Liang², Jiye Liu¹, Tingyue Zhang¹, Yifei Yin¹, Chenlu Geng¹, Shaobing Gao¹, Yan Feng¹, Hao Xu³, Dongqing Guo³, Amanda Roberts⁴, Yuchun Gu², Yong Cang^{1

5}

Affiliations

¹ Life Sciences Institute and Innovation Center for Cell Signalling Network, Zhejiang University, Hangzhou, Zhejiang, China.
² Translational and Regenerative Medicine Center, Aston Medical School, Aston University, Birmingham, United Kingdom.
³ Laboratory of Molecular Pharmacology, Institute of Molecular Medicine, Peking University, Peking, China.
⁴ Molecular and Cellular Neurosciences Department, The Scripps Research Institute, University of California, San Diego, La Jolla, California, United States of America.
⁵ School of Life Science and Technology, ShanghaiTech University, Shanghai, China.

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 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Cells, Cultured
Female
HEK293 Cells
Humans
Intellectual Disability / genetics
Intellectual Disability / metabolism
Large-Conductance Calcium-Activated Potassium Channels / metabolism*
Learning / physiology*
Male
Memory / physiology*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Nerve Tissue Proteins / metabolism*
Proteolysis*
SKP Cullin F-Box Protein Ligases / antagonists & inhibitors*
SKP Cullin F-Box Protein Ligases / metabolism
Ubiquitin-Protein Ligase Complexes / genetics
Ubiquitin-Protein Ligase Complexes / metabolism*
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / physiology*
Ubiquitination

Substances

Adaptor Proteins, Signal Transducing
Crbn protein, mouse
Large-Conductance Calcium-Activated Potassium Channels
Nerve Tissue Proteins
Ubiquitin-Protein Ligase Complexes
CRL4 E3 ubiquitin ligase complex, mouse
SKP Cullin F-Box Protein Ligases
Ubiquitin-Protein Ligases

Grants and funding

This study was supported in part by funds from the National 973 Plan for Basic Research (2015CB553803), National Natural Science Foundation of China (31671334), Fundamental Research Funds for the Central Universities and Key Construction Program of the National ‘985’ Project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.