Ubiquitin ligase RNF138 promotes episodic ataxia type 2-associated aberrant degradation of human Cav2.1 (P/Q-type) calcium channels

Ssu Ju Fu, Chung Jiuan Jeng, Chia Hao Ma, Yi Jheng Peng, Chi Ming Lee, Ya Ching Fang, Yi Ching Lee, Sung Chun Tang, Meng Chun Hu, Chih Yung Tang*

*此作品的通信作者

研究成果: Article同行評審

5 引文 斯高帕斯(Scopus)

摘要

Voltage-gated CaV2.1 channels comprise a pore-formingα1A subunit with auxiliaryα2δ and β subunits. CaV2.1 channels play an essential role in regulating synaptic signaling. Mutations in the human gene encoding the CaV2.1 subunit are associated with the cerebellar disease episodic ataxia type 2 (EA2). Several EA2-causing mutants exhibit impaired protein stability and exert dominant-negative suppression of CaV2.1 wild-type (WT) protein expression via aberrant proteasomal degradation. Here, we set out to delineate the protein degradation mechanism of human CaV2.1 subunit by identifying RNF138, an E3 ubiquitin ligase, as a novel CaV2.1-binding partner. In neurons, RNF138 and CaV2.1 coexist in the same protein complex and display notable subcellular colocalization at presynaptic and postsynaptic regions. Overexpression of RNF138 promotes polyubiquitination and accelerates protein turnover of CaV2.1. Disrupting endogenous RNF138 function with a mutant (RNF138-H36E) or shRNA infection significantly upregulates the CaV2.1 protein level and enhances CaV2.1 protein stability. Disrupting endogenous RNF138 function also effectively rescues the defective protein expression of EA2 mutants, as well as fully reversing EA2 mutant-induced excessive proteasomal degradation of CaV2.1WTsubunits. RNF138-H36E coexpression only partially restores the dominant-negative effect of EA2 mutants on CaV2.1WTfunctional expression, which can be attributed to defective membrane trafficking of CaV2.1 WT in the presence of EA2 mutants. We propose that RNF138 plays a critical role in the homeostatic regulation of CaV2.1 protein level and functional expression and that RNF138 serves as the primary E3 ubiquitin ligase promoting EA2-associated aberrant degradation of human CaV2.1 subunits.

原文English
頁(從 - 到)2485-2503
頁數19
期刊Journal of Neuroscience
37
發行號9
DOIs
出版狀態Published - 1 3月 2017

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